If you eschew hyperbole and hang in for the long haul, maintaining a discipline of understatement in the midst of a flashy neon world, you may be offered a modicum of credence when you make an extraordinary announcement. No one is entitled to this courtesy twice. If the news that you trumpet to the moon does not pan out, your readers will be justified in discounting everything you say thereafter.
Here goes.
I believe major rejuvenation has been achieved in a mammal, using a relatively benign intervention that shows promise of scaling up to humans. I’m going to stake my reputation on it.
In the race to effect substantial, system-wide rejuvenation, Harold Katcher is a dark horse. He has the right academic credentials and a solid history of research. In fact, in earlier life he was part of a team that discovered the breast cancer gene, brca1. I asked Harold for a biographical sketch, and have printed it in a box at the end of this posting.
But Katcher has no research grants or university lab or venture capital funding, no team of grad students mining databases and screening chemicals in the back room.
One thing Katcher has going for him is the correct theory. Most of the explosion in aging research (and virtually all the venture capital startups) are looking to treat aging at the cellular level. Their paradigm is that aging is an accumulation of molecular damage, and they see their job as engineering of appropriate repair mechanisms.
The truth, as Katcher understands it, is that, to a large extent, aging is coordinated system-wide via signal molecules in the blood. It was our common realization of this vision that brought Katcher and me together more than a decade ago. Katcher briefly describes his 2009 epiphany below. It was the source of his 2013 essay (it took a few years to get it into print) on the significance of parabiosis experiments for the future of aging science.
Of course, Katcher was not the only one to get the message about the power of signal molecules in the blood to reprogram tissues to a younger state throughout the body. The problem is that there are thousands of constituents represented in tiny concentrations in blood plasma, but conveying messages that cells read. Which of these are responsible for aging? A small number of labs, including the Conboys at Berkeley, Amy Wager at Harvard, and Tony Wyss-Coray at Stanford have been searching for the answer over the last decade and more.
Katcher has been able to guess or intuit or experimentally determine the answer to this question. With seed funding from Akshay Sanghavi, he set up a lab in Mumbai two years ago, and tried to rejuvenate old lab rats, using a fraction extracted from the blood of younger rats. The first round of experiments were encouraging, published in this space a year ago. He obtained the next round of funding from a reader of this blog, and had enough rats to titrate dosages experimentally, and to see if treated rats who aged again over time could be re-treated successfully.
There is a hole in this story that awaits the resolution of intellectual property rights. Katcher and Sanghvi have not applied for patents and have not yet found a suitable partner to provide financing for human trials. They have not revealed any details of the treatment, besides the fact that it is in four intravenous doses, and that it is derived from a fraction of blood plasma. Katcher thinks that the molecules involved will not be difficult to manufacture, so that when a product is eventually commercialized, it will not require extraction from the blood of live subjects, rodent or human.
We’re still waiting for longevity curves of these treated rats. In the meantime, the best available surrogate measure of age comes from methylation clocks, as developed by Steve Horvath at UCLA, and other scientists as well. Crucially, Katcher found an ally in Horvath, who didn’t just test his rejuvenated rats, but did the needed statistical analysis to develop a set of six methylation clocks specialized to rats. FIve of the clocks are optimized for different tissues, and one is calibrated across species, so that it can measure age in humans as well as corresponding age in “rat years” (about 1/40 human year). The two-species clock was a significant innovation, a first bridge for translating results from an animal model into their probable equivalent in humans.
In a paper posted to BioRxiv on Friday, Katcher and Horvath report results of the methylation measurements in rejuvenated rats. “Crucially, plasma treatment of the old rats [109 weeks] reduced the epigenetic ages of blood, liver and heart by a very large and significant margin, to levels that are comparable with the young rats [30 weeks]….According to the final version of the epigenetic clocks, the average rejuvenation across four tissues was 54.2%. In other words, the treatment more than halved the epigenetic age.”
Besides the methylation clock, the paper presents evidence of rejuvenation by many other measures. For example:
- IL-6, a marker of inflammation, was restored to low youthful levels
- Glutathione (GSH), superoxide dismutase (SOD), and other anti-oxidants were restored to higher youthful levels
- In tests of cognitive function (Barnes maze), treated rats scored better than old rats, but not as well as young rats.
- Blood triglycerides were brought down to youthful levels
- HDL cholesterol rose to youthful levels
- Blood glucose fell toward youthful levels
A major question in blood plasma rejuvenation experiments has been how often the cure must be administered. Many of the components of blood plasma are short-lived, secreted into the blood and absorbed continuously throughout the day. The good news from Katcher’s results is that it seems only four injections are needed in order to achieve rejuvenation.
A second question which these experiments resolve is whether rejuvenation requires both adding and removing molecular species from the blood plasma. For example, pro-inflammatory cytokines are found in old blood at much higher levels. Irina and Mike Conboy, people who I regard as most credible in the field, have said that removing bad actors from the blood is probably more important than restoring youthful levels of beneficial signals. They were grad students at Stanford 15 years ago, when the modern wave of parabiosis science was initiated, and have pursued the subject continuously ever since. Katcher’s experiments have achieved their results only by adding blood components, not by removing or even neutralizing others. This suggests that he has found the necessary formula for re-programming epigenetics, so that lower levels of the bad actors occur as a result. But it remains to be seen whether even better results can be obtained if some plasma constituents are removed.
A question that remains unresolved concerns the location and mechanism of the aging clock. I have been undecided over the years between two models:
- There is a central aging clock, perhaps in the hypothalamus, which keeps its own time and transmits signals throughout the body that coordinate methylation state of dispersed tissues
- Information about epigenetic age is dispersed through the body, and the body’s clock is a feedback loop that is continually updating methylation age locally in response to signals received about the methylation age globally.
There is a suggestion in the data that the hypothalamus may be more difficult to rejuvenate than other tissues. Does it play a more important role than other tissues in coordinating the age of the entire body? Horvath (personal communication) counsels caution in drawing this inference until measurements are corroborated and more experiments are done.
The Bottom Line
These results bring together three threads that have been gaining credibility over the last decade. Mutually reinforcing, the three have a strength that none of them could offer separately.
- The root cause of aging is epigenetic progression = changes in gene expression over a lifetime.
- Methylation patterns in nuclear DNA are not merely a marker of aging, but its primary source. Thus aging can be reversed by reprogramming DNA methylation.
- Information about the body’s age state is transmitted system-wide via signal molecules in the blood. Locally, tissues respond to these signals and adopt a young or an old cellular phenotype as they are directed.
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Harold Katcher, Biographical Sketch So, you might consider me a late bloomer. While I have thousands of citations in the literature, with publications ranging from the discovery of the human ‘breast cancer gene’, to protein structure, bacteriology, biotechnology, bioinformatics, and biochemistry, there was no center or direction to my work as I had given up my personal goal of solving/curing aging when I learned that ‘wear and tear’ was the cause of it. Yet something happened in year 1985 when I was in California working with Michael Waterman and Temple Smith (fathers of bioinformatics) that is inexplicable: I found myself in Intensive Care with a tube inserted into my trachea and the knowledge that I might not live. And then I had a dream: I dreamed that somehow in the far future (and on another world), I was being feted for ‘bringing immortality to mankind’. Clearly, I survived that incident (started with an infected tooth). I lived a wonderful life – becoming a computer programmer (which I loved), leaving that for the University of Maryland’s Asian division, becoming a full professor and then the Academic Director for the Sciences, in Tokyo, Japan. By the time I left Japan in 2004, (my daughter Sasha was a fourth-grader, (yonensei), in the Japanese school system), I was teaching for U of M online – somewhat retired, and looking forwards to writing computer programs for fun and profit. Yet I never ever forgot that dream. It was clearly impossible; I had no lab – and really, there was no way to repair all damaged cells – it’d be like sweeping back the ocean. And then, in 2009, I read an old paper from 2005, a paper written by the Conboys, (Michael and Irina), Tom Rando and others, coming from Irv Weisman’s lab, that completely changed my life; that showed me that everything I believed about aging was wrong – that aging occurred at the organismic level, not at the cellular level and could be reversed. Well, the rest of the story is about persistence and the blessed intervention of Akshay Sanghvi who too saw there was another way and provided the structural, monetary, and emotional support (and some good ideas) that had me start a new career at age 72 in Mumbai, India. I feel twenty years younger than I did three years ago, I guess that’s another hint about aging. Now the ‘mystical’ dream? It wouldn’t be the first time in history that that happened – take that as a datum. |
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Assuming this approach pans out, do you or Dr. Katcher have any ideas about how to get this technology out to the public in some reasonable period of time? Seeing as how the FDA to my knowledge still does not recognize aging as a disease, and their normal glacial pace even if they did, I fear we’ll all be dead by the time this is approved, if ever.
That’s easy, just bill it as the most successful covid-19 treatment ever discovered. FDA will fast track it, the rest is history. If it works as described, it should in fact be an amazing immune system rejuvenator, which would indeed help people avoid the more serious consequences of communicable disease.
Actually no… BS malaria and Ebola drugs get vast amounts of media.
But this SARS-CoV-2 human trial in Denmark is using a safe NAD+ booster… and no one has heard of it, or the preclinicals it’s based on.
https://clinicaltrials.gov/ct2/show/NCT04407390
They might have trouble recruiting enough patients for the NR trial, as there are only 100 Corona patients in the whole country.
Well yes. Needless to say we don’t want to announce our approach, but it’s not like there’s a substitute. If people really want it, advertising is superfluous. But being 75 myself puts a time-frame around the project. We plan to propose its use for the diseases of aging – eventually, everyone will use it.
I curated your 2015 paper and comments at https://surfaceyourrealself.com/2020/05/13/an-environmental-signaling-paradigm-of-aging/
I compared your framework to hypothalamic aging to another researcher’s approach to the same 2013 paper in https://surfaceyourrealself.com/2020/05/25/reevaluate-findings-in-another-paradigm/
I believe the first trials of an anti-aging drugs are going on right now. Metformin, and Rapamicin are being tested in humans throughout the USA. TAME clinical trials.
I agree that the political and regulatory issues will take us into unexplored territory. Not only that, it will transform so many aspects of our culture if people live dramatically longer. Not all the effects will be good.
That said, I don’t think the issues you raise will be the biggest problems. They may choose to do human trials abroad to save money. FDA approval as a treatment for, say, blood lipids or diabetes should not be more difficult than for other treatments. And once it is approved, doctors can prescribe it off-label.
Correct Josh, we’re going legit. No OTC stuff (requires injections, but if things scale, once every several years). This is not based on ‘theory’ (say mitochondrial aging or ‘wear and tear’) but on experimental evidence. Theory comes in explaining our results, not achieving them, but there is a theory becoming clear, one very different from the commonsense view of ‘wear and tear’ aging.
It’s really good to see someone following the hints that nature sometimes reveals with experimental science and letting the theories develop around the evidence. Thank you!
May your fever dream come true professor. It is my fondest wish that you have several centuries to further your efforts.
The golden future of mankind among the stars awaits us.
Dear Josh,
Thank you once again for staking your reputation on Harold. It is indeed a highly regarded reputation in aging research. Dr. Steve Horvath had very complimentary things to say about you and your blog. Many people talk about providing help, you have actually provided us a lot of help directly and through your readers. We owe you greatly. These results are a validation of your early belief in us.
Hi, Akshay:
Truly amazing results!
Was there any observable effect on how the rats looked?
Are there any photos at the end of the experiment for young, old-untreated, young-treated? If so, can you supply a link?
Thanks
Hi Zisos,
Thanks. We did not find any noticeable difference between treated and untreated although this was a short study and over a period of time there should be.
Hi Akshay:
Wishing you the best of luck.
Thank you Heather!
A typo:
I meant photos at the end of the experiment of:
Young, Old-treated, Old-untreated.
Photos were not part of our protocol but I will check if any team members have taken any.
Zisos I was sent photos that a team member took from our first trial which was of a single dose and taken on 30th day. If you would like to see them please send me your email
Thanks, Akshay:
Here it is:
zisos?computron?gr
Please replace ? with appropriate symbols
Please may I see these photos? This is very exciting, I’m wondering too if the Signaling compounds include GDF11 or something similar? use Green at Gohok dot com
Please send photos. Thanks Chris
I would also be interested in the photos.
Yes I’d love to see the photos as well. And a comprehensive update would even be better. We try to be patient but alas… 😉
Thanks in advance!
Yes, photos please!
Hi All happy to send the photo if you could please share your email id the way Ross did.
We have already formed our US company. Finalized our Lab premises in California. Hope to file patents in Sept/Oct. Hope to have a first close of early investors for our convertible round in Sept/Oct. We have been waiting since April to start our dog trial in California but pandemic continues to block the assembly of our team there. Once our round closes we plan to start manufacturing the gel. This could be available on Amazon around Christmas if we are lucky. We have also found a contract manufacturer in USA for the transdermal version but that requires FDA nod so can’t predict by when we can ship that. May be first quarter next year. We have used the time to discuss with various experts about our clinical path with FDA and this will help us speed up our trajectory towards Phase I human trial. We are hiring a very senior regulatory officer. Wish us luck.
We have been conversing via email over the part few months – maybe you didn’t recognize my name… I just responded to your email a little while ago.
Please send me a copy of the photo’s to
[email protected]
thanks
I would strongly discourage everyone from posting their email address into the open. Spammers love to lift those and you will be inundated. Akshay – it would be useful to post those pictures online in a shared folder on a Google drive or other file sharing service. It’s 2020 after all – very easy to do 😉
Or like Ross did put an ‘at’ and ‘dot’ in words
Good news Akshay, glad to see that things are moving.
What exatly is the effect of the gel? What kind of use is it for?
I will send you an email to have the photos too, even if I’m not sure to make the difference between to adult rats of different age.
I would love to see the pictures also. Thanks very much!!
Ed Quinn
[email protected]
Excited to hear your update! Fingers crossed for you. I would also like to see the pictures – please send them to: don leatham gmail com.
Don Leatham
Akshay:
I would be interested in the photos as well: stephan at bardubitzki dot com
Thanks!
Sure Stephan but these photos do not show much difference as taken at 1 month. Would rather send from next trial where we will make photo and video capture as part of trial.
You may already have my email for the pictures, but just in case it’s mcsprof at Gmail
Thanks Akshay,
Ed Quinn
Sounds good Akshay.
And thanks to you Akshay for literally putting your money where your mouth is. I am very excited about this project and wish both you and Harold all the best moving forward. And if you happen to look for a large lab-rat weighing > 80kg then please let me know 😉
Thank you Michael. 🙂 will keep in mind.
Do you have any updates you can share? Its only 2 months passed but maybe you have secured IP already so some of the info could be released.
We have been working on our IP and should complete filing soon but the details wont be out for 18 months. Our planned dog trial would have completed by now but due to the pandemic it is delayed. In the meanwhile we are working on adding more trials of larger animals after pre-IND discussions with FDA.
Yes I’m sure everyone following this thread is eager for an update. We’re not getting any younger! 😉
Can’t wait to hear some more! Even any small hint on the progress. Checking the blog + comments daily.
Yep! Call me eager. 🙂
Hey Akshay – the first week of April is upon us. Will the blue stuff be shipped out by Friday? We’ve waited a long time and even if there are issues with the packaging or branding, I don’t think anyone here cares about cosmetics (pun intended) 😉
Michael I have good news finally. The bottles are on the way to our warehouse- I am tracking them daily. My colleagues are primed t ship them out as soon as they arrive. After that should 2 to 3 days to reach you.
So how much more time you think it should take? Another week or more?
US residents should get their orders by next week.
Hi Akshay:
I received my blue Gel.
Thank you.
It has such a pleasant clean scent.
Thank you Heather! Yes a biotech or pharmaceutical product does not necessarily have a good smell or feel but we are fortunate with Neel having both. It feels good after application. Wish you tons of benefits!
Thanks, Ashkay.
Wish the same for you and everyone.
Intriguing news, Josh. I hope this does not end up being reserved for the wealthy or some other similar metric. I trust your conviction on the subject.
It won’t be Paul. It will end up changing humanity.
Apparently excess levels of SOD play an important role in the greater danger of Covid-19 for older people…
I thought SOD decreased as we aged?
Excess SOD may be due to an excessive immune response?
So, if SOD decreases as we age that exactly comports with what we observed. Only in Elixir-treated animals did SOD increase. In untreated old rats it decreased.
If I understand correctly, Superoxide Dismutase (SOD) is used by the body to reduce the damaging effects of inflammation. Since much of the damage from Covid-19 seems to result from runaway inflammation and since the treated rats had higher levels of SOD, I wonder if this treatment might be beneficial for Covid-19 patients?
Looking at your concept more generally most people under fifty have mild or no symptoms from Covid-19 while a staggering percentage over sixty five die. Arguably Katcher’s “magic potion” (Alan Green’s term) could be fast tracked by the FDA as a therapeutic drug for Covid-19 while others get the benefit off label.
Chris Burden
Elixir might work to ameliorate the effects of the coronavirus. We don’t know. I would suspect that it would simply because people have lower risks, but we don’t know. We haven’t examined the immune response, all that we know for sure is that the chronic inflammation of aging stopped. There is much to do, and the basic principles will create a new branch of biology (rejuvenation science). But whether this applies to the abilities of immune cells we don’t have experimental evidence for, however the disappearance of senescent cells (assayed by the rude and imprecise presence of SA-beta galactosidase staining – not enough to definitively implicate senescent cells (p16Ink4a expression in combination would be enough) but what else would explain the effects of Elixir and the disappearance of Senescence-Asssociated beta galactosidase staining cells after Elixir treatment?
Pardon me – “simply because ‘younger’ people have lower risks.
Hi Akshay,
Impressive paper! Glad to see you are shaking the world with such an amazing result during these difficult times. Welcome news which will hopefully help to shift paradigms.
I wonder if you plan to conduct lifespan studies too. It would be great to see the effect of even a single treatment on life expectancy. The implied assumption is that younger epigenetics means longer life expectancy but that could be not necessarily the case with the rejuvenated rats dying of some unexpected cause (cancer?) before the untreated control group. Glad to hear comments on that if any.
Thank you Guillermo,
Yes indeed lifespan study is very important. We were conducting it but were interrupted by the pandemic lockdown. But we will soon be conducting it.
What has been missed out on Harold’s bio is that he is a polymath of our times, he has taught Natural Sciences, Mathematics, Astronomy and Biology of Aging. He learnt computer coding when people usually retire.
Thanks Akshay, I have many interests and enjoy doing computer programming. My age resilience seems to be hereditary as my father was cogent until he died at age 98 (basically a suicide as he refused medicine and didn’t want to live. Losing his ‘girlfriend’ (AD) and his hearing (refused hearing aids) left him with no reason to live). As people already seem to have too much free time to begin with, what will people do with those extra years (decades, centuries, millenia (we won’t stop working to enhance humanity)), they will be given. It is my own belief that man will travel, immortal in the heavens, sail to the distant stars. There are infinite possibilities if you worship life, not death.
Harold, your wonderful reply here is my favourite in this thread! Congratulations to you and Akshay and your colleagues. Now that there’s no hurry, I hope you’ll consider writing an autobiography. ; – ) If you read sci-fi, who are your favourites?
Harold, thank you for posting here and thank you so much for your conviction and persistence in seeing this through. Humanity is indebted to people like you (people like Pasteur, Fleming, Van Leewenhoek, Schwann, Lind, and Hooke). You’re an inspiration.
A few questions:
1) What are the next steps?
2) When might we feasibly see a viable human treatment?
3) How much do you expect a human treatment might cost?
Aging in good health is aided with a hydroliser that creates H2-enriched water to eliminate free radicals and prevent inflammation. The other life shortening factor is the Hayflick limit of about 50 DNA divisions which is when the Telomeres that protect the cells have become too short .The discovery that the enzyme telomerase can lengthen telomers with the help of gotu kola, ashwaganda and cats claw was the answer.
Would be interesting to see some human data on e.g. change in human growth hormone levels, change in telomerase across different tissues etc.
Not all factors in the blood are pro-longevity, but perhaps the synergy achieved from increased glutathione levels, lowered levels of IL-6 from the injections cancel out the negatives. Hope is not a strategy…..
“We’re still waiting for longevity curves of these treated rats. “
in addition, this is still somehow in contradiction with
https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12897
Yes, that’s a question that has been bothering me since Amy Wagers post-doc, Shane Mayack and her papers were retracted from Nature and Blood. What Shane, who said she was innocent of everything, but made a mistake on which illustrations she used (one used previously), showed(she said) that blood cells weren’t affected by the rejuvenating factors in the blood (heterochronic parabiosis) but instead were rejuvenated (after a time) by bone marrow stromal cells. So, that was always a worry of mine – but the rats showed no ill effects at any time, I really don’t know about how good their immune systems were as we never challenged them, what I do know is that the chronic inflammation due to aging (present in all terrestrial vertebrates) disappeared. So, if nothing else, I can definitively say that chronic inflammation due to aging can be reversed with factors present in young blood. Hey, it’s a beginning and with great potential to end the diseases of aging, many of which have an inflammatory component.
Well done Harold and Akshay!
I read the paper and am very impressed. Chasing our tails with markers of cellular aging has not really got us anywhere and I’ve been slowly coming around to the view that the aging of the cells reflects aging of the organism, rather than the other way around. I can think of some examples but will not go into detail now, other than to say what appears highly complex can be simple once it is understood!
Best of luck with your lifespan studies.
Thank you Mark.
Mark, we’ve (scientists), spent the past 70 years trying to definitively prove the commonsense ‘wear and tear’ theories and have not succeeded. As Einstein pointed out, doing the same thing over and over and expecting different results is the definition of insanity. So, I tried something different, looking at the results of experiments rather than the arrogant theories of the ‘evolutionists’ who think they know better than Nature. Aging theories became an intellectual parlor game, where the goal was to frame a programmed, developmental process so that it could be explained by random chance. Why? The desire to avoid death; if it was a question of chance, rather than a certainty, then…
Looks really promising! Congratulations and thanks for you hard work and sacrifices!
I wonder how well do these results translate to humans.
CR for example does not translate very well. Did you consider how your results align with that of calorific restriction?
Did you get any feedback outside from other research groups who were not part of the community that created the paper?
From the likes of Belmonte, Rando, Conboys, De Grey, Longo, etc
Thank you so much GaborB. I missed your message. CR is based on a hormetic response. This is way more potent. I cant see how it wont work in humans. Logic, biology dictate similar response. All scientists have been congratulatory. Some scientists are finding it hard to believe due to the level of response across so many markers inluding senescent cells, epigenetic methylation, biochemical, inflammatory, etc. Fortunately Steve Horvath enjoys a high reputation and now there will be peer review which will also help. Followed by a full FDA evaluation. The safety profile has been 100% so far which is very encouraging.
The Conboys have their own plans for ‘rejuvenation’ products. Aubrey’s SENS foundation has a basis entirely opposite ours, but he’s a fair person and would publish our stuff. I haven’t heard from the others, but the last time I contacted Tom Rando (years ago), and told him I would cure aging, he said, “Good luck with that.”, so I guess I ought to thank him?
Looks like it is a race between you and Greg Fahy for now; what is your opinion of his (Fahy’s) approach?
Greg Fahy | Thymus Regeneration
Tim, Greg is a dear friend and collaborator. We are conducting our dog trials with him. He is a highly competent and hard working scientist. We are fortunate to have an opportunity to work with him.
Are there going to be in the near future larger scale human trials to follow? I mean dog trials are find but his original trial was only with nine Caucasian middle-aged males. Hopefully a larger, more diverse group of people for “phase 2” is currently in the works? How soon before we can expect more results?
Tim this is best answered by Greg although there is discussion between Greg Harold and Steve regarding a sizeable combined human trial. Greg and his team are launching a major phase II trial too to continue on their phase I research. By the way a visit to Greg’s lab is like visiting a sci-fi facility. He would sell millions selling tickets to visitors like me.
Fahy proved that the human thymus can be rejuvenated. I doubt that GH even with DHEA will ever be a general rejuvenation therapy. But hats off to him for the proof plus showing how to get anti-aging therapies into clinical trials.
Wayne I second that. Only Nir Barzilai previously had managed that too for an FDA approved drug. Greg has pulled off a remarkable feat and will help all those who follow.
The comments section of Josh’s original posting on this subject offered a wealth of additional information. I would be interested in the following:
1. What is the status of the effort to protect proprietary rights? My primitave search did not find a patent application (although there was something similar from Alkahest).
2. Has the idea of an n=1 skin patch been dropped? I suspect that a liabilty issue makes it unreasonable, but…
The recent trial on regeneration of the thymus shows that the “aging is not a disease” problem is easily surmountable.
Thanks Harold, Akshay, and Josh for the hope that I may live to see my 7-year-old son graduate from college. (I’m 79.)
Hi Wayne we plan to file patents worldwide sometime this year. The transdermal patch and a topical gel version is still very much in pipeline. In fact the latter should reach by market by early 2021. We were hoping for Christmas this year but the pandemic pushed back a few things.
Thank you for wishes.
It’s cheaper to file a PCT first, after which you can claim patent pending, but I’m sure you are very familiar with the process.
Thank you posting this impressive work!
Let me write this anyway in this expert panel! Can someone helps dissipate a (likely naïve) doubt: while allowing comparison between different species, if max life span is important to study, is it possible that the process of somehow normalizing the curves via the relative age (age/maxlifespan) is factoring out exactly the signal we want to investigate, i.e. the difference in life span?
Akshay,
I think last year you were talking about this treatment being a transdermal patch. From the above it sounds like it is now IV. Did the transdermal patch not work out? I’m not really surprised if so as the amount of a compound you can actually get through the skin on a practical basis is usually quite small and normally only works well on compounds that are effective in very small doses (fentanyl being a good example – normally dosed in micrograms).
Michael,
We have two separate products: one is a very powrrful anti aging molecule already tested on Harold with amazing effect (all his aging spots from his arms disappeared in a week). This product we wish to sell as a topical gel and transdermal patch. The gel will fall under cosmetic category with FDA so may be out early. Patch needs a FDA clearance so may take longer.
Apart from this is our flagship product code named Elixir which would be administered as injections or IV. The paper listed here by Josh is on Elixir results. I hope this clears the confusion. Good news for all of us anti-agers is that both the products should be affordable.
Can you get a systemic response with the gel or transdermal patch or are you mainly getting a cosmetic effect on the skin?
If you get a systemic effect then perhaps that product might “tide us over” while we wait to get your IV product through FDA approval, which I am sad to say being the pessimist I am I predict will take a decade and perhaps $1B USD, if it follows the normal FDA approval process. Understand I’d love to be wrong about that.
I think you guys should be thinking about establishing clinics outside the jurisdiction of US and European regulatory agencies if you can provide the data that what you have works. India proper, Eastern Europe, and various Caribbean islands in the western hemisphere come to mind.
Michael all good suggestions but entreprenuers are optimists 🙂 FDA has a new caregory called Breakthrough. If they feel that any treatment is a novel approach that can bring benefit to many suffering they will fast track it. So fingers crossed. Another great opportunity is the human trials under the FDA application. We will try to accomodate all enthusiasts recommended by Josh in thos trials. They were to start end of the year but may get pushed to early next year due to the pandemic. The gel is topical and patch is systemic. I would be using both till human trials start.
Since Covid-19 affects older people more seriously, perhaps testing of a treatment that potentially mitigates those effects of aging which make us more vulnerable to the virus would qualify for fast-tracking? I’m thinking of the test results that appear to show improved control of Reactive Oxygen Species.
Akshay,
If Canadians get an opportunity to participate in human trials I would be eager to be involved.
Thanks Stephan. Noted.
I agree with the previous Michael – I’d buy a trans-dermal patch or topical gel in a heartbeat. Please create an early alpha testing group and add me to it. Happy to pay to for the product to participate as well.
Will do
Akshay, add me to that list too. Chris B
Sure.
You can add me too. I’m ok if I’m the placebo but I’m on Rapamycin and D&Q so maybe that disqualifies me.
Larry we can discuss when time comes
I am probably not alone in saying that I would be happy to fly to India or Mexico to visit your clinic. I have been interested in gerontology since I was in my early 30s and that was 20 years ago – none of us are getting any younger! 😉
Michael hopefully you wont have to do that. We should have human trials under the watchful eye of FDA and all our friends and well wishers like you we would hope to give priority to enter the trial. By the way the treatment you receive in the trial is free 🙂
Well your discovery/research/work could not come at a better time. I mentioned that I had been interested in gerontology from a relatively young age – since the Roy Lee Walford experiment, if anyone remembers him. He passed away in 2004 at the age of 80 and I wish he would have made it just a few years longer.
Anyway, with diet, nutrition, supplements, and exercise I have been able to remain relatively stable at a plateau into my early 50s. When I told people my age they looked at me incredulously and simply couldn’t believe it. The oldest they usually guessed was early 40s with many thinking I was in my late 30s.
However due to a immune condition last year I have experienced a decade’s worth of aging in a single year. I very much look my age now and it’s been extremely frustrating after all the hard work and money I had invested in my health. The mere thought of perhaps reversing some of that fills me with a lot of hope and I would go to great lengths to recover at least some of the years I have lost in the recent past.
No pressure! 😉 J/K – I know the process takes time and that you don’t want to make any crucial mistakes that may affect your organization’s future. But let’s always remind ourselves that all our lives are literally hanging in the balance and anything that may slow down the aging process over the next year or two would be a heaven sent for everyone.
I suggest you reach out to this community in regular intervals and ask for help if you need it. Many of us are willing to do our part and of course reap the benefits over the short, medium, and verrrrrryyyy long term 🙂
Will do. Verrrrry long term sounds good 🙂
Michael Mehrle:
You wrote: ( “However due to a immune condition last year I have experienced a decade’s worth of aging in a single year. I very much look my age now and it’s been extremely frustrating after all the hard work and money I had invested in my health.” )
Perhaps all your hard work and money you invested in your health did pay off.
It’s possible, without all your self-administered interventions, you may have aged much earlier.
Yes, you are right of course. But seeing it all go out of the window in the span of a year is very frustrating. Well I should not complain I guess as there is hope given this discovery.
We think about all sorts of things Michael, but it seems that the effects of blue stuff are considerably more than skin deep. I’m not here to advertise anything, but it seems to affect my coordination and had hair grow back on my scalp and I no longer apply it to my skin. Some other time perhaps. Yes, there are amazing things that Big Pharma won’t touch as there’s not enough profit in them (they can’t be patented). So I guess we’re somewhat the same, but we know what to do and have proven it – for us, it’s not the money. However, money allows you to do things.
a week? Recently my age spots disappeared after acetyl l-carnitine, but it took a few years of taking telomere lengthening and senolytics substances before adding acetyl l-carnitine, and even after that it took next few months. ;/
Yes a week. Harold can confirm that. His skin to me looked younger.
Harold and Askay:
You two are the Tesla of anti-aging therapies. 🙂
Best wishes going forward.
Thank you so much Heather. You are a great researcher as well.
Other nutritional approaches to slowing accumulation of lipofuscin associate with age spots, in addition to acetyl L carnitine, are:
Centrophenoxine
Ginko Bilopa
Piracetam
Vitamin E
reduced gluthathione
and Possibly Dmae
Also Calorie restriction, if you can tolerate it,
Age spots are not formed by lipofuscin. Its just melanin, I believe.
Hi Mark:
Both lipofuscin and melanin play a role.
Lipofuscin is a yellow/brownish material that builds in cells as people age. Melanin reacts to UV light which also increases it. Pheomelanin if you are a redhead.
The excess of the two, and their abnormal distribution in the skin cause dark spots to appear.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420599/
Info. from the link:
————————————————————–
“Discoloration are symptoms of skin aging. They are connected with presence of melanin and lipofuscin, whose excess and abnormal distribution in the skin cause dark spots to appear. Melanin is formed under the influence of tyrosinase during melanogenesis.
Its content changes with age, which may be a result of menopause. Lipofuscin is another example of the age pigment. It is composed of proteins, lipids and carbohydrates.
It is described as an age pigment because its content increases with age. The formation and accumulation of lipofuscin is inevitable and leads to cell and homeostasis dysfunction because it reduces the proteasome activity.”
————————————–
And other links:
https://www.researchgate.net/publication
/316881637_Melanin_and_lipofuscin_as_hallmarks_of_skin_aging
https://pubmed.ncbi.nlm.nih.gov/28507486/
If it is something produced by the body, couldn’t a gene therapy be designed to produce it at constant levels?
Darian technically yes but in the case of the gel its easier to just apply a patch and get the benefits. In a way one can titrate with the patch based on how long one applies it.
For now external therapies are good. But I’ve never been a fan of ideas like Aubrey’s repeated visits to the clinic.
Long term we would eventually want a permanent treatment that allows negligible senescence without further treatment.
That way if there’s a global disaster and supply chains become interrupted, one does not suddenly begin to age for lack of treatments.
If this works at all I’d be thanking my lucky stars that we live in an age where the dreams of men since time immemorial have started to be fulfilled. I certainly wouldn’t quibble that I have to make periodic trips back to the fountain of youth for a recharge.
As a 75 year old I look forward to using this amazing product. My heartfelt congratulations. Also to Josh for following it and reporting it.
As Josh said it will have an absolutely unpredictable impact on society. However the progress of society dictates that this kind of transformation is inevitable. Why not now.
Good Morning Josh,,
This is truly stunning. Starting about five years ago I began pharmacological anti aging interventions. I’ve been watching GDF 11 (Steve Perry) but haven’t thought GDF11 was ready for prime time at least for me. Manufactured blood factors as described in the BioRxiv paper seem like a logical next stepping stone in anti aging science if not the holy grail. Manipulating Yamanaka factors intuitively seems much more complicated. I would love to be part of this effort if Akshay is looking for additional financing. This is a great piece of work.
Chris Burden
561-603-3064
Thank you Christopher
Add me to that list. Would be interested in becoming a shareholder in any company you decide to launch.
Thank you Michael
Me too
Josh you make the distinction between adding beneficial molecules and substracting harmful ones from the blood.
The distinction may be moot given the most recent Convoy results using an ALK5 inhibitor (and oxytocin) to block the effects of tgf-b. So filtering blood to remove harmful elements may not be necessary.
See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710051/
Extremely interesting post and kudos to you, Josh, for making it very clear how important you see this research being. That said, why weren’t other aging measures logged, such as muscle mass, hair restoration, activity levels, sexual activity, etc? Reason, for one, has heavily criticized methylation clocks as not telling us much about aging, and I take him pretty seriously. This paper as you pointed out does include other measures of aging, but why not the more obvious kinds of measure like I just mentioned?
Is there any synergy with this approach and senolytics, or is one of the mechanisms in play here that this approach causes senescent cells to revert to a normal healthy state?
It’s a really good question, and I’m pretty sure it hasn’t been investigated yet.
I guess there are methods of looking at the senolytic cell load in vivo, but I’m not well versed in that. Would be interesting to know what it was pre and post treatment.
We have done beta-galactosidase senescent cell test between the 3 groups post treatment. Please see figure 7 at the end. A significant reduction in load can be seen. It may be because of improvement in the efficiency of autophagy.
Congratulations Akshay. You and Harold deserve enormous credit for tirelessly pursuing this concept and having it succeed so very impressively . I certainly hope, for all of our sakes, that you have a product ready to roll out in the near future.
Thank you Paul. You and Mark have been a diligent anti aging crusaders as well and always encouraging.
Re. Quote from above:
“A question that remains unresolved concerns the location and mechanism of the aging clock. I have been undecided over the years between two models:
There is a central aging clock, perhaps in the hypothalamus, which keeps its own time and transmits signals throughout the body that coordinate methylation state of dispersed tissues
Information about epigenetic age is dispersed through the body, and the body’s clock is a feedback loop that is continually updating methylation age locally in response to signals received about the methylation age globally.“
It Is an important question and one that should be resolved. It would seem that a testable hypothesis could be constructed that would resolve this question.
It seems to me that hypothalamus cannot control mammalian aging because:
1) many, if not most organisms that get old and die do not have a hypothalamus. Imagining an evolutionary switcheroo that moved a process used by eukaryotes back to protozoa and yeasts over into a vertebrate brain seems too big a leap.
2) if the hypothalamus were in charge of aging the process would be so fragile that defects would have shown up as neurological diseases long ago where individuals would suddenly age or stop aging due to a SNP or after trauma or fever, etc.
3) the distributed participation hypothesis is much more robust and full synchronization of all key gland and organs is not necessary. For some the brain goes first, for some it the heart, etc. With only limited synchronization, we would expect slight differences in methylation between the various organs.
I have the same argument in mind.
But we know that rejuvenation at the cellular level is possible (conception, somatic nucleus transfer, iPSC), maybe it is feasible that higher order organisms had to evolve a system that promotes rejuvenation, otherwise they would have gotten really short lifespans like C. elegans. And that by hacking that signalling system you can rejuvenate your body in some way.
There is research I have read before that old muscle stem cells which are incapable of expanding in the old tissue when transplanted into young tissue were able to expand again. So systemic factors surely have a role in aging.
I am surprised though of the epigenetic rejuvenation effect.
The problem with inducing iPSCs, is that it’s akin to forcing a fully grown human to shrink back to a child again – maybe only 1 in a 100 or a 1000 could survive such an experience!
I find the top down rejuvenation approach to be highly credible – I am certain much of its success must be down to the removal of some sort of waste products. That way the body can return itself to optimum health, much as Josh has always suggested it could.
Josh, it makes total sense to me that the central clock of aging is not some hidden gene in the DNA but the blood itself.
This way the epigenetic state of cells is communicated out into the blood and then from the blood to the whole body. Other cells then adapt and pass on the ‘message’ to some degree perhaps depending on the degree of aging in the initial cells and their number compared to the rest of the body. Looked at like this aging is a malleable and editable process.
Even though you could argue it is programmed, it could also be argued it is compatible with Blagosklonny, where aging is like an accidental drift left over after growth is complete, but according to this new work the body can be recalibrated by the young plasma, back to a state of youth.
What do you think?
Mark, You have a high probability of being right. Aging is a quasi program as Blagosklonny says not a program. There was no evolutionary pressure to reduce mTOR after growth was complete as long as you lived long enough to provide for survival of the next generation thus the analogy to the speeding car with no brakes.
>the central clock of aging is not some hidden gene in the DNA but the blood itself.
I find this idea attractive. Certainly you could devise a timekeeping mechanism from the feedback loop where transcription factors in the blood reprogram gene expression system-wide, and gene expression changes signal molecules in the blood. But could you make this one system both homeostatic and progressive?
I don’t know enough biochemistry to figure out how it could work, so I think instead like a mathematician. Suppose I were to write a computer program to gradually change a bunch of numbers over time. I know how to do that (“progressive”). Also, I know how to write a program so that any small change to a set of numbers will be restored toward a target value (“homeostatic”). But is it possible to combine both features in a single program? The target of homeostasis gradually changes over time? This feels difficult to me, maybe even logically impossible, though I don’t have a proof.
Hey Josh – if I understand you correctly you are attempting to correct for a progressive series of parameters? Look at the Kalman filter which is used in areas spanning from navigation systems to quant trading. The idea is that you have a measured value and a projected/computed value. What you are trying to figure out is which one is more accurate and should be more trusted. if you solely rely on the measured value you may be getting faulty data. If you rely solely on the computed value you may be basing your it on faulty presumptions. The Kalman filter very cleverly corrects for that. Michel van Biezen has a very cool series on it which is well worth watching.
https://www.youtube.com/watch?v=CaCcOwJPytQ
I am only a lowly engineer – not a mathematician – and I managed to understand it. So you should be able to breeze through it in a weekend 😉
I am more interested in where the program is. My guess so far is the non-coding-but-transcribing parts of the genome. Wherever it is, it has to be easily reprogrammable or we wouldn’t have clones or Yamanaka. One nice thing about the elixir is that its possibility is not precluded in Harold’s published articles on aging theory.
The homeostatic part is easy. It could be a process whereby the blood averages out variations in the age state of cells and communicates the result back to all cells. This fits why young organs do worse in old recipients, old organs do well in young recipients, and why the hypothalamus was the least rejuvenated part of Harold and Akshay’s rats being behind the blood brain barrier. For the same reason it also explains why the brain is somewhat shielded from the aging of the body.
But how would it be progressive? It must be something to do with the fact that the ‘consensus’ opinion of what age cells should be, as held by the blood, must be more likely to average up than down.
I am not sure of the exact mechanism, but lots of small homeostatic corrections when the body does repair must be happening all the time and perhaps the net effect is a slight aging signal. Whereas outside of a young plasma infusion or stem cell therapy, I cannot see there being a source for a ‘get younger’ signal.
I am imagining a bunch of organs and each is hit with a random integer from -5 to +5. Next the blood having some age circulates through those organs and records the average of the organ’s ages and if that average is not more than 2 higher and not more than 1 lower than the blood’s age the blood rewrites its age to that average and on its next round also instructs each organ to move toward that average. If on the other hand the average age of the organs was more than 1 below the blood’s age, the blood just reduces its age by one and on its next round instructs the organs to move towards that age. If the average age organs was more than 2 above the blood’s age, the blood just increases its age by 2 and instructs the organs to move towards that age on its next round. Then the whole cycle repeats with the organs each obtaining a random adjustment in age from -5 to +5. (the random adjustment representing the environment’s effect on each organ). Is this artificially simple model and example of a program that is progressive and also homeostatic?
The clock seems somewhat like a distributed network of finite state machines, with feedback and some overlap between them. They would seem to exist in the blood as well epigentically in the various tissues of an organism. Factors in the blood would seem to be the easiest to target and influence, and their effect on DNA methylation would vary among the organs and tissues. Likewise organ and tissue transplants or DNA methylation changes might have some effect reflected in the blood as well. Conceptually the overall clock is like multidimensional a matrix of all the distributed and overlapping clocks.
> it could also be argued it is compatible with Blagosklonny,
I refer you to my book. I have a lot of appreciation and respect for Mikhail, but I think the quasi-programmed idea isn’t plausible. Here’s why:
The idea of epigenetic inertia is that genes that are important during development continue to be expressed later on because the body hasn’t gotten around to turning them off. Put this in the context of the whole, exquisite developmental program. Everything is so perfectly timed to create a body, to grow and mature on schedule. Clearly the progression of gene expression over time is very tightly and successfully controlled. Why would this suddenly fail once development is over?
It might fail if, as Medawar posited 70 years ago, the fitness cost is very low, so there is very little selection pressure to turn off the gene expression responsible for aging. Medawar didn’t live long enough to see this idea falsified with field data. Field data in the 1990s collected by Promislow [1991] and Ricklefs [1998] and the definitive experiment conducted by Bonduriansky [2002] demonstrate that aging carries a high cost in the wild and that individual selection against aging is substantial.
It is for this reason that I have concluded that the aging programs that we observe in nature must have evolved via group selection that overcomes individual selection.
I agree with what you say. Good arguments. But there’s also some evidence for a special role for the hypothalamus. Claudia Cavadas in Lisbon and Dongsheng Cai in New York have worked on this.
Congratulations to Askhay and Dr Katcher! Just this morning I was checking my retirement options. That’s all out the window now, I have to keep working for at least another 5 years. 😀
Thank you Larry 🙂 you can retire happily for now but better make plans for what you will do if you are 25 again.
Congratulation to Harold,
This changes everything. The theoretical significance is on the level of Columbus showing earth was not flat. Dr Katcher’s magic potion is almost impossible to believe; but Horvath proved it is real. Also a complete proof of Josh’s idea of programmed aging. Also proves epigenetic changes are controlling aging and not a clock measuring age. Breakthrough is an understatement. This is huge.
I agree! Great stuff!
I curated this blog post and the study at https://surfaceyourrealself.com/2020/05/12/a-rejuvenation-therapy-and-sulforaphane/
Yes, Alan – Though we’ve worked toward this day and imagined some aspects of it, I don’t know anyone who is writing about the full implications for society, for politics, for ecology, for the future of humanity. Perhaps it stretches our wisdom beyond the breaking point.
My mother was born in 1922, and as a child she has memories of the clip-clop of a horsecart on the cobblestone streets of Brooklyn, stopping at her house to deliver milk in the morning. Plastic was in the future. Antibiotics were in the future. Could she have imagined the consequences of the Internet if you described the technology to her 80 years ago?
“Alexa, order a quart of organic goat milk for delivery this afternoon from FreshDirect.”
Think also of the dystopian consequences. Vast surveillance bureaucracies that monitor our every text message. Companies so powerful they have the ability to suppress political and even medical truths under the pretext of protecting us from “fake news”.
Life extension will certainly be such a double-edged sword.
For some time now its been clear that the future is perilous, and could as easily become a dystopia as a paradise.
I am extremely happy that this Elixir has been discovered by Harold and Akshay, who want everyone to be able to benefit.
Alan is right, this is huge – we must be careful. The pharmaceutical profit-from-illness industry may not go easily to its grave!
This seems to be getting a bit ahead of ourselves. Perhaps human trials should be completed before we assume this actually works in humans? Many many therapeutics work well in murine models only to fail on humans.
Josh, if you have an interest in sci-fi, the Mars (it’s about settling and terraforming Mars) trilogy by Kim Stanley Robinson, is intelligent and breathtaking in its scope. A gerontological treatment is part of the social economic dynamics described in the book. Apparently Elon Musk read the series when he was younger.
@Alan,
My God, don’t repeat that Columbus showed the earth was not flat. Any illustrated man knew it was round centuries before. Almost one thousand years before
Eratosthenes even measured the radius of the earth with fantastic precision. The Queen of Spain was too clever to be convinced to fund Columbus (not cheap for Her) under the assumption of a flat earth.
The funny thing is that Eratosthenes was much more brilliant than Columbus in mathematics. Columbus thought that the radius of the earth was much smaller, and that an expedition would reach the far east to open a new trade route, which was the reason the trip was funded. Put in another way, Isabel funded Columbus’s expedition under the assumption that the earth was round.
Well in Columbus’s defense, he had a financial incentive to believe (or at least say) that the earth’s diameter was on the small side. When you’re trying to sell sailing to the east by traveling west a smaller earth is more attractive.
@Michael,
that’s right, very good point!.
Great work Harold,
In 8-8-2017 4:27 pm in Josh’s column Harold posts a hint in comment that all in miRNA that control age-related transcription and this can be used in plasma exchange. Harold also says all it his 2015 paper:
“Towards an evidence based theory of aging”. (available on internet)
Regardless of if and when the Elixir is available; the proof of the elixir has huge impact on aging theory.
I am an assiduous reader of this blog, I am not a scientist, thanks to this blog I acquired a great enthusiasm for the topics discussed here and I am excited about this post, I think we are privileged to see the beginning of a new era for humanity.
I’m already feeling sorry for the masses of soon-to-be-unemployed biomedical workforce.
I hope you guys get a patent on record as soon as possible since hopefully you’d be able to discuss the your discovery in detail.
I am still concerned about the time and cost to get your IV treatment through FDA approval. I hear “fast track” but even with fast track I believe you are looking at a number of years and several hundreds of millions of dollars at a minimum. And it is my unfortunate belief that the regulatory agencies both in the US and Europe are pretty much co-opted by the incumbent pharmaceutical companies and will be highly resistant to approving any sort of break thru technology that will render much of their current drug portfolio obsolete. Do not underestimate this. The existing drug approval process – expensive and lengthy – is pretty much the process that the incumbent players desire (as counter intuitive as that might seem). The high costs and long lead times serve as a very effective entry barrier to new upstarts with disruptive technology. It is very unusual that a small company is able to muster the resources and time to get a drug approved alone. Most frequently they have to partner with a large incumbent player to have any hope of getting something approved and buying a controlling stake in a company purely to put it on the shelf isn’t exactly unheard of. I hate to be so cynical and jaded but watching this industry for a long time now leads me to no other conclusion. By all means go for US and European drug approval – but I’d have Plan B in the back of my mind.
All good points Michael
Agreed. There are many years ahead and many shoals on which even a successful therapeutic could founder.
Unfortunately I would have to agree with my namesake above. A close relative of mine worked as a FDA liaison at a large biotech firm and he was richly rewarded for his role. Many drugs spend years and sometimes over a decade passing through the FDA approval process and the resources required to make it through are immense. This not only creates high barriers for entry but also forces smaller players to raise a lot more capital than they may have needed otherwise. By doing so the initial founders in most cases lose control and are relegated to minority partners. And that in turn means that corporate/VC interest exerts full control and in the end dictate the pricing of the drugs that finally make it into the marketplace.
The only way forward is that the authors publish their method of the Elixir so that others can experiment and improve it so that FDA and Big Pharma cannot marginalize it. 🙂
Hi Michael
I am a retired biotech consultant and I agree with everything you state. I worked on bringing an important drug to the market and during the many long and tedious meetings between the biotech I represented and the large pharmaceutical we were attempting to partner with, I did not hear anyone once mention the benefits to humanity or the reduction of pain and suffering this advancement would bring about. Many long hours were devoted to manufacturing cost analysis and profit projections.
There are however exceptions to your argument; resistance will be an inverse ratio, proportional to the general population’s demand for access to something that will be regenerative, palliative and a disease preventive. Underestimate that demand at your own peril. I don’t anticipate that there is a single politician in the world that has the fortitude to stand in the way of the demand, clamor and press that combination will generate. That combination will generate another group of powerful and influential advocates that have equally deep pockets and lobbyists; Insurance companies, HMOs and businesses who insure their own employees. Do you anticipate US citizens will idly stand by while the citizens of Japan, South Korea, Spain and many others cure their citizens of most of the diseases associated with aging while turning the most knowledgeable and experienced segment of their population into productive individuals, again. Politicians will immediately resurrect an old and trusted campaign promise, “Healthcare for all!”, but finally armed with the ability to fulfill that previously empty promise.
Harold Katcher has agreed to do an AMA at the futurology Reddit. See the link for info.
https://www.reddit.com/r/Futurology/comments/gi91pa/reverse_aging_success_in_tests_with_rats_plasma/
I wonder if exosomes have a role.
The procedure cannot be as simple as giving a plasma fraction as the Conboys have tried that before with mice and it didnt work.
A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood Nature 2016
There’s something we’re missing here Gabor. Harold’s past comments have mentioned exosomes (we know from other work they are highly beneficial due to miRNA signalling controlling gene transcription), but Harold didn’t use his planned HPE due to difficulties doing it with rats. So they just injected some plasma fraction. But then he and Akshay have also said they can now make this elixir without using young plasma. So they must have identified the important molecules (and it can’t be exosomes). This is remarkable as even the Conboys appear to have given up on finding the most important plasma fraction and instead just hit certain inflammatory targets with drugs.
We need a patent to be granted so they can tell us, quick!
I’ve filed a few patents and can tell you that they take at least 2 to 3 years – there’s a way to fast track but even then it takes time. The good news is that you can claim patent pending right away and are free to share your findings. If/once the patent is granted the intellectual property is protected all the way to the filing date although the valid patent period spans 20 years from the day it was granted.
In short – as soon as Harold and his group decide to file his patent and hopefully PCT as well there is little that should keep them from sharing their work/findings.
On a related note, if you have a real rejuvenation therapy do you really need FDA approval? Open a clinic in India once you’re happy its safe (you don’t need FDA for that) and start churning out young people – the condemnation from the FDA will soon give way to deafening cries of US/European citizens to have the treatment available to everyone. If this treatment does what we think it will, then you are going to break the system anyway. Might as well start how you mean to go on. Just an opinion.
India is a long drive for me. The Caribbean would be better. BioViva seems to be showing the way (only the treatment procedure is performed offshore).
But the thymus rejuvenation trial, also with Horvath’s participation, didn’t seem to have much of a problem with the FDA, so the conventional route shouldn’t be discouraged.
Exactly. I agree Wayne.
What you say is true but only if FDA is non responsive. We can target a disease of aging like Alzheimers or IBD. No cure. People suffering. If we show evidence of resolution in a few weeks it would very difficult for FDA not to fast track us.
Yes fair enough Akshay.
I was only suggesting it as a back up plan.
Agreed Mark.
Seems like the Summer of Love might roll around again
Congratulations Dr. Katcher! Very impressive results.
Adding on to the discussions around getting this through human trials, you may reach out to Brian Delaney who is running the “Vitality in Aging Longitudinal Study” (https://vitalityinaging.org/). Beginning last fall Brian and his team enrolled a large group of participants and did induction testing (blood, body fat, reaction timing, gait, etc.) on each person. The blood screen was very comprehensive and I remember signing a consent to have blood/tissue stored, so you may find a very willing and well documented test group to assist in your testing. If you are interested, reach out to me at don*leatham[-at-]gmail*com and I can connect you to the study’s operational lead.
Hello Harold, many congratulations! Do you have an idea of a “realistic” timeframe that this might become available to the public, assuming trials are successful and not run in the US?
Also as a suggestion, I’m pretty sure that you’ll have financial backers after these results, however, if not, I’m fairly certain you would have no problem raising several millions by crowdfunding this in a short period of time. You could probably raise enough for a small three phase human trial.
Final success with the elixir will result in huge losses to the health care (I mean “sick care”) system. Some people have suggested that Harold and Akshay should find ways to protect their rights to the elixir.
Since the stakes are so huge, in my opinion it is even more important that they take necessary measures to protect their lives. Big companies don’t necessarily play fair. Maybe I am paranoid. But it pays to play it safe.
If I understand correctly, the compounds they are using are not patentable (I get the impression they are naturally occurring, but they could also be older off patent man made compounds). So, I would assume they are applying for what in the US is called a “use patent”, i.e. patenting the use of compounds x, y, and z for a specific application.
Use patents are are not as protective as patenting a compound. Someone can come along and make a claim to use your set of compounds for another application. Say for instance, curing warts. Keep in mind, it doesn’t even have to work for the application they claim to get a new use patent, though that will definitely help if they have to defend it. So, some other party could potentially patent their set of compounds as a “wart elixir” and it could be marketed as such, but by various means consumers could be alerted to the fact it contains the same ingredients as “Harold and Akshay’s Youth Elixir”, and nothing would stop someone from purchasing it for that application.
This is why use patents are considered to be weak and why I can’t recall the last time I saw a pharmaceutical company that pursued a therapy that was only patentable on a use patent.
Or I could be completely off base and they do have a novel patentable compound. Also it’s possible that patent law has changed since I last looked into this.
Adding to the above thoughts something that just occurred to me:
There is however one good thing about going the full FDA approval route on their IV therapy. I don’t believe any doctor in the US or Europe is going to administer anything IV without it being approved by the relevant regulatory agency (FDA in the US, EMA in Europe). That actually helps them quite a bit. You have to make a claim as to what you’re treating when you apply for regulatory approval. You can’t make the same claim as Harold and Akshay since you would then violate their use patent, and you just can’t make up some crazy claim to treat something else because these agencies aren’t going to approve for something frivolous. So, a use patent paired with a requirement for FDA/EMA approval for an IV drug is together much more protective than a simple use patent in other fields.
Michael you are an intelligent man. FDA approval also carries one very imp advantage: a regulatory exclusivity of 5 years.
Question for Harold and/or Akshay: What is the impact of the elixir on HSCs? Does it make them younger as well? I think there was some discussion in a previous Josh blog post stating that unlike other cells, stem cells seem to keep the age of their donor and do not rejuvenate when transplanted into younger hosts.
Hi Mark,
I think the story was that Harold and Akshay initially had a hypothesis about pathways to be manipulated to achieve rejuvenation. They probably wanted to achieve this by plasma but due to budget and time constraints, they used herb extracts that were injected in high concentration into rats. Following that they identified the compounds in plasma that causes the rejuvenation effect.
But this later step is not an easy feat. It might happen that they did not find the actual molecules, but used some coarse approach, like take newborn rats, get the plasma, throw away albumin, throw away immunoglobulin, throw away clotting factors and inject the rest. And they got the results, but now need further funding to identify the actual effector molecules.
I believe the natural herbs were a completely different experiment, though they may more weakly hit the same targets as the plasma fraction.
Because Harold said they wouldn’t need blood from young people I assumed they had identified biosimilar molecules to the ones in plasma that are doing the job. But I could be wrong. In any case there will now be somewhat of an arms race in other teams to replicate the results and find the important molecules.
Re Klotho, I read an article in scitechdaily.com: “Scientist identify factor in young blood that helps rejuvenate aging muscle. Done at University of Pittsburg and the original article was published in Nature Aging, December 6, 2021. I wonder what has become of that research?
I’m sorry but like you know, I’m not convinced. If this treatment was so successful why not to keep a few rats alive just to prove they could live longer? They would be the oldest rats in the world by now if the treatment was successful.
Or directly after the treatment why not to start a second experiment just with two small groups of old rats, one with the treatment, the other without? In this case also, we would have the oldest rats in the world by now.
Akshay earlier in this thread: “Yes indeed lifespan study is very important. We were conducting it but were interrupted by the pandemic lockdown. But we will soon be conducting it.”
Thank you Nick.
Even a therapeutic health span improvement would be a breakthrough IMHO.
As far as I know we only have health span improvements in rodents with CR so far.
Thanks GaborB
I agree, I don’t like it either. Why would the pandemic make it necessary to kill the rats? You just need to keep them alive.
There was a complete lockdown with University shutting down for unknown period. There was no option. This fortunately is not our last trial. Many are planned, lifespan study included.
Thanks for your reply! I’m looking forward to new lab results.
Thank you Martin. We will have 2 of our own labs and a few reputed third party labs conducting multiple trials that are planned. For example we have a double dose trial to check the response curve, we have a old infertile female trial to see if they become fertile again, we have old dogs trial and possibly a old marmoset trial. Any of these can be extended assuming we have sufficient resources a lifespan trial.
I’m sorry, but your first experiment was finished long before the lockdown. It was perfectly possible to let a few mice live at this time. And it was also perfectly possible to start a second experiment at this time.
How is he supposed to keep an eye on a bunch of lab rats that nobody can care for as the university is on complete lock-down? They would have starved to death. Give the man the benefit of the doubt and let them repeat the experiment, which is already in the works.
Thank you Michael! When you are trying to cover a lot with limited resources you are always struggling against the flow. Its supporters like you that give the strength to carry on. And we havd been blessed with a few. Some like Josh, Mark, Paul have been from many years.
You’re welcome Akshay. FWIW, I am far from being a blind follower – quite to the contrary. However while I do appreciate critical thinking my inner optimist compels me to give you guys the benefit of the doubt, at least for now. Clearly by publishing your paper and continuing your experiments you will be exposed to a lot of scrutiny by much more qualified individuals than myself. Until then it does not make sense to impose undue and IMO unproductive suspicion on actions imposed by the confines of a worldwide epidemic. A lot of rather renowned members of the scientific community seem to have bet their reputation on your work, which is very rare, especially in these politically charged times. So until I learn otherwise I keep my fingers crossed. As I already mentioned: none of us are getting any younger 😉
Fair enough. There is lot more still to be done before it can be of use to anyone.
I write it again. The experiment was finished long before the lockdown. And there was no rat kept alive so not any measure of lifespan. And there was no second experiment started what was possible long before the lockdown.
Why would we not want to conduct a lifespan study. I can assure you we are as keen. The number of rats we had in the first trial were all required fir certain assays like histopath and biochenical for it it to be meaningful. The costs were not just to purchase more rats or manufacture more Elixir, we would need to lock space at animal facility for long term and the same team members who we needed for the second trial would be needed to look after them. We could not hire more. We had practical limitations.
I don’t understand where the mice came from. I also doubt that I’m the only one more interested in healthspan than lifespan, and the measured parameters all relate to that. You’re not by any chance a researcher in this field? Sour grapes?
Didier we are a bootstrapped start up. When you have limited resources you have to decide one trial for 4 years or another trial to check the dosage. I am not asking you to remove your doubt. Please hold it till we complete a lifespan study. Hopefully now we may have the resources to do multiple trials simultaneously. May be one day we will earn your approval.
@Didier
Yours is a fair point but I can’t see them publishing something they can’t replicate again. What would they have to gain?
This is either the greatest medical discovery of all time or it’s a fraud. The results in the paper are too unequivocal to have any serious errors so that leaves fraud. Could Katcher’s Indian partners be using him as a pawn to get rich old investors to funnel money at them for a chance for an unofficial test of the Elixer? Maybe but Harold has tried it on himself with great results so that makes no sense. Harold would have to be in on a fraud. Why would a 75-year-old scientist risk his reputation and maybe his life (angry duped investors) on a fraud? Harold has been working on this for years so it would have to be a very slow-moving scam. Steve Horvath has an excellent reputation and he is the first cited author of the paper. I noticed Harold is last so Steve must trust the results. All we can do is wait for the study to be replicated and phase one testing to start.
Your wish came true!
A test of 8 treated with elixir / 8 untreated 24 month rats has already started. This test will be completed when all rats are dead (hopefully never). Within a year we will probably have an idea, as many rats normally die between 24-36 months.
Zisos by the way this lifespan study is happening because of Didier’s generous grant. So did not just criticize he also enabled ability to disprove him. Very rare to see that.
That’s wonderful news Akshay, and we should thank Didier, but weren’t lifespan trials already planned? I would have thought you had plenty of capital to fund trials now.
Not yet on the capital but improving everyday
I had received the investment deck a few months back but it was missing a lot of data related to valuation, the total number of shares issued, share price, dilution protections, etc. Maybe I missed something? FYI, I work in the financial field and have access to a large pool of potential retail investors. However unless the basic checkboxes are ticked I would not feel comfortable exposing this to anyone in my circle.
MIchael, I’ve been trying to line up significant financing from oil patch investors in Texas, but my lack of financial acumen (among other things) has slowed this down and it seems likely that any participation may have to begin at a lower level. Any suggestions regarding your group would be welcome.
Are you associated with Akshay and his group?
Akshay sent me Yuvan SAFE round investment information a few months ago, but I am not directly associated. I’ve followed Harold Katcher’s work for years and was excited to hear of Akshay’s support in Mumbai to get the research off the ground. The possibility of eliminating or a least slowing the chronic disease of aging has to be the most important development of our time.
Is there anything that ordinary enthusiasts like myself (“small” investors) can do to help? I suppose it might be more hassle than it’s worth, but I’m sure there are many of us who would jump at the chance to use Kickstarter to get a tiny piece of the action, or pre-order products. Just to be on the right side of history. ; – )
Again if an investor prospectus is available I would be interested in circulating it within my group. What I received a few months ago looked incomplete.
Nick thank you for the desire to support. In this round only accredited investors can invest. But its the thought that counts. We are getting such incredible support that we want to build a community of Yuvan. We can have an annual gathering where we can share latest updates, socialize and have fun. So save up for that trip to California:)
Akshay:
I did not realize that Didier was the one that financed the lifespan study. He proved with actions that his critisism was constructive. Sorry I did not realize that. Thank you.
@Didier
Akshay just mentioned that you actually financed the experiment that I was “informing you about”. I feel so stupid …. and so humbled. Please accept my sincere apologies. And a big thanks you for your generous action. It helps all of us.
You have probably heard the joke about the grandson that said to his grandfather: “Grandpa, let me show you your farm!”
Evaluation of umbilical cord serum therapy for persistent corneal epithelial defects
2003
They created eyedrops from umbilical cord blood plasma and treated eye conditions.
They did not remove the albumin though so it was probably too diluted to have a strong effect.
From Harold’s comment above I guess they remove albumin, as he referred to the Elixir as blue stuff, which is probably because of Blue Sepharose chromaography.
Also I found this company they are into umibilical cord blood based therapy
http://www.saneron-ccel.com/news.html
There has been a discussion in this blog about the most appropriate course of action, to ensure that the benefits that should be reaped by Harold and Akshay are properly protected. They definitely deserve the highest monetary rewards .
It is possible that stronger parties might deprive Akshay and Harold of some of the economic benefits they deserve. However, if the success in human trials proves to be similar to those with rats, the two will be written in History as the Greatest Benefactors of Humanity. I am trying to think of anyone that has managed to offer something to humans more valuable than an extra life. I can’t think of anyone. This great achievement can not be taken away from them.
I cross my fingers that they will be successful. Then their glory will be for ever and ever. In my opinion, this is worth much more than any monetary reward.
Kudos Harold and Akshay and so grateful to Josh for so generously sharing his wisdom and experience with this blog and this incredible news. If the details hold solid, I feel this is such a monumental leap forward. Finally the “programmed” theory of ageing may get the respect it deserves and change the overton window from spending so much needless time and expense toward research on cellular repair to discovering and manipulatiing an ageing clock; allowing the body to do what it already knows how to do to rejuvinate and maintain itself.
This paper is already garnering superlatives from the scientific community as evidenced by this article discussing reaction from David Sinclair.
Interesting Engineering: This Young Rat Plasma Just Reversed Aging 54% in Old Rats, Say Scientists.
https://interestingengineering.com/young-rat-plasma-successfully-reversed-aging-54-in-old-rats-say-scientists
Thank you Howard.
So the entrepreneur in me started thinking about what you had mentioned regarding the possibility of a transdermal patch. And I began to wonder if this approach should not command more of your attention over the short term.
Take me and my wife for example: We have been using Lifeline Skin care cream for almost ten years now with very favorable results. It contains peptides derived from pluripotent non-embryonic human stem cells, and shortly after starting to use it daily in my early 40s (i.e. a decade ago) we both observed rather pronounced changes in our appearance, e.g. disappearance of age spots, reduction in wrinkles, less sagging, more skin flexibility, etc.
Now this stuff is pretty expensive, a set used to sell for a little under $300 but the price has gradually been cut in half over the past decade. Not a cheap luxury, especially if one adds international shipping. Clearly during its time the company has earned hundreds of millions of Dollars selling this product, aided by the fact that regulations in the beauty industry are a LOT less stringent than they would be for medical treatments including human rejuvenation via injections.
So I pose the question if it would not make sense to focus at least a portion of your efforts and resources on distributing a beauty product that helps diminish signs of visual aging within a relatively short amount of time? You mentioned that Harold put some of your ‘elixir’ on his arm and I quote “all his aging spots from his arms disappeared in a week”.
I can honestly tell you that my lovely wife would literally kill for such a compound if it existed, plus more importantly: pay a pretty penny for it – and I’m embarrassed to say that I would probably too 😉
From a pure business perspective it would make a lot of sense to focus at least some attention on a market sector that is more than willing to pay top Dollar for a beauty product and in the process raise significant amount of capital for the more noble and long term aspects of your work, i.e. extending human lifespan.
Just to give you some numbers: The global facial care market size was valued at US $94.2 billion in 2018 – that is just for face creams alone. If you can demonstrate a topical product that reduces the signs of aging within a month’s time by even 10% you won’t be able to manufacture quickly enough.
Another side benefit would be the free media attention you would be able to enjoy. Assuming it is favorable it could help you explode on the market and quickly establish competitive fences that would make it more difficult for your competitors to take you down or at least stifle your progress/growth. There is a benefit in operating in the shadows during the development phase, but you will wake the ‘sleeping dogs’ at some stage. And you better be prepared and properly funded when that happens.
I know this is a science blog and I hope everyone can forgive my rather capitalistic outlook on this. However in my time I have seen too many promising projects fail due to a lack of funding and felt compelled to offer some pertinent perspectives. Akshay/Harold – we can continue this discussion via email if you are interested in exploring this topic further.
Michael we have two distinct products. Flagship is Elixir which will now move towards an FDA application. We have a separate product which is a very powerful anti aging molecule for which we are following the same strategy suggested by you. This gel is the one that removed the age spots for Harold. We were planning to have this available online by Christmas but now I am not sure exact timing but its iminent. If this gel is successful it will provide any additional funding required for getting Elixir to market.
Suffice it to say that I would be interested in participating in an early round of funding, either this or next year. I take it you already put me on the list 😉
Hi Akshay
People on this site who don’t know you underestimate what a very successful and accomplished entrepreneur you are in your own right. I have no doubts that you’ll have great success marketing your product. It’s smart to start with creams and gels. The FDA has restrictions on claims that are made regarding natural supplements when those supplements are ingested , but they are much more “ forgiving “ when it comes to gels.
I also know that you’re the master of natural supplements and you and I have discussed various ones in the past. I’ll be curious to see what, if any role these will play in your future plans.
Thank you Paul. I admire your research. Very few practising doctors research so deeply. Benefit goes to thoussnds of patients that come to ypur clinics. Yes we are keen to get the benefits of the gel available as soon as things go back to normal. I guess normalcy may require a vaccine for Covid-19?
As the old saying goes: Hope dies last 😉 Not to be pessimistic but I personally don’t believe there will be a COVID-19 vaccine anytime soon. Last time I checked we didn’t have any vaccines for the common cold, herpes, measles, HIV, etc. How many top scientists have been conducting research in that area for how many years now?
Unlike me (I’m just an engineer turned entrepreneur) most participants on this blog are scientists and perhaps I’m wrong but the odds of finding a vaccine for a highly infectious RNA virus with a high mutation rate do not seem to be very good – are they?
I’m pretty certain that there will be several waves of COVID-19 until widespread herd immunity takes hold. Politicians are merely covering their sixes, especially here in Spain where I currently reside. It’s been a royal mess after incumbents missed every single opportunity to address the problem ahead of time in January and February.
However at some point economic and public pressure will increasingly begin to outweigh political damage control and nations will be forced to open up again, at least to a certain extent. It’s either that or we are facing an economic depression not seen for over a century.
We may experience another series of lockdowns or semi-lockdowns in late 2020, 2021, and 2022, and of course in the interim it’s a somewhat chaotic situation. It would certainly not hurt to start looking for private facilities when things start open up again this summer 😉
Agreed. There will be no effective vaccine. It will be like a seasonal flu, with a less hysterical reaction ( hopefully) with each iteration.
Everyone seems convinced that we’ll have a significant recurrence in the fall, but isn’t it fall in Australia? I’m not aware of a resurgence there. Is anyone?
It looks like the Oxford vaccine only gave partial protection to monkeys. It failed to significantly clear the virus.
Well this appears to be all but over in Europe and the US, but southern hemisphere countries may have more to come in 2020..
I was referring to the period when Corona viruses are generally active in Europe, approx Jan-April. Presumable this one will do the same.
Moderna just claims their vaccine produced antibodies in the first 8 test subjects.
https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-positive-interim-phase-1-data-its-mrna-vaccine
And this is just one of the 8 clinical trials running worldwide. I believe we have a good chance for a vaccine by early 2021. Until then its everyone’s guess what happens.
Response from Josh:
It’s easy to promote an antibody response. You could do that by infecting people with COVID. The hard thing is to promote an antibody response without killing more people than you save. That’s where vaccines for Coronaviruses have failed in the past. They have easily been able to induce immunity in rabbits, but more rabbits died of the vaccine than were saved from fatality in future infections. – JJM
Well, according to this paper, SARS -Cov1 vaccines were far from hopeles
“Only a small number of SARS-CoV-1 vaccines made it to
phase I clinical trials before funding dried up because of eradication of the virus from the human population through non-pharmaceutical interventions when case numbers were still small. Results from these trials, performed with an inactivated virus
vaccine and a spike-based DNA vaccine, are encouraging
because the vaccines were safe and induced neutralizing antibody titers (Lin et al., 2007; Martin et al., 2008).”
https://www.cell.com/immunity/pdf/S1074-7613(20)30120-5.pdf
Thanks, Gabor!
The mRNA vaccine approach by Moderna is very clever and they seem to be neck and neck with the Oxford group in getting a vaccine to market in record time. UK announced that they could have millions of doses of vaccines ready by September , which would of course be record time. I am concerned though that the Oxford vaccine in monkeys did poorly in actually reducing viral load and gave a pretty low level of antibodies. And then there’s the tried and true method of dead whole viruses which totally eliminated viral load in monkeys and gave a robust antibody response. This race will be interesting and I think that this year is very possible.
It’s puzzling to me why the company line now is that we don’t know if antibodies actually confer immunity. We’re all seriously screwed if they somehow don’t.
Sounds great Akshay! I’m sure many (if not most) of us following this blog would love to support the cause, in some way, if given the opportunity, by either participating in trials, funding or just purchasing of product when these opportunities become available. I hope, if you and Harold deem appropriate, we’ll be hearing more about your company’s products and needs in the near future. 🙂
Absolutely Howard. Working hard towards that.
I agree with Howard that most will be interested. Including myself. So I also look forward to participating in any way, should the possibility arise.
You have a lot of people who wish to be part of a trial. Sounds great. Want to do it also. I will be happy to pay to defray your expenses and provide a donation to the cause. Maybe I can become a practicing scientist again. Or some other second career. Civilization is more than just experience. It must be contributed to as well.
Thank you to everyone showing interest to participate in the trial and help us. I am taking notes and will take Josh’s help closer to the trial to contact you.
Please add me and my wife to that list as well. I also have leads to private funding sources as I work in the financial arena. Not that you’ll have a hard time finding willing investors if things pan out as planned.
Please add me to the list of people interested in funding. I‘d like to help too if I can.
I have been following the subject of extending the health span for decades and have greatly enjoyed reading the positive support and energy surrounding Josh’s announcement and the research results. It may be that a fit 79 year old will be outside of the protocols for the human trials. But if not, I will be most interested. Either way, I look forward to learning of the outcomes.
Profound thanks to people like Harold, Akshay and Josh who have imagined what might lie over the crest of the hill.
These guys did something similar
Therapeutic Potential of Plasma Proteins Derived from Umbilical Cord Blood for Acute Liver Failure
2019
The survival rate in the UCBP-treated group was found to be increased compared to the control group (85 vs 55%, P = 0.029). UCBP treatment significantly decreased apoptosis and increased cell proliferation. These effects may be secondary to specific bioactive molecules in UCBP. In vitro experiments revealed that adiponectin is one of the key biologically active components of UCBP in facilitating this result and promoting hepatocyte proliferation. Furthermore, this effect is mediated by p38/ERK mitogen-activated protein kinase (MAPK) signaling pathways.
Adiponectin. Its been known for 25 years. Whatever I read about it is hugely positive, yet no therapies?
I believe that was some of the drive behind the development of the glitazones, but they had side effects.
i dont understand why no company is developing a recombinant adiponectin therapy. it has a very favourable effect on metabolic syndrome and it wouldnt be the first human hormone therapy. you can actually buy human adiiponectin 25ug for $350 for research purposes.
All these plasma fraction experiments could have been done 50 years ago. Really frustrating how the world fell for wear and tear.
Totally agree. We’ve been on the wrong track for a long while. But it’s not unique to the science of aging. Much of science as currently held to be true and above question is anything but.
Actually, one of Lenin’s cronies was doing parabiosis experiments on himself using blood he got from… kulaks… it reportedly worked well too until he killed himself from either malaria or blood-trpe mismatch depending on which story you hear.
Your presentation is factually in error, and reflects a blinding bias. Oddly, similar dismissive terms are not used when discussing the Stanford elite and capitalist titans hoping to exploit financially strapped students.
In fact, Alexander Bogdanov was an eminent polymath in the early Soviet Union who headed an official institute for blood transfusion research. Ahead of his time, he recognized that blood transfusions have great potential, and was aiming to spread the benefit throughout society. His actual transfusions did not begin until 1926, long after Lenin died of complications related to an assassin’s bullet, and long before the Moscow Trials and the associated mass murder at the hands of Yeshov.
Hopefully, this will mean an end for the “antioxidant” industry worth billions of dollars in annual sales.
@Akshay, are there any preliminary data on the gel’s ability to break up crosslinked proteins (due to glycation) in the ECM? A lot of skincare products can reduce age spots, but I know of none, which can break up crosslinked proteins.
Ole something for us to investigate.
@Ole “Hopefully, this will mean an end for the “antioxidant” industry worth billions of dollars in annual sales.”
LOL – guilty as charged. That was me a decade or so ago. I must have spent thousands of Dollars on dozens of completely useless compounds laden with empty fillers like microcrystalline cellulose.
Hi Akshay and Harold,
I wish to be part of the trial if possible? Also following this blog for years now.
I’m happy to make a donation or help in the best way I can.
Cheers from the Netherlands
I assume the first trial will be a small scale screening for safety, followed (hopefully) by larger trials to determine dosage and efficacy. I would be interested in participating at either stage. I am located on the west coast of Canada.
The Horvath clock shows that humans age at a slow constant rate to age 36, a faster constant rate to 60, even faster rate to 78, then even faster. Do the blood signal molecules suddenly change at these ages? These time spans drop by 1/3: 36, 24, 18, …
Could this be a clue to the age ing clock?
Also, the gut microbiome changes “profoundly “ around age 36.
Hi Akshay and Harold! Congratulation for your amazing results! I don’t know what compliment I could say that haven’t been already said here. When I sent you an email, Ashkay, few weeks ago, to have some news from your experiment, I didn’t expect to see results that soon (I know research take a very long time).
By the way, something is not clear form me: in the first test, you didn’t use a young rats’ plasma but a mix of plant extracts presumed to have a similar effect. Did you use the same formula this time or did you use the real rat’s plasma? Because injections of plasma seem to me hardly scalable if we want to treat a large number of people.
Anyway, I look forward to testing your patch/gel in 2021 if possible, and also the so-called Elixir. But as I live in France and am “only” 45, I may be not allowed to apply.
Thank you Patricio. Yes 45 would be too young for proposed trial. We would like to see significant reversal. But let us see what protocol is designed by Harold. We have had 3 major trials: First one on 10 natural extracts. Each one selected to upregulate a key known repair system whose efficiency goes down with aging. We have had very encouraging results with that but it wont quantify as systemic compared with Elixir. We followed this with 2 trials of Elixir: single dose 30 days and repeat dose 155 days. You have the result of that. Although I cant disclose about ElixirI will say this: Harold came up with brilliant work due to which hopefully we wont have scaling issues and prices will remain reasonable.
So let’s assume that this treatment works as advertised and we can roll back the epigenetic odometer.
I’m assuming that’s still going to leave a host of systems that have been degraded that will need remediation. For instance, the buildup of AGEs. Atherosclerotic plaques, etc. etc.
Unless we believe that the body has mechanisms for addressing these issues at an younger age that simply break down as we get older.
Is there any reason to think this is the case? I might see it for atherosclerosis. I think I’d be pretty surprised if there is a built in mechanism to break up AGEs that we lose as we get older, since AGEs probably aren’t much of a burden on us when we are young. Unless AGE accumulation is a real problem in our younger selves, it’s hard to see how there would be any selection pressure to have evolved a way to break them up.
It seems that the paradigm of accumulated damage as the fundamental mechanism for aging is almost certainly wrong, but it is true that we *do* accumulate damage as we get older. How much of this is due to the breakdown of repair mechanisms and how much is real damage that the body has no inherent ability to fix?
Hi Michael, All good points. On the one hand reversing aging markers should up regulate the ability of the body to repair damage, on the other hand some type of damage may be irreversible. There is the additional complication that the elixir doesn’t seem to rejuvenate all tissue equally. I think the answer to many these questions will all need to come empirically.
What is true of the body like any complex system: Once you remove one bottleneck (in this case to longevity) another one that wasn’t immediately apparent will appear.
I wouldn’t say some damage is “irreversible” as I think in theory almost anything is reversible given enough technology. But, surely there are types of damage that simply accumulate at such a slow rate they never limited reproductive success given the built in time limit imposed by the epigenetic clock, so there was never any selective pressure to develop a mechanism to repair these sort of damage. Accumulation of AGEs is the one that came to mind. I’ve never seen any evidence that even young organisms have any ability to break up AGEs, which isn’t any wonder if the epigenetic clock is likely to reach a terminal count before they come into play. But there is no doubt that young organisms have a myriad of abilities to repair a number of insults which are turned off as the clock counts down.
It would seem that in vivo partial reprogramming experiments could point to answers to your questions about damage repair. If fibrosis and scarring can be reduced…
https://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/stem.2842
Further, perhaps damage is not as age-limiting as might be expected. I seem to remember a recent article that indicated AGEs had no effect on lifespan. I admit that I cannot offer an explanation as to how lisosomes bursting with materials that cannot be broken down could somehow be rejuvenated, but neither can I explain what happens to old eggs at conception. Perhaps the bad stuff and defective organelles can simply be expelled?
Anyway, I am enjoying your discussion, so thanks.
” I admit that I cannot offer an explanation as to how lisosomes bursting with materials that cannot be broken down could somehow be rejuvenated, ”
Very simply, the material is exported out of the cell, and the lymphatic system moves it to an excretion point.
It is likely that these accumulations are similar to the tangle accumulations that occur in the brain with alzheimers when the glymphatic system fails. The lymphatic system fails with age, and cells have trouble being able to export molecular garbage out of the body.
“The accumulation of lipofuscin-like material may be the result of an imbalance between formation and disposal mechanisms: Such accumulation can be induced in rats by administering a protease inhibitor (leupeptin); after a period of three months, the levels of the lipofuscin-like material return to normal, indicating the action of a significant disposal mechanism.”-wikipedia
Even if this wasn’t lipofuscin it is conceivable a mechanism exists that disposes of molecular garbage. In society we do not recycle inside our homes, we send garbage away in trucks to be dealt with elsewhere. The body may have a similar solution, especially for things that can’t be processed.
It is already known that the brain is one of the highest metabolism organs, and there are superagers with seemingly extremely well preserved brains. It is also known the glymphatic system serves to remove damage. And thus when properly working one of the highest metabolism organs can keep working easily for over a century, as it starts to fail so does garbage accumulation become a problem.
Exactly right. Everyone is always talking about cells’ garbage disposal systems forgetting about the body’s disposal system – the two work together. The body is, in a way, a big cell. And its not a closed system.
One of the damages that might be in the “irreversible” category is osteoarthritic damage (cartilage wear & tear), and tendon damage. I wonder if the effect of the elixir on cartilage and tendon damage can be measured in future mouse or human trials.
If damage on cartilage and tendon are not reversed, but muscle becomes young again, there is very big potential of damage to both cartilage and tendons. The rejuvenated subject will easily exert much force, but tendons and cartilage will not handle that force. I have heard of many such accidents do happen to older people that do heavy weight training. It would be interesting to know Harold’s and Akshay’s thinking on that.
I think it is already known that the same signalling (resulting from the inflammation caused by muscle fiber damage during exercise) triggers the repair of both the muscle fibers and immediately adjacent connective tissue, provided the connective tissue comes in contact with the signalling chemicals. I am a layman, so please take this opinion with a grain of salt (and maybe a dram of Elixer).
Jim you are probably right. As the inflammation resolves it could lead to rejuvenation. Anyway its something we have to test in the next trial.
It will be very nice if the elixir rejuvenates cartilage. A lot of people suffer from osteoarthritis in old age. I am one of them. From what I have read, cartilage’s ability to repair itself is severely limited because it does not contain blood vessels. Would injection be an alternative delivery method?
I believe that a lot of that damage is due to fibrosis which can be mitigated and sometimes reversed by taking Wobenzym. I personally prefer Optizym which is a competing German product that still uses the old formula: Pancreatin, Papain, Bromelain, Trypsin, Chymotrypsin, and Rutoside trihydrate. Alternatively you can use Wobenzyn N which is harder to find but still has the old formula.
Yes, Michael, the idea that the body would be holding back and refusing to repair damage that it’s capable of repairing — this is surprising indeed. From the standpoint of the traditional (selfish gene) version of evolution, it would be ruled out.
On the other hand, this point exactly has been the center of my career in aging. I’ve written two books demonstrating that, yes indeed, the body is holding back its ability to repair damage as we get older. I’d be grateful if you would read it and then tell me if you’re still skeptical of the thesis.
As a teaser, I would challenge you with this: We know that the body does a much better job of repairing damage, neutralizing free radicals, and maintaining chemical homeostasis when it is starving. Conversely, this is evidence that when the body is fully fed it doesn’t want to do all the repair and maintenance of which it is capable.
This is exactly the story that launched me into the study of aging 24 years ago.
Once we roll back the epigenetic clock, I think it will be interesting to see what damaged systems the body starts to repair (because it had an inherent ability to do so that was turned off as it aged) and what damaged systems do not get repaired (because the ability to make such repairs was never developed because it never limited an organism’s reproductive fitness). We’ll like to believe that everything falls into the former category and none in the latter, but it seems unlikely we should be so lucky. None the less, rolling back the epigenetic clock should be a *huge* advantage at increasing healthspan and lifespan, hopefully giving us a window to figure out how to repair those nagging issues that won’t repair themselves.
On your teaser, I’m going to guess that the reason these repair mechanisms get turned back on during times of famine and turned off turning times of plenty is that when times are lean, it isn’t a very good time to reproduce and in fact most organisms aren’t very successful at reproducing and in many cases reproduction may be turned completely off by the female of the species. It seems as though evolution is declaring a “time out” when these sort of external factors intrude and things are refocused on simply biding time/treading water until food once again becomes plentiful, at which point it’s “game on” and aging again runs at a normal pace, since aging is beneficial to the entire species, but not the individual organism. Or I could be completely wrong about that. 😉
There are serious problems with CR in the wild.
-The most widely accepted theory is that this effect evolved to improve survival during times of famine. “But we think that lifespan extension from dietary restriction is more likely to be a laboratory artefact,”
says Dr Adler.
-Lifespan extension is unlikely to occur in the wild, because dietary restriction compromises the immune system’s ability to fight off disease and reduces the muscle strength necessary to flee a predator.-link http://www.sciencedaily.com/releases/2014/03/140317084742.htm
I would also add that since the calorie restriction is done with dense nutrient enriched optimal nutrition, this is unlikely to occur in the wild. Without optimal nutrition calorie restriction is said to fail to extend life, small amounts of nonenriched foodsource as found in the wild is in my opinion unlikely to provide optimal nutrition required for extension. edit: especially at levels that cr can work in some animals like 60+%, at 60% deprivation not only would the nutrient density likely be insufficient, but in an environment lacking resources the small amount of calories would be insufficient for sufficient exploration, cr appears to work and extend life even in calorie amounts beyond what would be sustainable in the wild.
Another problem is that famines can be quite sudden, but I seem to recall that sudden transition to CR in adulthood, without a gradual transition, might actually reduce lifespan. Could be that viewing food is suddenly scarce, the body decides it is best to shorten lifespan to make way for the next generation.
Assuming the epigenetic re-programming is 100% successful how would it effect brain/cns cells? I mean they don’t normally divide much after puberty or so anyway; so what happens to them? Would we end up with “young” appearing bodies skin/muscles/even organs etc. but ageing brains? Someone who looks 30 give or take but has the Alzheimer/dementia of a 95 yr old?
The biggest problem with the brain is probably the dividing cells aging.
Neurons can last for over twice the lifespan of a species, potentially centuries or indefinitely.
The Alzheimer likely develops due to age related failure of the glymphatic system that exports molecular garbage. A rejuvenated garbage removal system might allow the brain to operate youthfully for centuries. Look into superagers which seem to have a more youthful glymphatic system into later ages and appear to have youthful memory and mental acumen.
That said the brain can withstand massive cell loss and still function, but it needs spare capacity from education and learning to withstand it. There are people who’ve had severe alzheimers brain pathology and died asymptomatic. Due to higher amounts of education and study giving them spare capacity.
Eventually it is likely gradual cell loss might noticeably compromise brain function, but by then we will likely have developed the means of regenerating the brain.
Another contributing factor is that the blood brain barrier degrades as we age and becomes “leaky”. Presumably restoring various repair systems through epigenetic reprogramming would do something positive about that.
I wonder if it would be possible to use the epigenetic re-programming to regress selectively the brain/cns to roughly puberty or even before? Maybe regress it more than the rest of the body. In effect “trick” the brain/cns into thinking it still growing, maybe inducing neuron growth to replace damaged/old/ or senescent (if that’s the right word) nerve cells?
It was my understanding that neurogenesis continues throughout our adult life. I recall studies for example that indicated that the generation of new neurons in the hippocampus is necessary to prevent psychiatric illnesses such as depression.
I think neurogenesis continues in hippocampus, and probably olfactory bulb. But the rest of the brain has fixed number of neurons.
I don’t understand your concern. Even if brain cells don’t divide (and indeed, they don’t do it very much) the reprograming should restaur their functions as young cells and the brain should be rejuvenated too.
It remains the problem of previously lost brain cells. Will the brain regrow? Only further experiment could answer this question.
Well the concern is that even with a “reprogrammed” newly “young” brain the patient would have to contend with cell loss over time. Both before and after the reprogramming. Unlike other somatic cells brain/cns cells don’t divide much after puberty. I was suggesting that the brain/cns could conceivably be reprogrammed to a younger perhaps even pre-puberty state to facilitate new cell growth. I thought one of the issue with the epigenetic re-programming anyway is that the bodies’ tissue/cells etc. age unevenly over the entire body necessitating different treatments for each type.
“Eventually it is likely gradual cell loss might noticeably compromise brain function, but by then we will likely have developed the means of regenerating the brain”
Hopefully; or maybe Elon Musk’s “neuralink” if it works out.
Hi Tim, I think the work on bio-electricity and emergent morphology that Michael Levin and his lab at Tufts U. are doing hold the key to understanding this kind of questions.
Where does morphology come from? why do cells behave the way the do?
I have harped a few times on this on the comments of this blog, but I believe that likening a body to a machine is very misguided. And along with it cybernetic-like approaches to health questions. A body is a collection of clonal cells cooperating and communicating with each other. Sure, a single cell may be a bit more similar to one of our machines, although a self replicating and self repairing one at that. But a multi-cell organism is a different paradigm.
I think we are too tempted to apply the machinist and industrial point of view to biology, as it has been so successful at other endeavors, but cells, life, just doesn’t behave quite like that beyond biochemical processes.
“Katcher and his partner Akshay Sanghvi have put together a company to organize human trials by the end of the year. (Nugenics Research of Mumbai does not yet have a web site.) I’ve asked them if I could be patient #10.”
Any word yet Josh on whether you will get to be “patient #10”? Good luck to you if you do!
Get in line, guys!! 😉
Our collective rush to get in line for the trials is most understandable, given the nature of the topic. But I bet that each of us is already practicing some of the many lifestyle and pharmaceutical approaches to life/health extension. Some may be working on Greg Fahy’s concoction, some on the various SIRT/MTOR approaches. Some may be more concerned with resisting sarcopenia and some maybe fasting. I think if I were one of the test designers I’d be looking for a group of more ordinary individuals. Perhaps a special group of heterogeneous enthusiasts could be create that could be informative, but not easily transferable to the general population.
You make a good point Arejay but hopefully the results could be so transformative that a little bit of slowing the clock wont matter. We would definitely want to give preference to our supporters where possible.
In fact if this succeeds in humans Harold and I would probably like to hunt for the kind hearted volunteers who devote their life to service for very little as a priority list way before the billionaires. Next probably the genuine environmentalists devoted to protect the planet. Then the brilliant minds, the living geniuses so that they can continue to contribute. We may have an opportunity to change the ratio of the type of fellow citizens we want to stay around for long. But this is getting ahead of ourselves.
I am a little bit concerned by your message. If the treatment is scalable, as you seem to mean, I don’t see the point of any selection. If it is not the case, then it is a very complex ethical question, and I think it would have to be the object of a great and public debate.
Patricio, you must be in a dream where maximum public good is the top priority. If it were so, the inventors wouldn’t be sweating the rigged patent system – just as a small illustration of antisocial reality. Capital doesn’t care, except in the rare case when its owner cares. Frankly, I am concerned about the entire enterprise because global “big pharma” has so much to lose if this product succeeds, and inherently does not care about a few injustices to secure it. So where are they?
Walter, I am not in any dream. I live in France where Big Pharma are strong and make many profits. Yet all treatments are given to people who need it, if it is necessary, no matter his wealth (or his diploma, his political opinion, his religion etc.) thanks to our public health insurance and healthcare system. I don’t say the system is perfect, but it works quite well.
If a treatment shows a dramatic effect on the health span (as it seems to be with this one, but let’s wait for confirmation), of course it will have heavy consequences on big pharma, but the global effect will be positive and no opposition will be strong enough to stop its use.
But if the treatment has a dramatic effect on lifespan as we hope (but there is no proof of it yet), the implications could be so huge at many levels, that the opposition will be very very strong from many sides and big pharma’s opposition will be the least of all.
Well that puts me on top of the list. I’m as ordinary as it comes – no scientific background here and I’m in my mid 50s.
Is the raw methylation data from the study available? Usually raw data is submitted to some public database during the publication of a new study.
GaborB the raw data was shared with our collaborators and now will be shared with the peers referred to by the journal. Some journals do not encourage full dissemination pre publication. So post publication can share it in public.
Thanks! Looking forward to it! So the peer review already started? Did you get any questions from the reviewers yet?
May I ask which journal did you submit to?
Its in the process. We expect to be grilled.
In the first round of experiments, they didn’t do plasma exchange. They used combination of known herbal supplements Did they do plasma exchange this time?
From previous post on your blog
—
“Try as we might, we could not perform plasma exchange in rats. Time was growing short (I was on a two-month visa) so what to do? I made the decision to completely change my approach: yes I believed HPE would work, but I decided to leap ahead, to see if we could make the process of HPE into a marketable product.
Our first pass was to try a combination of known herbal supplements that are known to bind with the targets we’d identified. We gave them to rats.”
Chris we have three products developed: natural extracts mix, young plasma fractions: Elixir and powerful anti aging molecule: gel and transdermal patch. We have completed pre-clinical trials in all three.
That’s quick! Thank you so much for your contribution to medical science. I’m a healthy 59 your old so I’ll let those in greater need to get in any studies but if you do need a healthy middle aged cohort I’ll be happy to join and pay travel expenses. Cheers!
The graphs of the time course of the results remind me of a question I have never resolved for other situations of rodent vs. human: how long would the same improvements take in humans?
Do you only have the one human example who has tried it? What indications of time to achieve results and the durability of the results can you potentially infer from that?
How is Alahest’s plasma fraction different from Harold’s? It seems they are having similar results from their fractions. If the fractions overlap I see patent problems. This is from their May 28, 2020 presentation. https://www.youtube.com/watch?v=LooCV2HvSPM&t=633s
According to ALZFORUM.ORG, GRF6019 is composed of about 400 proteins. The difference from Elixir might very well be like the difference between a shotgun and a rifle. If there is a more specific description in Alkahest’s patent applications, my old brain couldn’t decipher it.
It is interesting to see that different teams are testing similar treatments. I didn’t seen many details in the results of the Alkahest test shown in the video and there is no comparison with young people. Actually, they are focused on AD, not aging itself.
However if their treatment had had a notable rejuvenating effect, they would have mentioned it. They mentioned an improvement of the vision, which is good, but quite limited.
It would be interesting to see the differences between the two treatments: maybe the factions are different, or it is the dosage. Or maybe we are just not rats…
I think there’s a significant difference between the shotgun and the rifle. Alkahest is taking a broad sample of proteins in the blood of young people because they don’t know which are most important. Katcher claims to know which one(s) are more important. He hasn’t revealed the formula or filed a patent claim yet, so we can’t know if he will be vindicated. But if what he says turns out to be true, then we’ll have an understanding and an economy of manufacture that Alkahest can’t offer.
Thank you Josh. We are quite excited by the potential potency and economy of our therapeutic for reversal of aging but Alkahest is run by really smart people, they have already raised $50 million and have quietly made multiple products reach Phase II with FDA. They are doing all the right things for commercializing their technologies. Their focus seems to be on individual diseases of aging especially neurodegenerative diseases rather than aging itself which may be driven by FDA. I admire how well they seem to have progressed.
Grifols, which is a Spain based pharma company has a large, probably commanding majority in Alkahest (45%). They are also market leaders in blood plasma technology. So I guess their interest lies in blood plasma products either of extracting fractions from young individuals or removing bad proteins from old ones.
They are probably not that interested in rejuvenation technology because that would be implausible with their technology, too many young donors would be needed to provide all the plasma. However on the long run they might be interested in the recombinant protein therapy technology but for this they need to enter into a partnership with a company that has the recombinant know-how.
We, however are more interested in a treatment that consists of a few important proteins and they better be recombinant so that the treatment becomes affordable.
So one way forward would be for you to team up with a biotech company which has expertise in recombinant human protein technology.
As usual very well surmised GaborB. Fortunately Harold brilliantly came up with a patentable technology that will allow us to mass produce at reasonable costs. We wont need to tie up with anyone. Only the origins of our therapies are similar but Alkahest and our product developmrnt approach is different. It is commendable how rapidly they have reached Phase II with FDA. The Genentech background of key team members has probably contributed to their good progress.
Thanks for the article. I would appreciate your comments on aging and the decline in nicotinamide adenine dinucleotide (NAD). I have been supplementing with nicotinamide riboside (NR) supported by studies NR increases NAD levels in senior age individuals. I have not found studies indicating there is an increase in the NAD entering into the mitochondria Krebs cycle for electron transfer to the electron transport chain. The result would be a favorable impact on adenosine triphosphate (ATP) production.
This was released today by Alkahest. More akin to what the Conboy’s are doing:
“Alkahest’s preclinical research has demonstrated that Beta-2 microglobulin, which is present at higher levels in older individuals, is drastically elevated in patients undergoing dialysis and may contribute to the high prevalence of cognitive impairment in these individuals. By reducing the amount of B2M in the plasma, we hope to introduce an effective way to lessen this impairment and allow patients on hemodialysis for ESRD to achieve improved treatment outcomes and quality of life [2].”
https://www.longevity.technology/alkahest-annonuce-phase-2-study-treatment-of-cognitive-impairment/
“The device, called AKST1210, is connected in series extracorporeally with a standard haemodialysis circuit. AKST1210 removes a protein called Beta-2 microglobulin (B2M) from the blood; B2M is a harmful inflammatory immune-associated protein that has been demonstrated to impair cognition in animals. It is thought that it may contribute to cognitive decline and other conditions in patients undergoing haemodialysis for end stage renal disease (ESRD)”.
Seems like there is a largely ignored treasure trove in blood plasma thats been largely overlooked by the medical community. Both removing bad proteins and enriching good ones.
I wonder why it took so long to seriously start experimenting with rare blood proteins. I guess the technology has been available for at least 30 years now.
I think it is time to get a collaborating team of MDs together and do some case studies on this. What do you think? I know a few you could possibly reach out to! They tend to push the envelope on mainstream medical views on their own.
The FDA has approved the route so to speak on that! Just gotta do it!
My wife and I are in our sixties, I’m 63, my wife is 60.
We would happily join any human trial you want to conduct.
We live in Australia but would gladly travel.
If you decide to go with treatment clinic’s in non FDA countries please pick warm and tropical so we can get the treatment and a great holiday
Mike
I’m a lot less fussy and would happily travel to the Arctic circle if it meant even just a few years worth of rejuvenation 😉
Might this be able to reverse other epigenetic damage besides things associated with aging?
We would have completed our old dog and marmoset studies but due to the pandemic we are delayed. We are using the time to complete our IP filings worldwide. We will update you as soon as we can launch our trials.
I would appreciate being able to view the pictures and being on any list of potential investors or trial participants
The study showed that old treated mice when injected with the elixir, become young again, as measured by Horvath’s clock, and as indicated by blood parameters.
I wonder if the opposite is true. Here is what I mean.
I am aware of a person 70 years old for whom aging.ai predicted his age to be 35. Would that mean that this person would have in his blood the substances of the elixir?
To my knowledge, there are no proteins in young blood that aren’t also present in old blood – just different concentrations. BTW, my aging.io age is 44. I’m 79, and I feel like I’m 79, so…
An Update:
Our Mumbai Lab has finally restarted and is moving fast. Our first trial next week would be to test lyophilized Elixir. Next trial will test double dose, female fertility and more which should launch in November. In this trial we will also be taking photos, videos and conduct third party medical test to confirm same old rat has become young. We will also prolong it for lifespan study. Our 2 year Dog trial work has restarted. We hope to launch in first Qtr 2021. We are working with attorneys, ranked in the top 10 in 2019 for biotech patents issued, from many months. It has taken this long as it is our foundational IP. We are in final stage, claims are shaping well. We should be able to file within a few weeks. So that will be a big relief. Our gel and patch both are moving as planned. Vendors have been identified and final product development work is being done. Followed by regulatory filings. Our marketing partner wants us to launch in Feb/Mar 2021 on Amazon USA. We are planning a human trial for gel and patch before launch for aging spots and wrinkles. We will share the results here with Josh. One of our supporters and investor who has background in biotech is leading the vendor development and management, QC, packaging shipping, etc. We have incorporated our USA co called Yuvan Research Inc. HQ in California. We have launched our SAFE funding round for early supporters to fund our preIND and IND work with FDA for Elixir. Many of you had shown interest to participate so you can reach me at: atomicblissventures at gmail dot com
Fantastic! I’m saving up from my Social Security to become a customer! Keep up the good work!
Thank you Wayne!
Thanks for the update Akshay. To participate in the trials one has to live in India or US?
Hi Ashkay:
Thank you for the update.
Best wishes going forward on all counts.
Many thanks Heather.
That is excellent news, Ashkay! Keep up the good work.
Thank you Michael. March April next year we are also getting ready to launch our first products: blue gel and transdermal patch. Currently technical work with vendors, regulatory lawyer and marketing team have been underway. We are also planning a human trial in Bay Area California which will be published in a peer-reviewed journal so if any of you are in BayArea you, your spouse and friends/relatives 55 years to 85 years of age are welcome to participate.
When will the clinical trial start and for how long is it scheduled?
We are in talks with dermatology institutes so can’t yet predict exact dates but hopefully by January.
I’m about to turn 55 (crikey – where did time go?) but don’t live in the U.S. – currently in Spain. I may have traveled there to participate but given COVID-19 restrictions that’s probably not a possibility.
Michael this one for our blue gel which is for age spots and wrinkles. You are probably on the younger side for both so you can skip this one. I have you on my list for Elixir Phase I
How about wrinkles and sagging skin? I’ve got a ton of that! 😉
Michael mantenerse estable for a few months. But to properly wish them adios you may also wish to try the patch. You must share with me before and after photos. I am wishing you baby smooth skin 😁
I would send you before and after photos if I get a chance to self-test the blue gel and patch!!!
Noted.
Same here – I am happy to send you some. I also suggest you come up with instructions on how to take them. Passport photo rules are a good guide. Lighting should also be comparable, so it’s crucial the photo is taken in the same place if possible.
If you recall from my email – I looked at least 10-15 years younger a year ago. But then I got sick and saw myself age about that much in less than a year, especially around the eyes. Very frustrating as I had always taken very good care of myself. So if I can just could get half of that back I would be elated.
Lets aim for full back to youthful skin
Shoot for the sky but keep your expectations low. That’s usually a good policy to live by.
You propose a good policy but sometimes on rare occasions you want to take the risk and want high expectations from your customer family 😛
Great news! Thank you for this update. I’m to young now to apply for the test (anyway I live in France), but I will look with attention any new results from your lab.
Thank you Patricio. We will always cherish the support that has been given to us by friends like you.
This one of the few times I regret living in Australia, we cant currently travel to other countries and just have to sit back and watch. Good luck with your trial, I hope its a raging success.
Mike
Thank you, Akshay for giving us the opportunity to invest in Yuvan Research. As a result, a member of my family was happy to participate. Best wishes for successful experiments and a profitable business!
Zisos, the gratitude is ours to you and your exceptionally gifted ivy league educated and successful family. It is support from investors like you that will hopefully benefit billions suffering from age related diseases and change humanity forever. In the future we should go to musuems to see how old humans used to look. If a tree, a fellow brethren of Nature, can live in full bloom of youth for 1,000 years why cant we?
Maybe they can use me in a special exhibit 😉
J/K. It’s difficult to feel hopeful in a year like 2020 but maybe there’s light at the end of the tunnel. Thanks again for everything and keep up the good work, Akshay.
here, here, Akshay – I’ve never been much a fan of being older for longer – only rejuvenation will do!
Have you had the chance to read Tony Wyss-Coray’s latest work on the effects of parabiosis on single cell gene expression? It is just out in pre-print:
‘Molecular hallmarks of heterochronic parabiosis at single cell resolution’
https://www.biorxiv.org/content/10.1101/2020.11.06.367078v1
Thank you Mark: a very interesting paper. I have always admired the research of Wyss-Coray. Kind of explains to some extent why we see such a comprehensive systemic reversal of age with Elixir. Multi-tissue/organ RNA seq with single cell tracking of changes is his new toy and he and his team are very gratifying results 🙂 Even his last paper he had used this design to track changes caused by aging. Although the basis of Alkahest and us is the same we use a different approach, strategy and technology to get much more significant results than them.
Could someone maybe dumb it down for the non-bio-med-engineers (i.e. me) in this thread? Thanks in advance.
Josh, Mark or Harold can do that very well
I’m only halfway through the paper, but I was struck by a statement that substances in young blood were responsible for improvement in mitochondrial function and substances in old blood had little to do with its decline. This would seem to argue against the Conboy assertion that substances in old blood are responsible for aging and must be removed.
I and others have argued that substances in old blood do not necessarily have to be removed as they will degrade naturally if new pathway stimulations counter their production. This paper seems to indicate (only from what I have read so far) that maybe they don’t even need to be diminished.
I shall now return to my study.
Absolutely right Wayne. When we are young Nature’s tools ensure the repair and recycling systems keep at bay various by products that build up later when efficiencies come down. Instead of removing various harmful build ups how much better it is to bring back the efficiency of Nature’s brilliant tools for true reversal to a youthful state.
I haven’t actually read it yet, just the abstract. But I will soon. The abstract seems to support the general hypothesis of Harold’s papers that the supposed causes of aging may in fact be consequences, i.e. the gene expression and mRNA levels (and presumably protein levels) that change with aging also change in the same directions with old or young blood. Lots of intriguing detail in there, however.
I may have read it too quickly but I don’t think this paper imply that the Conboys hypothesis is wrong, it may well be that absence of aging factors triggers a mitochondria rejuvenation though their presence doesn’t actually age this pathway in particular.
More likely though removing aging factors have some benefits, and young blood have some more.
Which is too bad because I really loved the idea of diluting plasma to rejuvenate us. So simple, elegant and quite “civilization collapse”-proof. No offense Akshay 🙂
I have questioned whether the Conboy plasma dilution study used a “neutral” replacement solution. Albumin receives very high weighting in aging clocks based on lab blood tests. If the study showed that each old rodent had exactly 5% albumin in their blood before replacement, then I missed seeing it and I stand corrected.
It must have occurred to the “Molecular hallmarks of heterochronic parabiosis at single cell resolution” researchers that since it not known whether the rejuvenating molecule or molecules are one or many and what the gross characteristics, say…molecular weight, polar/non polar, protein, lipid, lipoprotein etc, much could be learned from fractionating the young blood and check the mitochondrial effect of the various fractions. The clever test protocol they developed provides a relatively inexpensive way to bring knowledge to the next level.
Having fully read the paper I agree with other commentators on the potential importance of plasma proteins.
For example, albumin, quite apart from its liver functions is an antioxidant buffer in the blood, which should help mitochondria, particularly when in the procedure you are replacing partly oxidised with fully reduced albumin.
Fibrinogen is an acknowledged ‘damage associated molecular pattern protein’ (DAMP) and could impede rejuvenation via decreased blood flow when it causes blockages in capillaries (that are not severe enough for a stroke).
Transferrin moves iron, of which the main intracellular recipient is mitochondria, and intracellular transferrin is known to increase in Parkinson’s Disease, which also implicates it in mitochondrial dysfunction.
Finally, immunoglobulins – the immune system is known to react to pieces of mitochondrial DNA in the blood, leading to the rise in age related ‘sterile’ inflammation.
At the very least these arguments suggest blood protein removal should be eliminated as a cause of aging in these parabiosis studies.
Mark
https://link.springer.com/article/10.1007/s11357-020-00297-8
Conboys showing the opposite?
I know I’m becoming a broken record, but I still question whether the Conboys’ Neutral Blood Exchange was in fact neutral. Albumin has highly significant weight in aging clocks based on blood factors. Perhaps I missed the part in the studies that showed that each creature had exactly 5% albumin before treatment. (It wouldn’t be the first time my speed reading has failed me!)
Chronological age was significantly associated with 754 proteins (p < 1 × 10−5). Of these, the majority, 427 (56.6%) proteins, were positively associated with aging while the remaining 327 were negatively associated. The top proteins that were significantly positively correlated with age included pleiotrophin (PTN), WNT1‐inducible‐signaling pathway protein 2 (WISP‐2), chordin‐like protein 1 (CRDL1), R‐spondin‐1 (RSPO1), transgelin (TAGL), EGF‐containing fibulin‐like extracellular matrix protein 1 (FBLN3), and growth/differentiation factor 15 (MIC‐1; Table 2; Figure 1). On the other hand, epidermal growth factor receptor (ERBB1), a2‐antiplasmin, and A disintegrin and metalloproteinase with thrombospondin motifs 13 (ATS13), among others, were negatively associated with age
@Tom Blalock. Here’s my problem with such measurements: is an increase with age the cause or effect of aging? Same can be said for transcription factors, microRNA, etc. Therapies should address causes, not markers. Mendelian Randomization examples have taught us a lot.
For those interested, Centella asiatica extract has been found to be 4 times as effective increasing telomerase as TA-65 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755196/).
And far less expensive.
Nice study Tom. Thanks. The other name is gotu kola.
I’ve been on it for many years now since I began combining it with pine bark extract. The combination essentially stops the atherosclerotic process. It’s fascinating because gotu kola addresses the problem of soft plaque , which is actually the most dangerous and likely to rupture, by creating a hard covering over the plaque, and thereby stabilizing it from rupture.
For those of us taking rapamycin, it’s particularly important to maintain telomere length. There was a study showing the danger of rapamycin in the presence of critically short telomeres. I have Mark to thank for bringing that to my attention.
Centella Asiatica (Gotu Kola) causes light sensitivity and can make sunshine blindingly bright. Suggest taking at bedtime
Very interesting
Who would have thought…
https://www.yahoo.com/news/human-ageing-process-biologically-reversed-153921785.html
Except:
“Our knowledge in this area remains limited, but it is nevertheless clear that epigenetic aging is distinct from the process of cellular senescence and telomere attrition.”
Wow! That’s amazing. Who would have guessed that hyperbaric oxygen would yield such impressive results. I foresee a future of that plus gotu kola, rapamycin, lithium, and melatonin. Akshay’s elixir?
Paul,
If one is on Elixir one would need very few if at all any other supplements to be taken. When we were young we did not need any supplements. The hyperbaric experiment data was quite interesting which Tom brought to our attention. In a post I wrote many years ago I compared Yoga to hyperbaric oxygen therapy. If one has learnt breathing well which is a big part of yoga basically when he hold a assan/posture we compress a key organ and when we release the posture highly oxygenated blood from the breathing would rush to that organ/tissue.
As always, very informative Akshay. I may go into withdrawal if I stop all of my supplements, but I get your point.
Excellent comment Mark. Just a question on albumin: you say “For example, albumin, quite apart from its liver functions is an antioxidant buffer in the blood, which should help mitochondria, particularly when in the procedure you are replacing partly oxidised with fully reduced albumin”: do you think these are the main reasons it scores high in several aging “clocks” totally different in methodology (typically the higher the better outcome, e.g. see Levine’s, Mitnitski’s, Aging.ai, …). Apologizes if slightly off-topic …
Akshay,
I meant to write ‘At the very least these arguments suggest blood protein removal should be eliminated as a cause of REJUVENATION in these parabiosis studies.’ (before looking at other causes)
So my comment is in agreement with the Conboy’s study.
Albedo,
The importance of albumin to aging clocks could reflect the change in redox balance with age. Albumin is also important for moving fats around the body during fasting, and stem cells self-renew more during this time. Perhaps oxidation or some other alteration prevents this binding. There are many plausible explanations that await investigation.
@Mark Williams
Thank you Mark re albumin: fascinating !
Yes, I take an asiaticoside concentrated extract of Gotu Kola too. I’m not sure the light sensitivity is present in the concentrated extracts (which is what you want for telomeres). I only experienced it when taking larger amounts of a less refined gotu kola supplement.
Regarding the hyperbaric oxygen therapy, I wrote down some of my concerns here (https://www.longecity.org/forum/topic/102169-alternative-methods-to-extend-telomeres/page-13#entry900378).
In short, how do we know we are not just killing lots of cells with ROS and forcing replacement from the hematopoietic stem cell compartment? This would likely lead to a short term increase in health but a long term cost.
Hello. First of all you guys do an incredible thing! I can not believe I live in the era where it can be achieved by a super talented and exceptionally hard-worker scientists. You mean so much to me as I will be able to dramatically increase the lifespan of my dog. That’s incredible and outstanding. Thank you Dr Katcher, Akshay, and everyone else involved in the study. How soon could we be able to try an “Elixir” for the dog? When Dr Katcher mentioned in an interview on YouTube: “your dog will live as long as you do” I was the happiest person, really. Thank you in Advance.
Leo thank you for your kind words and encouragement. We will update Josh about our dog trial results. When your dog can get Elixir will depend on FDA. If you live around LA and if your dog is already older than I can check he/she can be added to the trial.
Thank you for your reply. Unfortunately I do not live in the US, I live in Georgia but getting a product is not the problem for me. There is a flight every day from the US to Tbilisi. That’s how I buy some products. As for my dog she is raw-fed and 5 year old yet. I do not know if it’s older enough but Elixir is our hope. P.S I have a friend who has really an older dog. Adding to the trial could be a miracle to us.
Leo unless your friend lives in California it would be difficult to enlist his older dog in the trial.
Thank You Akshay, please, keep us posted about the dog trial and Elixir release. Good luck to you!
The whole idea of this method is so unbelievable. I hope to hear more good news from Akshay and Professor Katcher in a near future. I am in my late 30s but have parents around 70. They are healthy and very energetic as for their age but not the same as 10 years ago. I will be glad to help them restore their youthful condition. I just hope that the Elixir solution will be on time for that and we will be able to afford it (unfortunately I do not have millions of dollars on my bank account).
I’m 74 and that is why I take Rapamycin and Metformin so that I will live long enough and be healthy so I can take full advantage of the progress in longevity science in the future. Got to slow everything down especially after 70.
You’re absolutely right Van. However, my parents are still not convinced to use any medicine. The other thing is that here in Poland there is not so easy to get a prescription for these drugs. They are still working on the farm and have an excellent shape as for their age. Actually my father has even better endurance than me and I am almost half his age. I hope that the Elixir solution would be commercially available relatively soon (optimistically within next 5 years) and we all will be able to benefit from it.
Hello Van,
I take Metformin, Rapamycin, Senolytics and a few other things. I would like to compare notes. If you are interested email me.
Chris
I take 7 mg Rapa a week. Started at 5 mg. Have tried larger doses, but 7 mg is good for me. Every person’s system is different. Was Dr. Green’s 2nd. patient. Now I live in Spain, and have not visited for 3 years. Also, take Fisetin, 20mg/kg monthly for 3 consecutive days. Dasatinib, 100 mg. x 3 consecutive days monthly. Azithromycin 250 mg x 6 days monthly. Do not take Fisetin and Dasatinib together like some recommend. It is too much for my system. Also take Metformin (ER) 1500 mg daily. Controls my glucose. Fasting glucose 88. Very important to keep blood pressure under 120/70, weight 165 lbs., 5′ 11″. Linsopril 15 mg. daily. Dosage has gone down with weight lost. Crestor 5 mg. daily to reduce inflammation, not LDL. Also, measure inflammation via a Urinalysis measuring the Microalbumin/Creatine ratio. Should be less than 7.5 for white males. Inflammation main cause is Diabetes, and Pre-diabetes. Inflammation causes plaque build up in arteries. Measure my arterial plaque level with a CIMT every 6 months, and a CBC, PSA with complete liver and lipid results.
I am curious about your regimen for senolytics. I recently started a senolytic (Doctor’s Best) with 1500
mg over two days. However I am concerned about it’s effectiveness when taken orally. Do you have any advice?
Thanks
What drug are you taking? Many senolytics on market. Fistein, Dasatinib, Azithromycin and many more.
Fisetin 15 100 mg tablets Doctors Best
Ed Dr. Green recommends Vitamin C 500 mg with Fistein. Suppose to help with bioavailability
Thanks! I had seen comments that taking it with soluble fats helped, but it was unclear to me the best way of doing that.
Yes, many have said to take 2 tablespoons of olive oil. Also, read about TMG,(Trimethylglycine) suppose to do same. Many choices.
I am curious about your regimen for senolytics. I recently started a senolytic (Doctor’s Best Fisetin) with 1500
mg over two days. However I am concerned about it’s effectiveness when taken orally. Do you have any advice?
Thanks
Hi Van
Your rapamycin dose is the same as mine and I also like the 7 mg dose. I’m considering switching over to everolimus now that the price has dropped. It’s more mTOR 1 specific with a much shorter half life but I’ve done well on rapamycin and am hesitant to change. Any thoughts?
Paul,
I have increased my dose to 10 mg. weekly. So far so good, but would not hesitate to drop back down. Been doing this for 4 years now. Also, Dr. B has recommended that one should slowly increase there dose of rapa until side effects appear, and then back off 1 mg. in order to get max longevity benefits.
https://www.aging-us.com/article/103493/text
Everolimus is another story. Remember, the drug was developed for transplant patients who were taking it daily and keeping a high blood level to suppress immune response. Yes, it is more targeted to Tor 1, but at what cost. Shorter half/life requiring you to take it more often, and more expensive. In my mind, if you are having no problems with rapa, I would stick with it. Rapa keeps getting cheaper and cheaper. US Compound Pharmacies, at around $1 mg., and powder from China for about .10 cents mg.
Thanks Kerry. You make some great points I too have been gradually upping my dose over 4 1/2 years. You need to hit your own sweet spot and I’m going to take that advice in dosing.
How do you feel on it? Any clear benefits or side effects?
I clearly feel an improvement. My HbA1C is 5.6 and I’d prefer it a little lower, but no big deal. I don’t follow my cholesterol levels, so I don’t know. I’m not anemic and don’t have stomatitis.
The short half life of everolimus would allow for higher dosing since the half life is so much shorter and side effects like hyperglycemia should be avoided as well, but the longevity studies are done with rapamycin and “ why fix it if it ain’t broken “.
Did you just contact a compounding pharmacy for that great price?
https://tailormadecompounding.com/
Need a Rx from doctor. Dr. Green uses them
Excellent. Thanks.
Sorry Paul, I gave you the wrong cite on rapa dosing. Here is the correct one:
https://www.aging-us.com/article/102355/text#fulltext
Hello. How do your studies go? Are there any news? We stand with you, geniuses!
Hi Leo we have launched rat trials and the dog trial is slated to start in February 2021. We will update here within first few weeks with early results from blood draw after treatment.
Hi Akshay, Any idea when we might be able to purchase the gel in the US? I know the Elixir will be later, but it would be nice to get a head start on my skin! LOL
We are working towards a launch on Amazon in USA in March or April next year. You will also win lots of brownie points by gifting it to your wife/girlfriend.
My wife will be the guinea pig – if her skin doesn’t fall off then I’ll use it. JUST KIDDING!! Yes of course we’ll both use it. She would kill me if I started to look a lot younger and she didn’t get to use it LOL
And what will she do if you gift her youthful skin? 😉
Probably leave me instantly and run off with the mailman! LOL 🙂
LOL!
Guys – we better think this through. Let’s use it on us first (and get super handsome again) and THEN give it to our women!! 😉
Vadim Gladyshev has a new paper where he finds that cells start aging shortly after conception. This seems to rule out the hypothalamus as a central regulator of aging.
Since this thread has recently become more active, I would like to introduce a new sub-subject. Vince Giuliano has weighed in on the main subject with his “Younging” blog posts. As I understand Vince, he maintains that the effects of therapies such as Katcher’s require many years to become apparent physiologically. This brings me to my new subject: grip strength.
Can anyone offer an explanation as to how grip strength could be increased essentially immediately after treatment?!? I doubt that new muscle can be formed this quickly. What I am thus left with some change in the neuromuscular junction, but… somebody give me some help here.
Why is this important? Because it would provide an immediate feedback loop for trials that we may wish to conduct on ourselves. Strength is pretty much an objective (and cheap) measure.
Hi Wayne:
If I understand your comment right, you are concerned that there might be disbelief in the effectiveness of the elixir, due to the long time frame of the observable results. This is definetely a valid concern. In fact, I suspect that many (or most) of the people that have read Harolds & Akshay’s paper just dont believe it. It might sound “too good to be true”. In fact, I remember seeing a recent video on youtube, where Aubrey De Gray states just that: The effects of the elixir are “too good to be true”. Maybe he has true concerns, or maybe he is a bit jealous. In fact the huge success might be the reason for disbelief. In fact, I was a bit surpised that the recent israeli study got so much coverage in the media, with very very weak results, yet Harold’s and Akshay’s paper with outstanding results, got so little mention in the mainstream media. The only reason I can think of, is that results were so good, that they were unbelievable. Something like room fusion in a test tube at room temperature. Too good to be true. and proved to be not true. Josh was ready to stake his reputation, but mainstream media journalists were not.
Your suggestion might be a good way to prove the effectiveness of the elixir. However, I believe that there is a much simpler way. Akshay has suggested that the Gel made the dark spots and winkles disapper in a matter of weeks (and maybe even induced hair regrowth on the scalp). These are not small things. In fact nothing has been so effective till now. So if the tests are successful, the FDA approval is given, and some people try it with quickly observable results, then all of a sudden the currently unknown “Yuvan research” will become known and TRUSTED. So, the elixir will also be trusted. It will take very little convincing.
Therefore, I suggest we wait for the test results, FDA approval of the Gel, and initial good results on patients. The rest will be a “piece of cake”.
Zisos. I am not concerned about belief in the elixir. That will all be resolved in the relatively near future. My first point is simply an intellectual curiosity as to the mechanism involving grip strength. My second point involves determination of efficacy. I appreciate your suggestion about age spots, but not all of us of Irish descent could apply it. Even my dermatologist can’t distinguish an age spot from a freckle.
Wayne, Both Harold and I have a lot of respect for Vince and would consider his prediction seriously but Harold feels one would begin to see the reversal within months not years. In the rats its within 1 week. This would include grip strength.
Akshay. I mentioned Vince relating to the “time of abandonment”. I noted his assertion about the time required to notice efficacy, and I questioned it. Unfortunately, I couldn’t post a comment as I couldn’t negotiate the registration process. “Childhood dog nemesis?”
As I’ve stated before, I would be ecstatic to merely see a reversal to how I looked like one or two years ago. To actually visibly look younger is almost unfathomable to me, so far outside the realm of expectations and what has been achieved in modern science (in humans at least), that I have a hard time embracing the sheer possibility within my lifetime. Keeping my hopes high but expectations low 😉
Thank you Zisos for your faith in us, your unflinching support and your kind words! Fortunately our patent attorney has confirmed the gel will come under cosmetics category so wait wont be very long: March 2021. We hope to complete a IRB approved human clinical trial before that at a reputed dermatological institute for aging spots and wrinkles. We hope the gel brings joy to the life of millions.
Any updates on your timelines ?
Michael, our team has moved to Bay Area. We have set up Lab and will soon be producing Elixir in USA as scheduled. The dog study should start by end of this month. These are big dogs weighing 40kgs so it will be interesting to see how Elixir works on them. We will soon launch a human clinical trial with the dermatology department of a highly reputed University for blue gel for wrinkles and photo damage. We hope to launch the product on Amazon USA by April. We are applying to an IRB for Phase 0 human clinical trial for Elixir. An award winning documentary maker will be covering this trial. Wish us good luck to make 2021 a very important year for all of humanity. We are really grateful to all the incredible people who are reaching out to support us.
Wonderful news, Akshay! I may yet become the world’s oldest man.
Best Regards, Wayne
Thank you Wayne. Oldest young man you mean 🙂
Can’t wait to get involved!
Hi Wayne,
I get what you’re saying about an immediate feedback loop.
How do I know if a treatment is working?
A drop in grip strength would show a need for the next round of Elixer treatments.
My guess is that grip strength is limited by energy levels.
My question is: What is the best device to measure grip strength at home?
@Gerald. It doesn’t have to be grip strength, although I think doctors sometimes use it. It’s more a rodent thing. Got barbells? Deadlift. With a bad back, I can’t do lifts, but I have lots of options in a gym. I guess a sitting leg press machine would be my first choice.
I’m still guessing neuromuscular junction – some sort of transmitter changes, but I really don’t have a clue.
Way too complicated guys. Pull-ups! Very easy to install a pull-up bar in your home and using it involves a large number of muscle groups, including your hands of course.
How about using an epigenetic clock such as Grimage acceleration which is a significant predictor of polypharmacy, frailty, and mortality. “Results indicate that the GrimAge clock represents a step-improvement in the predictive utility of the epigenetic clocks for identifying age-related decline in an array of clinical phenotypes promising to advance precision medicine.”
Why isn’t GrimAge epigenetic clock used which outperforms other epigenetic clocks. “Results indicate that the GrimAge clock represents a step-improvement in the predictive utility of the epigenetic clocks for identifying age-related decline in an array of clinical phenotypes promising to advance precision medicine.”
I have argued that GrimAge is not the best measure of the effectiveness of an anti-aging therapy. Yes, it is the most tightly correlated with age and mortality risk, and very useful for that. If you want to evaluate your own biological age, or assess how long you as an individual are likely to live, the GrimAge clock is probably the most informative.
But the whole reason that I trust methylation more than grey hair or wrinkles as a surrogate measure of success for an anti-aging intervention is that I think methylation is part of an epigenetic program that is the actual cause of aging. If you change key aspects of the methylome, then you reprogram the body to be younger.
KEY aspects but not ALL aspects. There are some methylation changes with age that are downstream of aging, and the way the GrimAge clock is constructed, it is liable to pick up these sites preferentially. I prefer the PhenoAge clock, not because it is better correlated with age or mortality, but because it is constructed in such a way as to be enriched in the upstream causes of aging.
More details here: https://joshmitteldorf.scienceblog.com/2019/10/15/methylation-clocks-and-true-biological-age/
“…I prefer the PhenoAge clock…”
Josh, have you a take on Levine’s Phenotypic Age mortality risk calculator which is then converted to a biological age number in years. It is the prior step before regression to methylation data (PhenoAge) and I guess has merit by its own?
Liu et al. (2018) A new aging measure captures morbidity and mortality risk across diverse subpopulations from NHANES IV: A cohort study
Any clock that uses chronological age as an input, cannot possibly be a good clock for determining if age reversal interventions are effective. Let’s assume that an intervention exists that halves the “biological age” of a person. Since phenoage and grimage are so highly correlated to chronological age, there is no “reasonable” combination of the remaining independent variables that will accurately predict the new biological age or new life expectancy.
Here is an example of sensitivity analysis using Levine’s model. All input variables were kept the same (the actual values), except chronological age:
Chronological Phenoage
——————- ————–
70 59.8
40 34.2
20 16.3
10 7.4
If phenoage is lower than chronological age even for 10 or 20, I conclude that the other input variables are close to “optimum”. These “near optimum” values predict an age of 59.8 for a 70-year-old. It is highly unlikely that even “absolutely optimum” values will predict 35 years for a 70-year old that was rejuvenated to a physical condition of a 35-year-old. A “chronological age” agnostic model has much better chance.
@Zisos. AMEN! My aging.io score is 46. My PhenoAge is 77. I’m 79 (and feel 89). The two “clocks” use pretty much the same blood test values. Aging.io is deep learning trained to chronological age. There isn’t a carnival age-guesser who would miss my real age by this much. PhenoAge doesn’t use deep learning but depends heavily on chronological age. For example, if I input my chronological age as 46 (the aging.io result), I get, wait for it, 46! This means to me that I have the same serum profile as a healthy 46-year-old.
I can’t afford multiple methylation tests, but tests based on my routine blood tests are within my budget, but neither of these clocks appear ready for prime time. It would be interesting to see a deep learning clock based on mortality. I have suggested such a model to Deep Learning. I really don’t need a guess of my actual age. On most days, I can remember it.
Thank you Zisos. Interesting. Btw, do you know how and where one can take the DNA GrimAge test?
@albedo
Sorry, I am not aware. I googled, but could not find anyone offering DNA Grimage test to consumers
Thank you. I appreciated your research and reply.
Thank you Zisos for your reply. Do not confuse Levine’s PhenoAge with Phenotypic Age, I guess you mean Phenotypic Age in your table. I do not understand well these matters but to me your argumentation looks a bit too theoretical. I guess halving the biological age BA of a person is going much too far to assess validity of these estimators which probably were not constructed for such an hypothetical role. Phenotypic Age formula, as constructed, gives a risk of mortality at 120 months (risk which is then converted to a number of years using a Gompertz law and interpreted as biological age BA). I think jury is not yet out regarding the inclusion of not of chronological age CA. From my reading of literature estimators such as aging.ai do not make use of CA and similarly Mitnitiski et al have explicitly written on not using CA (though methodology is completely different that the one used by Insilico Medicine). Klemera-Doubal methodology includes CA a bit along Levine’s.
@albedo
You are right that my table should read “Phenotypic Age” and not phenoage.
Levine’s model is very valuable for predicting mortality rate and for giving an indication of an individual’s health. This does not mean that its predictions will be accurate if major rejuvenation is achieved.
I have used an extreme example of BA being halved by rejuvenation, to show that an aging clock that uses the CA as an independent variable, cannot possibly be accurate for measuring rejuvenation efficacy.
I agree that grimage is probable not the best clock, but not for the same reason as you Josh: I actually believe an epigenetic clock tracking chronological age rather than fitness and mortality risks is more useful for the purpose of tracking rejuvenation therapy. The reasons are:
-At any age, by implementing lifestyle changes like exercise you can improve your fitness and reduce your mortality risk. Yet this is not rejuvenation, otherwise, you could exercise your way to immortality. This is not even slowing aging, because there is actually a removal of certain damages (mitochondrial dysfunction, senescent cells,…), to a small degree. Which means the body has some leeway in terms of fitness, but with no impact on the underlying aging program.
-If you can measure an epigenetic signature of chronological age, especially if it is not necessarily correlated to mortality, then that must be as close as we can be to the aging program, and that’s what you actually want to measure. The rest is noise. Useful in terms of health tracking, useless for rejuvenation purposes.
@Wayne and @Zizos
I also looked at this (inclusion of chronological age in biological age estimators) and interacting with you on other sites, was at Longecity or ARN? I also suggest you both should have a look at Mitnitski & Rockwood, e.g. https://doi.org/10.1093/gerona/glw089 along similar lines of thought. I feel jury is not out yet on the all matter though. I also appreciate Josh’s position on GrimAge and your and Mark’s as well weighting on albumin coming up in many measurements, but not a coincidence as it is one of the most abundant proteins in blood and might reflect many things such as adequate nutrition.
Have you guys applied for your patent yet? Will you publish the ingredients to your topical product or will they be kept as a trade secret?
We have filed provisional patent for Elixir. We have filed full patent for blue gel. The ingredients of blue gel will be public upon product launch.
Hello Akshay , I’ve been following this thread for a few months now after finding a link on Longecity , over time most of my questions have been answered apart from one ,
Originally Harold mentioned that the Elixir would be made in India but that now appears to have changed to the USA that will make the price 5 to 10 times the cost of an Indian produced Elixir not a problem for most on here , but a bigger concern would be obtaining the gel , patches ,and Elixir of you don’t live in the USA , do you have any plans on making the items available to overseas buyers ,
Regards and good luck in your endeavour , John
John fortunately producing Elixir in USA will not impact cost. Initially the gel will only be available on Amazon USA but we will enable international shipping and it should be worth a few extra dollars. But once we have stabilized production for US we will be launching in Europe next. We are in talks with companies that are keen to do that. So it hopefully around Christmas. Patch should be available only around the end of the year. But may become the most exciting anti aging product in the market. We will be conducting human clinical trial for all 3 this year so you will have evidence of benefits before you place your order.
Hi Askay:
Are you taking volunteers for the trials? I
Live in the USA but not close to California. However I might still consider a few visits if that would be sufficient. Also will there be a fee to defray the cost of the trial? I would suggest one to allow you to broaden the scope of the trial.
Ed,
Thanks for the suggestion. For our first, upcoming blue gel trial we are paying a small fee to 25 volunteers to participate. It involves 3 visits to the dermatology center. At all times there will be an MD. What is your chronological age? Do you have wrinkles on your face? Do you have photo damage that can be seen like spots?
I am 76. My face has lines but not wrinkles. No age spots.
Good for you but then you aren’t our ideal volunteer 🙂
@Akshay, you said participants need to have age spots. If you can say – are you saying just “lentigos” or including the various types of “keratoses” etc?
Nick this is regarding blue gel human trial we are looking for volunteers with wrinkles and by spots more like photo damage.
Thanks Akshay. There are many kinds of spots. ; – ) If you aren’t excluding them it will be interesting to see the results of the gel on different types.
Yes we plan to have many trials. Fir example for someone it helped their hemorrhoids problem. The first one is limited to wrinkles and photo damage.
Wow, so it’s OK on mucous membranes? Sounds like people will be applying this *everywhere*.
We have to find out but he stopped using pain medication and Preparation H from next day
@Akshay – in that context: How about varicose veins? My wife has the most beautiful long legs but has been battling nasty varicose veins since her pregnancy 30 years ago. She had some type of treatment (I think they injected something) but after a few years they came back with a vengeance. It’s a real shame as she never wears dresses anymore as she feels very self conscious about it.
Michael Mehrle I don’t think blue gel may be useful for that condition but the blue gel patch may be. We will have to find out.
@Akshay – well she’s certainly willing to try. As soon as the patch is available I’ll get a box and we will document the progress.
Don’t think I can help because I have got a few IPL treatments to reduce my sun spots (ageing). WIll be interesting to see how your gel works vs Rapamycin cream. Thanks for the good work
@Kerry Bell – Like you I spent a lot of money on having all those age spots lasered off. I guess timing is everything…
Akshay , thank you for your very prompt reply and the news is fantastic , the extra postage costs are not a problem I live in the UK and have ordered items from across the pond a few times so do know that there is the extra cost and the news that eventually it will be available in Europe although we’ve done brexit it has also set my mind at rest , although by this time next year I might have relocated to Mexico !!! regards from a healthy 76 yr old , John
I live in Spain right now and the biggest issue over here are usually import taxes and pertinent delays. Assuming the item costs ~$100 one should expect at least €30 in import charges. If the item is labeled as beauty product that is, otherwise it may cause undue complications and in some cases it is outright rejected (e.g. experimental compounds). Now assuming Elixir works as expected I am happy to pay that fee for a few months but the sooner a distribution channel in Europe can be secured the better.
Michael, John was asking about blue gel and not Elixir. It will fall under cosmetic. The expected price would be around $35 for a months supply.
Hello Akshay , I should have given you more information when I wrote , I intend getting all three items as they become available in the US now you’ve confirmed that you will do overseas orders , if I wait until the trials are over and until they are available in Europe I might find there’s a ten year waiting list ! ,
Are you going to offer monthly recurring shipping? Would make things easier on my end. Otherwise I would order a 3-month supply each time and place it way in advance to assure timely delivery.
We do plan to offer monthly subscription for blue gel.
Hi Akshay, Could you recap what each product should be useful for.
Gel – Will this only be useful at reversing wrinkles and age spots? Will it help regenerate hair?
Patch – Does it accomplish all the above and more? Or is it meant to regenerate (ie “reverse aging”) internally only?
Elixir – I assume full internal rejuvenation as per methylation clocks, but will it also resolve issues that the gel and the patch would “fix”, or is the idea that these 3 products are complimentary??
Thanks to you and Harold for all you are doing!
– Armando
Thank you Armando. Gel should make the skin younger. It helped someone’s hemorrhoids- he could avoid surgery. But not expecting hair regrowth. Harold did get a fuzzy on his pate but I did not see that turn into thick new hair. So we can rule that out.
Patch should do that internally. We could check before and after biomarkers for metabolic diseases. Shoukd definitely make one feel and look younger.
But once Elixir is available these two may not be needed.
Hi Akshay , no I won’t be waiting for the trials to conclude as you mention I’ll be ordering it as soon as Josh announces here on his blog that it’s available , I already have an Amazon and PayPal account ,
Thank you for the faith John we hope to make you proud.
@Akshay,
Vince Giuliano, Anti-Aging Firewalls blog, opines that the result of the Elixir and other treatments affecting the same epigenetics will take several years to produce results. I note that grip strength in your rats reverted to youthful levels immediately upon treatment. I’m guessing neuromuscular changes, but..
This leads me to a question I have posed for years without anyone even offering a reply: What is the relative rate of therapeutic healing between species following a treatment? Relative life expectancy seems to be assumed by most researchers, but proof is never offered. I maintain that relative metabolic rate makes more sense. This, if my 79-year-old grey cells aren’t failing me, would be about 6 times for human vs. rat.
What say you?
Wayne you could be right. We have to find out. More than healing I see this as resetting the epigenome back to youthful signature, the cell to youthful gene expression, the proteome, the cell secretome, the ECM back to youthful composition. This may have cascading effects so may take time as Vince Giuliano suggested. Personally I feel the rejuvenation timing will be variable and depend on the rate of renewal of that particular type of cell. Tongue, skin should be much earlier and heart, bone, brain should be much later. Aging is pervaded by feedback loops hopefully opposite feedback loops will progressively youthenize all of us.
Akshay, we probably won’t have to wait for human data to get a handle on the speed of “younging” question. The dog experiments will allow periodic tissue biopsies without sacrificing the animal, and the size of the dogs should make therapy speed quite comparable to that of humans.
I’m still intrigued by the grip strength data. Perhaps immediate significant reduction in inflammation applied to neuroinflammation? Nobody seems to have a good explanation for dynapenia, so my guess might be as good as anybody’s.
What you say about dip in inflammation and neuroinflammation as the cause may be right. I agree that the dog trials will give us a major glimpse at how Elixir will function in humans. These are 40kg dogs.
@Akshay
I refreshed my memory concerning the variables that were measured regularly. The fact that inflammatory markers dropped immediately after the treatment leads me to surmise that epigenetic factors were also changed early on. However, Vince believes that the reason his regimen did not change his DNA methylation age was that it would take years to do so. I suspect what is really happening is that his herbal supplements do not act as quickly as the Elixir.
I am reminded that you had a previous experiment using herbal substances in rats and had almost given up when, several months later, beneficial results started to appear. Using my relative metabolic rate as a guide, this would in fact cause Vince’s similar herbal regimen to require a few years for measurable results and epigenetic changes.
In conclusion, I’m betting that Vince is correct about the speed of epigenetic change in his regimen, but that oral herbal supplements are not the Elixir. Both treatments probably work on the same or similar pathways – Elixir just works much faster. I’m eagerly awaiting DNA methylation results from dogs immediately after treatment.
Wayne you completely right and your memory indeed is amazing. I agree with your conclusions. Elixir or now we call it E5 will have much more comprehensive and system wide changes vs a herbal intervention.
At this late date, after aggressive pursuit for uncounted centuries, we can rest assured that no simple herb or herbal combination will reverse aging significantly. We know there are natural interventions that have a favorable effect, but we also know that after all is said and done, even the most disciplined and careful people will fall by 130, even using every available intervention.
Indeed, it seems clear that nature long-ago “decided” death was good for individuals at a certain point after child-rearing, as evidenced by both obvious and subtle programmed degenerative conditions that increasingly become obvious with age, from baldness to weak immunity. “E5” marks a new approach to medicine, based upon modern and detailed understanding of predictable-but-adverse endogenous expression or suppression of DNA segments, effectively causing blood plasma toxicity, destroying cellular health unto demise of the organism.
I can’t speak for the entire group here, but I for one would be ecstatic to live to the ripe age of 130. Especially if it is in relative youthful condition and accompanied by the physical/mental stamina required to still feel productive and enjoy life to the fullest. In my case that would mean another 75 years of life and at that point I may just get bored of it all and be ready to exit gracefully 😉
Wayne is pointing the way already siring children at the age of 71 and still being in full control of his mental faculties. That’s very impressive and it fills me with hope for the future, which is a sentiment sorely missing durin these dire times. Phoenix from the ashes – one can only hope!
Less than 1/100 Americans now live to age 100, and none of them are in enviable physical shape. I used a max of 130 optimistically, assuming that a tiny, tiny few will crawl to that age, utilizing all of the latest technology and obscure herbs available today, atop excellent exercise, diet, and sleep practices. Fortunately, we can expect emerging technology to leapfrog past piecemeal, incremental improvements, and actually substantially reverse biological aging of humans. …Probably including H5.
What’s H5? Sorry that’s the first time I see it mentioned here.
I find these discussions to be very interesting but they always leave me wondering, what are we in the anti aging community actually trying to achieve? I have treated many people in the 85 to 95 range who are still extremely active and with excellent cognitive function. Between 95 to 100 they don’t generally deteriorate slowly, but it’s more like a sudden catastrophic event occurs, like a heart attack , stroke or cancer .
So, would that be satisfactory, if say we could postpone the event to about 125 years?
Or , do we want to actually reverse aging and wake up tomorrow looking and feeling like a 25 year old?
Is it actually immortality that we seek?
What if we age but are fully functional and vibrant until maybe 200, would that suffice?
Do we even know what we want?
I think waking on my 125th birthday, looking and feeling like a 25 year old would be just fine. I know something “unexpected” will eventually get me, but until then perpetual youth would be just fine
Here’s a brand new and interesting article on senescence and aging which you may find interesting https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13314#.YCJ_Tp38ucs.twitter
It discusses how NK cells are used to eliminate both cancer and senescent cells. As we age and accumulate senescent cells, NK cells are so overwhelmed that they are unable to effectively prevent cancer. This certainly supports the notion of either inhibiting or removing senescent cells, or both.
Nobody I know of feels like they have time enough ahead to do everything or even most of the things they want to do, nor do they celebrate their aching joints, bad hearing, forthcoming cancer surgery, etc. Immortality? It is unknowable, and talking about it is little more than an idle parlor game. From way down here, living a thousand years is essentially the same as being immortal, especially since there is every reason to believe that new therapies developed in that thousand years would extend the limit yet further. For now, I’d be happy to have one more full lifetime of robust health, and a couple new careers to look forward to. As that draws to a close, ask me again.
I’d be pretty happy to feel like I do today at 120. It’s gravy after that.
We know that a well functioning immune system is almost gone by the time we reach 60. Talking about living to the age of 200 years or even beyond the next COVID19 mutation seems like an illusion without a balanced immune response.
We know for sure that declining immune function plays a central role in some of these ‘catastrophic events’ that Paul mentioned, especially cancer and rare autoimmune disorders like Wegners, but even something as common as pneumonia could kill you.
Shouldn’t we start to appreciate the importance of the immune system. We already have plenty of tools to mitigate strokes and hearts attacks, but very little to truly rejuvenate the immune system.
I wonder how many on this site are actually using Greg Fahy’s protocol and what the outcomes are so far? Also, very excited to see, if the Elixir will have any impact on thymus?
I’m 74 yo, and have an excellent immune system due to controlling weight, exercise, blood glucose, and taking Rapamycin. Rapamycin improves your immune response to any disease including Covid, and Cancer.
Kerry, it may postpone cancer, but it won’t extend your lifespan compared to DR
https://onlinelibrary.wiley.com/doi/10.1111/acel.13302?fbclid=IwAR3G7hrjGuYT2QHAheaBNL5rT7mWKYnFWKhJv_z8at1FO1U3ywMmbpOgYYs
Wrong again Ole, CR does not compare to Rapa. https://peterattiamd.com/richardmiller/
2019’s Cohort 15 dimethyl fumarate results will be interesting.
Yes we can agree to disagree on the use of Rapa for life extension
It is the only intervention that extends life in all species tested. Also, proven many times to increase immune response in viral diseases including Covid. It is the Gold Standard in extending health and life span. You can certainly disagree, but that would be exactly opposite in direct evidence of overwhelming expert opinions.
I recommend you don’t go with the ‘youthenize’ phrase, Akshay!
Regarding Vince’s opinion on the (delayed) effect of his herbs on biological aging as per methylation markers, I’ve done a lot of testing – something like 7 or 8 methylation tests since 2017. And most things just don’t affect methylation age, even if they can be shown to benefit health in other ways. Even 2 years of 2-3mg/wk rapamycin had only a very slight reduction (a few months) on the methylation age of this ~40yo rat. AKG took about 6 months to work, but did reverse my methylation age by 5-6 years. GDF11 also appears to reverse methylation age quite substantially according to reports I have from friends that have tried it and tested.
So as Paul mentioned, what exactly do we want? I have no doubt Vince’s anti-inflammatories have kept him healthy. But they probably haven’t and will not affect age as measured by methylation. Remember that clocks like Horvath’s original one measure markers that become more common in the aged. Are these really likely to be to be drivers of biological aging? Unlikely, as they wouldn’t be selected for in those that have survived for longer. It is likely they are closely associated to the consequences of aging, and hence are also reversed by a rejuvenation treatment, but they for the most part are probably not that magic subset Josh is searching for that drive the changes we see with age.
To sum up: epigenetic age is just a biomarker. A useful one, yes. But it is not the same as aging.
Well Mark E5 (formerly called Elixir) has reversed 30 biomarkers to youthful levels. Also we will soon find out what it does in dogs and humans with a Phase 0 trial. Both could be interesting depending whom you like more 🙂
Why the change to the name ‘E5’?
Bill Andrews calls it the ‘Betty White’ test. If Betty White (or any of us) wakes up one day looking and feeling 25, then we’ll know we’ve reversed aging!
Elixir was a just a working title that we have outgrown. Well our Phase 0 human trial is going to be covered by a documentary maker so hopefully we will see the physiological changes but not overnight.
Akshay and Mark,
I personally believe that DNA methylation together with histone modification is causal, but that is only of academic interest to those of us past our use-by date. What is important is whether a clock accurately reflects remaining healthspan. A “clock” “trained” to mortality, such as GrimAge, would seem to be more instructive than one trained to chronological age. As I told Alex at Deep Longevity, I already know how old I am (at least on good days). (My aging.ai age is 46. PhotoAge is 56. PhenoAge is 76, ActualAge is 79. I’m not sure that any of these clocks are ready for prime time, but the standard medical tests in the E5 rat study can stand alone as proof of extraordinary results.)
Akshay,
Thank you. Mark, for the personal data. It helps me determine my course of action on a limited budget. I suspect that the question of causality will not be resolved for quite some time, but good biomarkers of projected health are still needed in aging research. By the time E5 has completed its first human trial, I would expect to see highly reproducible clocks based on mortality.
What would be great Akshay, is for you to get your patent sewn up, so you can share the more technical details of your plasma fraction youthening factors. Any timescale on this?
Mark we have filed patents. We have shared that its fractions derived young plasma so only thing left to share is its formula as a for profit why would I want to share that?
Doesn’t your patent do exactly that?
Nope. Not till 18 months
@Michael Sansom: That’s a specious question. What does Akshay have to gain by sharing his proprietary secrets? This is business and one single slip up could cost him the entire patent. Little to gain and everything to lose.
My advice to Akshay: Loose lips sink ships. Ignore the incessant prodders and do what you have to do to get your compounds to market.
That’s not specious at all. The purpose of a patent is to accomplish two things:
1.) To disclose to the world the specifics of the invention so the world can progress by learning how it works.
2.) To protect the inventor by giving him exclusive rights to the invention for a finite amount of time.
If you are granted a patent, you will disclose the details of exactly what you are doing. There is no other way.
In fact, it at least used to be the case that your patent application is a public document even before the patent is granted. You are protected at the moment you file, assuming that you application is eventually granted.
Now you have an option of 18 months silent period post application.
@Michael Sansom – I know how the patent process works. I actually own three of them – look me up at the USPTO and the PCT 😉
You are indeed correct that one is granted priority retrospectively, starting even at the provisional level, but you seem to approach this from a purely academic/legal perspective while I was referring to business strategy. Once again Akshay has little to gain and plenty to lose by giving too much away right now.
So why? Because the pharmaceutical industry didn’t turn into a $1.25 Trillion behemoth by being either fair or nice. The sooner Akshay publishes his secret sauce, the sooner he exposes himself to being attacked in a myriad of ways. Some of that may be legally (the low hanging fruit), others which are actually a lot more effective include ad hominem attacks, good old fashioned FUD, or rushing into producing something similar that may or may not infringe on Akshay’s IP. And that’s probably only scratching the surface.
The very frustration you are experiencing right now about not knowing what exactly accounts for the amazing results Akshay and his team have been reporting is shared by everyone in the know in the industry, and rightly so. Because THAT is called a competitive advantage, and it is a benefit, it’s a feature not a failing. Maybe consult Sun Tzu for pertinent perspectives.
Let’s remind ourselves that we are talking about a compound that is potentially able to visually turn back the clock by not just by years but potentially decades. I can confidently say that my lovely wife would literally kill for something even remotely resembling such a treatment and I don’t think she is the exception.
Patience is key here. There are two ways of doing this: the virtuous way or the right way. I am happy to see that Akshay has chosen the latter. Because in the long run that will benefit us all.
Very well put Michael Mehrle.
Thank you Michael Mehrle I agree.
Yes, the important thing is that it works as demonstrated in the clinical trials and in practice.
Well given we know Harold worked out the important components of the plasma, I am hoping for a greater insight into mechanisms. I don’t expect you to give away IP when you don’t yet have protections in place.
If it is a natural substance derived from the blood, what exactly is being patented? You sure can’t patent GDF11 or Oxytocin. It would have to either be a modified molecule from what is already found in the blood, would it not?
I would assume that they are getting a “use patent”, where you aren’t patenting the compounds themselves, but are instead patenting the use of some array of compounds for a specific application (age reduction, treatment of some disease, etc.).
Use patents are typically the weakest patents available because someone can conceivably take your same list of compounds and claim usefulness in some other application. But, if you were able to couple a good use patent with an FDA approval at some point, you’d have a decently defensible product.
Or a patent on a manufacturing process to cheaply make E5? In any event, I strongly suggest we drop the guessing game and the probing questions. We’ll know soon enough.
Thank you Wayne. All I can say is we have multiple strong claims including the one you mentioned drafted by one of the largest biotech patent law firms in USA.
Natural products are generally not under FDA approval as they are not drugs.
You can’t make the claim that you’re preventing or curing any disease. Is aging a disease?
Mostly you just give the ingredients without revealing the exact mg’s of each and call it a proprietary blend.
Of course, they can’t steal your name.
My takeaway from this discussion is that the sooner Akshay and Harold can deploy Elixir the better. Best if still under the 18 month non-disclosure period.
I suspect that a decently large number of participants would be interested in participating in a phase 0 or (or later phase) clinical trial involving reimbursement of the drugs cost at its projected market price. The larger the trial the better. It might also help in getting the manufacturing process for the drug validated and established in advance of other attempts by the pharmaceutical industry to circumvent the patents as well.
Thats our thinking Ed only we can not charge volunteers to participate and so it will be a limited trial. I am organizing this for the science but also to help my co-founder who is 76. Covid put a scare in the loved ones of people in that age group. Kind of tells us why we need E5 as soon as possible. We will also prioritize a few early investors in that age group as long as the doctors approve. The result being the first in humans will be interesting to find out for all of us.
As morbid as this may sound, you could not have picked a better timing to release your line of products, Akshay 😉
P.S.: Apologies in advance to anyone who lost a loved one to COVID-19. As one of the non-scientists here I merely try to contribute from an entrepreneurial/business/financial perspective. I leave the big brain stuff to the rest of the group.
There’s no reason you can’t apply and be granted FDA approval for a natural compound (or a collection of natural compounds), it’s just that no one does it anymore since it’s so outrageously expensive to get through an FDA approval process and what awaits you at the end is FDA approval on something that you have only a use patent on. That’s some protection – it’s pretty likely that no one can get around you as a prescription medication with both of those in hand. But it’s also pretty likely that someone could sell your collection of natural compounds as a non-prescription supplement. So it’s just just not very attractive to spend the hundreds of millions or a billion or two dollars to get FDA approval in that situation.
That’s why we’re in this weird situation where some university does some small scale preliminary research on a natural compound that shows promise yet no one ever funds a larger scale trial to prove it out. What they do instead is try to come up with some synthetically derived analog to the natural compound which can be patented, which can be pretty perverse. You end up with a very expensive medication that may be no better (or perhaps only marginally better or worse) than the natural compound it mimics.
There’s several things gone wrong in that’s caused this. It cost far too much to get a new compound through FDA approval. Also, public universities have in many cases abandoned basic research in the public interest in order to become drug development centers. So they use public funds to pay for drug development, but if they find a useful compound that becomes a FDA approved drug it is owned by the university and the researchers, not by the public that paid for it.
This whole system is in need of an overhaul.
@Mark
Remembered that you started taking Berberine together with AKG.
I just viewed a “modern healthspan” interview of “Tom Weldon”.
He suggested that AKG has no effect if taken together with Berberine (or other type 2 Diabetes drugs)
Did you do any more methylation tests after taking Berberine for a while?
If so, what was your experience?
I have also been taking AKG (acid form, diluted in Green Tea). I did a methylation test before, but not after. Unfortunately, for most of the time I have also been taking Berberine or Metformin most of the time, I am afraid there will be no effect.
@Mark, interesting anecdotes and thoughts about methylation clocks. I only really trust them in the hands of experts like Horvath. Do you take the calcium form of AKG or some other?
I only measure those things once per year, so I can’t give you an answer(yet).Those drops seem rather large; my blood markers were all already good the last time I measured them, so I doubt I’d see such pronounced changes. It is interesting that AKG would have such an effect (increase in fat burning).
My lipid panel improved markedly after five months of AKG. I can send results if you wish.
@Mark
Hi, Mark:
5 year methylation reversal with AKG is Huge.
I have a few questions:
a) Is this the only change in your regiment during these six months? Many of us make many changes so it is difficult to pinpoint what has caused what.
b) In what form did you take it? (I guess there is acid, calcium salt…)
c) What dosage?
Thank You
@Zisos, the Rejuvant science page (and a video presentation by their CSO) shows varying results for trial patients including over 20 year reduction in “biological” age reduction – which from memory is a methylation test. https://www.rejuvant.com/science
@Nick Quite interesting. I was aware of the company but did not realize that they had such impressive results.
@Zisos, yes it’s interesting, and although I’m surprised that just throwing in more AKG could do this, I’m also reminded by the possible effects on lipid results that moving biomarkers (TC, LDL-C etc, e.g. with niacin) doesn’t necessarily translate into altered outcomes. The CRP reduction is more interesting, but only healthspan and lifespan trials will show how meaningful the results are.
No need to buy Rejuvant. I used Kirkman labs AKG salt (mixture of Mg and Ca AKG) @ 900mg/day for 6 months. No improvement@3 months but significant improvement@6 months. I then had a 2 1/2 month break from AKG then restarted on 600mg/day with berberine for a month and then 1 month increasing the dose to 900mg/day (still with Berberine). Resulted in further improvement to 6.6 years under biological age (35 vs 42). Someone I know just used Arginine-AKG and that also seems to ‘work’ as well, although I haven’t tested that personally.
No obvious improvements in health (BP, HRV, Pulse rate, Reaction time) or appearance (skin thickness, lines, first traces of white in beard) to report. So unclear if epigenetic aging test is really a good proxy for real aging. Or perhaps there will be ‘real’ improvements with a time delay.
@Mark, thanks for all those details. I use AAKG myself, but there was some suggestion it couldn’t be given as a bolus (rapid elimination) and that sustained release was necessary. Personally I just sip it from a drink over time. Did you take your AKG in a bolus once a day? Again, I really like the points you made before about (commercially available) methylation clocks and what they’re measuring. Something like GrimAge might be more meaningful, so would be interesting to see if that sees improvements.
@Mark Thanks for sharing. I have actually ordered from China 1kg AKG @ 42$ plus 30$ shipping for a total of 72$. Expect it next week. No Ca or Mg. Just plain AKG.
Can you please explain why you took 2.5 months break? Also, any synergy with Berberine?
Re AAKG: I avoided it because Arginine up-regulates mTor1.
Re Epigenetic aging test: I know of several clocks: myDNAge methylation, Epi-aging Methylation, aging.ai, Levine DNAm Aging, young.ai Photoage. I am not a Biologist, and I am not sure which is best. So my aim is to find interventions that will help me reduce my Biological age as predicted by all those clocks. If that happens, and at the same time my health improves as I physically observe it, then I am confident that my age has been reversed. In other words: “If it looks like a bird, if it sings like a bird, if it flies like a bird, it is a bird!”
At what age would the consumption of AKG be beneficial? Also is it risky? TINSTAAFL. This is the first time I hear about this, so a quick primer on the topic would be appreciated (fyi – I don’t have a PhD in biochemistry so please be gentle).
I am not a biologist, so it would be difficult for me to explain. But here is some info.
Published paper by Kennedy (Buck Institute): https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30417-4
Company that created supplement on basis of study: https://www.rejuvant.com/How-Rejuvant-Works
Extremely low risk, as it has been used extensively in the “Bodybuilging community” with no known issues.
True TINSTAAFL. But at my age of almost 70, the risk of doing nothing is very big, and getting bigger exponentially. So I consider it a “no-brainer”. But @Mark is 40 and nonetheless managed to get 5.5 years epigenetic reversal, using a more economical alternative for AKG. I consider such age reduction huge. Let’s remember that Dr. Fahy’s intervention reversed epigenetic age by 2 years, and was considered a huge success. AKG is simpler, safer, and more effective assuming that in less than a year it can yield more than 5 years reversal.
@Zisos, thanks for the explanation. So you plan on taking 900mg/day? Do you trust that Chinese manufacturer? Is that a trusted source?
@Michael As far as trusting Chinese products. It is difficult to know. They have the necessary test documents. But there is always risk. For daily dose: I suspect there is no magin in 900mg. It is just 3 x 300. I have not decided yet on my dosage, I will do some further research before starting. It is very likely that I will use 1gr/day,
Supposedly you need delayed release, but I suspect that is just Rejuvant selling their product. As I said I know someone who just took Arginine-AKG in his shake and it reduced his methylation age. I just took 3x300mg tablets in the AM.
If you’re interested in some speculation, supposedly adjusting the AKG/succinate ratio in the krebs cycle is sufficient to modify histone (H3K27) methylation – this one is repressive when methylated, and AKG also upregulates the TET enzymes, which demethylate the genome. This perhaps allows progenitor cells to maintain pluripotency more than they would have otherwise done.
@Mark, someone sent me a paper about that (“The role of α-ketoglutarate–dependent proteins in pluripotency acquisition and maintenance”) but it tests the limit of my biology knowledge. Also, it only makes me more suspicious of AKG – to think that throwing more of any one such molecule in the mix could have ONLY positive effects seems unlikely. The mechanism is too low-level. I’m excited about Howard’s Elixir because (apart from the obvious) I’m hoping that it illuminates a higher level programmed aging signal.
Nick, you are right to be suspicious! But if you think about it, any single molecule turning back the clock or even making it tick slower seems to be pretty far fetched. And yet the mouse studies show single molecules such as rapamycin can do just that. Elixir is interesting because it is (possibly) based on endogenous molecules already in the plasma, so like you I think it at least plausible that it could meaningfully alter signalling and feedback loops in favour of a younger body.
@Mark, one more thing. Did you or others notice any change in lipid panel results from AKG? This is something that was mentioned in the presentation by the CEO of Rejuvant. He had ~70% drops in LDL, TG, CRP and a 50% drop in TC. https://youtu.be/1qeCVaAzR8Q?t=470
I took a break because I was feeling tired. But with hindsight, I don’t think it was the AKG. It takes some effort to eliminate all other influences.
It is a good idea to give your body a break, either with a long break like me, or a few days off a week. Just in case of impurities. I also wouldn’t recommend pure AKG – it would be very hard on your stomach.
My latest results from Jan 2021 are even better: 6.6 years age reduction. So perhaps the added berberine helped. Again, this comes with the added caveat that I haven’t really noticed any physical improvement in the biomarkers I look at daily. But then I’m only 42 and in quite good shape (albeit clearly not 25 anymore!)
I’m tired of reading hundreds of aging papers and speculating endlessly about possible mechanisms for or against using various compounds. We all have to test. Methylation markers, telomeres, blood profiles, physical biomarkers. End of!
@ Mark I fully agree with all your points.
Re Breaks: I also take breaks 2 days per week plus 1 week every two months.
I will give AKG a try as soon as I get it. I currently sip on 1.5 litres of cold green tea during the day, and I intend to dissolve it in there, along with some other stuff. So hopefully no major problem with stomach. But I will keep your suggestion in mind, just in case.
I have just taken an epigenetic test and will take it again six months after starting AKG. While the health difference between 42 and 35 is hardly noticeable, I know there is a substantial difference between now @69 yrs, and 7 years ago. I will be thrilled with half that 😉
Thank you for taking the time to give detailed info. Extremely useful!
Mark, what lab have you been using to check your methylation age? I have found about 5 different ones.
@Wayne Johnson – your 79 year old grey cells seem to be functioning better than those of most 25 year olds I run into these days 😉
And I agree, to linearly project from mouse/rat to human would be foolish. Only human trials will be able to establish a rough baseline.
@Michael, Thank you for the kind words. Perhaps those who say that raising kids keeps you young (hormesis?) are correct, as I have a 7-year-old son. I’d like to still be able to know what’s happening when he graduates from college. Anti-aging science is thus more than just an academic interest for me.
Is there any indication the topical product might help with hair loss? Starting to get a bit thin on the crown. 😉
I think it was mentioned today that there was no improvement in the hair department. So we both are out of luck 😉
This thread has gotten pretty long and difficult to search, so forgive me if this has been covered, but does the topical product have systemic effects or only localized effects?
Michael,
The gel should have topical effects for the most but Harold uses it and notices improvement in energy, strength and his walk so may be there may be some secondary limited systemic benefits.
Ashkay:
Although not a clinical trial, I presume that Harold is the first subject to use E5. What can you tell us about the results? Biomarkers, personal experience, …
My career has taught me the benefits of compounding as part of a long term strategy. To that end I would be most curious about the longer term effects of Elixir (or whatever it’s called now) in combination with a healthy lifestyle. Of course it would be nice to see positive effects in a matter of months, but consistent use for several years is where things get really interesting 😉
Hi Ed,
Harold will be the first for sure but in 3 to 4 months in our Phase 0 trial
Any chance you will offer this offshore first to bypass long approval times from FDA much like the Riordan stem cell clinic in Panama for example?
Not as of now but there should be many large Phase II and Phase III trials to enrol before it is available on prescription
Hi Akshay. I wanted to know will there be any senescence markers for the E5 trial on Dogs and could plasma dilution be added at a future trial to see if reversal of biological clocks could be further enhanced? And how many markers are you using for the dog trial?
Ghalib very good questions.. There is potential for further reversal as we had taken DNA samples 60 days after the peak of the dose response curve in treated rats. This time we will try to take multiple samples at various time points. But the variable this time is much larger animals so we may discover a new longer dose response curve. We may not get tissue biopsy so senescence testing may be a challenge but we are testing many blood based aging biomarkers. So there will be lots of before and after data.
Is there any indication that the topical product (Elixir? E5?) helps with old scars?
Michael the topical product is different from E5. It may not help with scars.
Thanks. Apparently I’ve gotten confused on the various product name. Apologies.
Here is a brand new and comprehensive review of where things presently stand in terms of epigenetic reprogramming:
https://www.researchgate.net/publication/349593004_Aging_and_rejuvenation_-_a_modular_epigenome_model
They bring up a good point in discussing Harold’s and Akshay’s results, namely that they saw a partial reprogramming. Is that because some parts of the epigenome were unresponsive to the elixir?
Thank you Paul for sharing the paper. Professor Goya has given a good review on cellular and epigenetic reprogramming. Yet we can’t conclude from result from one particular study design that E5 leads to only partial rejuvenation. It was a limited study at a particular dose frequency. We are investigating various other study designs which may result in more comprehensive reprogramming. The results of the completed study gives us evidence and confirmation that reprogramming is possible and there is way open towards complete rejuvenation to a youthful state.
That being said, there’s nothing wrong with being reprogrammed from an 80 y/o to a 50y/o, especially if the 50year old state could be maintained. Most would sign up for that.
The paper needed more examples than this to support their narrative:
“Old rats were not brought back to a complete young condition. For instance, their body weight, known to increase significantly with age in male rats, was not reduced by the treatment.”
I agree. I also wonder if that example is significant. I am not a biologist, but body weight reflects an accumulation of adipose tissue. That might be something that would take a protracted time to reduce as compared to changing the state of a cell.
I had the same thought , There’s a difference between reversing age and reversing time ,
Absolutely. Maybe that could be the next version of the elixir (ha ha).
That’s an interesting thought John. If we are transformed from an 80y/o to a 20y/o it changes our conscious relationship with everyone around us and even changes how we relate to ourselves. I mean we’re no longer grandpa right? We’ve done something with time.
I don’t think it effects time in the way you mean , if our memories are not changed and we remember things after the age we’ve reversed to we’re just young granddad nothing else is changed ,
The buildings put up in your street in the last few years will still be there as will anything invented and built after the younger age you reverse to ,
I don’t disagree, but as I think back to how much easier it was to put on muscle and take off fat in my 30’s vs. my 50’s, I would much rather be working to reverse the ravages of time with a body full of rejuvenated and de-aged cells. Today we have the challenge of reversing time’s impact on our body with aged-cell phenotypes working against us. I can’t wait to try to lose my belly fat and show off a rippling six-pack with a body full of youthful, de-aged cells helping out! 🙂
Times a constant and can’t be altered , if E5 works as we’ve been told your age will half approximately , but the change to your cells will take time they may change overnight but you won’t go back to what you looked like at half your age without the exercise that gave you the six pack ,
I’ve had an eye problem since I was 16 years old and can’t lift weights due to thin retinas that split and tear easily so I’ll go back to a skinny guy although I prefer to say slim ! Your skin cells live about a month normally E5 may reverse that in a short time but then as as been said we will age at a normal rate then have the injection after two years that takes us back again ,to the age after the four initial injections ,
Yeah, that’s a bit lame, but their overall point of a partial reprogramming seems valid. It’s not really a criticism but is merely pointing out that we haven’t yet reached the point of total reprogramming. That’s fair I think.
I don’t think we understand or can distinguish at present between ‘aging’ and ‘things that change with age’. For example, photodamage is not really aging, though it tends to accumulate with age. Likewise accumulation of adipose tissue tends to occur with time, and undoubtedly has an aging component to it, but plenty of people have proven it is possible to stay slim with increasing age – without reversing their age.
I tend to agree with Paul that there would be a psychological element to age reversal, and that it would indeed change your whole outlook.
Those are good points Mark. The marker which I find correlates most closely with aging is fatigability. At 62 I noticed a change in my hiking pace, endurance, and most notably my recovery time. After 3 months of 2mg of rapamycin , all of those parameters improved by about 20-30 percent. After 5 years this hasn’t really changed, but neither has it improved even with increasing doses. I’ve hit a plateau.
I am able to increase endurance with various supplements that improve my endothelial function, but the most sensitive marker, recovery time, isn’t changing.
@Paul:
We are about the same age and I’m an avid hiker too. For about 8 years I commit to resistance exercise 5 times a week and for 2 years I do daily intermittent fasting 18:6 or 20:4. I believe that are the reasons why I can still enjoy hiking in the mountains. In general, I don’t have problems with recovery time but noticed endurance decline last year. To overcome that, I changed my gym routines, which consisted of almost 100% strength training, stretching and flexibility, and started jogging again.
I do workouts and hikes in a fasted state and break my fast after the workout or when reaching the summit. However, I take one teaspoon of Creatine with plenty of water at the start time.
I have been pondering another aspect of aging that to my knowledge has not been discussed here yet. How about libido? By all intents and purposes a healthy sex life is part and parcel of a happy life. Not for everyone but for me personally it would definitely be a factor.
It would be wonderful if I could live another 50 years looking like I do now or perhaps even younger. If i just get my hair back but alas, beyond looks and improved athleticism in general one would most likely find oneself once again in situations that involved a functioning libido. I imagine it could be very frustrating to look/feel like a 25 or even 30 year old but not be able to enjoy the benefits that come with that.
My question goes out to Akshay: Have there been any indication thus far that the rejuvenated mice started to feel a bit more ‘frisky’ again? 😉
Michael, I can’t say about Rats in a qualitative manner as we have not tested this aspect. Personally even using rapamycin or upregulating Nrf2 does seem to give a noticeable effect at the appropriate dose. So something like E5 should certainly bbring back the joy you were talking about.
I guess if all goes well we’ll find out how much of deterioration is due to aging, and how much is due to other things like bad lifestyle that cause deterioration over time irrespective of biological age.
At 42 I shouldn’t be moaning about age too much, but for me it was disturbing that at 35 aging was something that happened to other people, but at 40 it already had me in its grip. And it only gets worse from there. Many of my friends a little older seemed to be holding it at bay. A few hard years later and it had caught up with them: Drying up, wrinkling skin, hollow eyes, grey, receding hair, spreading waistline, reduced energy levels. Lots of symptoms none of which are aging on its own, but taken as whole certainly due to age.
For me a true solution to aging will be waking up and looking and feeling 25 again, with limitless possibility ahead of me once more. I hope it will be possible.
It will be possible.
@Stephan
At 65 I also practice IF and hiking together. I have noticed a decline in RBC and hemoglobin in the last couple of years and think it might be related to my 16:8 IF. I wonder if you noticed the same. No particular symptoms.
I don’t know. When reviewing my next blood test with my doctor I will look at past test to see any difference. Thanks for the pointers.
Albedo:
Because you mentioned Hiking I wonder if your decline in RBCs and thus Hemoglobin is related to foot-strike syndrome associated with intravascular hemolysis and sports anemia.
Here is link to an NIH study and an excerpt from it:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824146/
“The decreased Hct in athletes has been termed “sports anemia.” For a long time it had been explained with increased red blood cell destruction during exercise and thus appeared to be the same phenomenon as the well-known march hemoglobinuria (Broun, 1922; Kurz, 1948; Martin and Kilian, 1959).
Intravascular destruction of red blood cells occurs at shear stresses between 1000 and 4000 dyn/cm2 (Sutera, 1977; Sallam and Hwang, 1984), values well above physiological values at rest (Mairbäurl et al., 2013).
It is related to the intensity and the kind of exercise (Yoshimura et al., 1980; Miller et al., 1988). FOOT STRIKE in runners has been the most often reported reason for intravascular hemolysis (Telford et al., 2003), which can be prevented by good shoe cushioning (Yoshimura et al., 1980; Dressendorfer et al., 1992).
It also occurred during MOUNTAIN HIKING (Martin et al., 1992), in strength training (Schobersberger et al., 1990), karate (Streeton, 1967), in swimmers (Selby and Eichner, 1986; Robinson et al., 2006), basketball, Kendo-fencing, and in drummers (Schwartz and Flessa, 1973; Nakatsuji et al., 1978).
Running exercise has been found to increase plasma hemoglobin from ~30 mg/liter at rest to ~120 mg/liter indicating that about 0.04% of all circulating red blood cells were lyzed (Telford et al., 2003). Exercise had been shown to alter red blood cell membrane appearance in correlation with elevated haptoglobin (Jordan et al., 1998).
Senescent red blood cells may be particularly prone to exercise induced intravascular hemolysis as indicated by a decreased mean red blood cell buoyant density and a density distribution curve that was skewed toward younger, less dense cells in trained individuals indicated by increased levels of pyruvate kinase activity, 2,3-DPG and P50, higher reticulocyte counts (Mairbäurl et al., 1983).
Other possible reasons for “sports anemia” under discussion are nutritional aspects such as insufficient protein intake and altered profile of blood lipids (for review see Yoshimura et al., 1980), and iron deficiency (Hunding et al., 1981). “
@Heather
Thank you so much for you detailed response. I will go through all when more time. My first impression is related to the intensity of activity which is not my case. Thanks again. I will post here if I find more. I found more correlation with intermittent fasting during the last year or so than physical activity which I am doing since long time.
Hi Albedo:
This linked article is more reader friendly and shorter:
https://www.livescience.com/61270-foot-strike-hemolysis-ultramarathon.html
Link excerpt: Footstrike hemolysis is not only seen in long-distance runners: It has also been observed in other types of athletes, such as cyclists and swimmers, and in nonathletes, such as soldiers after a strenuous march, DeGeorge said.
Because the man’s mild anemia was considered “clinically insignificant” — in other words, it did not affect his body’s functioning, and it did not impact his athletic performance or endurance in any way — he did not need to make any changes to his workouts, training or lifestyle, DeGeorge said.
@Heather. Thank you. I learned something new which is always good for our brains.
I’ve just passed 50 and compared to 10 years ago, I certainly need more recovery time. It’s kind of self reinforcing and turns into a vicious cycle for many people.
Exercising is not nearly as fun and encouraging as it was 10 years ago. Intensity and speed have dropped, general body pain has increased and so on.
Still exercise is non-negotiable. It can’t reverse the damage, but it can slow it down.
I’m crossing my fingers that E5 can not only slow down but actually bring back the energy level I had in my early 40’s.
Ole it will. Hopefully even earlier than 40 years energy. Till that time write to me at atomicblissventures at gmail dot com
I will share with you certain supplements and regimen you should be able run for 2 hours non stop and will stop only because you get bored. Fortunately 50 is quite young so if not reverse at least we can ensure to stop or slow down your aging.
I also had the same problem in my RBC’s and hemogloblin. I had this for a few years at least. I’m 74 and thought I could get more energy if I could increase these numbers to at least average. Already eat a lot of beef because I have a keto diet. Plenty of iron. I was taking B12, and decided to take Vitamin B complex with high amount of folate acid and B3. It worked. Had a noticeable jump of my numbers into the normal range. Hard to tell if I get more energy with more RBC’s. Got lab results only last week, so will have to monitor for awhile.
I’ve fasted 20 hours a day for the last 5 years, and haven’t noticed any reduction in hemogloblin. In fact the opposite.
Supplementing with iron is not necessary, especially not for men. Iron is a double edged sword. You need just enough, but too much will set you up for a bunch o health issues. I did however change my diet to include a bit more meat, as I had almost turned vegan.
@Ole
Which is your age? Fully agree on iron (actually had high ferritin ans succeeded lowering, likely using IP6). I am tracking biomarkers since 20+ years but bad in tracking diet (looking for AI assisted tools also incl. microbiome, glycemic response and physical activity).
albedo, I’ve just turned 50. This is what I do every day with very few days off:
20 hours fast. (I stop at 7pm and starts eating at 3pm)
I run daily (I mix HIIT with longer runs)
Core body exercises
Strength training like push-ups. (Unfortunately I can’t do deadlifts anymore due to lower back issues)
I eat primarily plant based (low GI foods like cruciferous vegetables, spinach, kale, beans, lentils but also lean meat). I do eat fruit, but try not to overdo it due to fructose.
I combine quercetin rich foods with apigenin rich foods as an inhibitor of CD38, which is a major consumer of NAD during aging.
I use no ‘exotic’ supplements. The only supplements I do take daily is a multivitamin, omega3 capsules, extra vitamin D, magnesium and vitamin K2.
I donate blood every 3 months to keep iron levels in check.
Reduce stress and try to get enough sleep and not worry to much about aging (which can de difficult at times)
I do not supplement iron. Get all I need in diet. But to make more RBC’s you need more of the vitamins I was talking about, and it works
@Akshay
I wonder if you could you share here thoughts regarding RBC and hemoglobin?
@Ole, thank you. These look to me wise and balanced choices.
Hi Akshay,
Have you seen the study: Prognostic value of grip strength: findings from the Prospective Urban Rural Epidemiology (PURE) study.
“This study suggests that measurement of grip strength is a simple, inexpensive risk-stratifying method for all-cause death, cardiovascular death, and cardiovascular disease.”
If E5 increases grip strength in humans as it does in rats this would be very good news for all of us.
Hi Gerald,
I agree with you. In our rat study we have grip strength data which showed reversal back to level close to young rats. It will surely be part of the protocol of our Phase 0/Phase 1 human trial.
I’m not sure you’d need this for a human trial. It might be useful for mice or rats, but with an old person any improvement that is going to markedly increase their grip strength should surely be obvious in other ways.
Instead I’d recommend using daily biomarkers for BP, HRV, pulse rate and reaction time. I’ve been doing that since last December and as a result I have been able to see what actually works and what doesn’t.
I’d expect E5 to reduce BP, pulse rate and reaction time and to increase HRV. In my experience Reaction Time is the most difficult to reduce with supplements/drugs, so it is a robust indicator of real rejuvenation. BP can be reduced by various supplements but reducing it at the same time as increases HRV shows something special is going on.
How do you check reaction time and HRV? I check HR variability by taking my pulse and seeing a speeding up with deep inspiration and a slowing with expiration.
With a chest strap and smart phone app. I do a 2 minute check once per day. Gives me HRV/ RMSSD, and HR. Get BP from BP monitor. I use a smartphone app for simple reaction time (take average of 5 results in moving finger off once screen changes colour).
Mark all good suggestions. Thanks
I would think that reaction time is a pretty good gauge of neurological age, whereas the others that Mark mentioned would be assessing cardiovascular status. Grip strength is a proxy for overall muscle tone and strength.
Just park.com also has a reaction time test where you’re driving along and a stop sign appears. It then gives you your reaction age based on 2000 people tested.
Paul We are planning many assays so muscle strength endurance will also be tested. We are even planning cutting edge assays for example I found a new technology that can measure blood oxygenation in the brain non-invasively yet accurately. As you know oxygenation tends to go down with age. In our rat studies we had tested 30 biomarkers so humans would be more. I am also keen to find out E5 can fully cure chronic diseases.
You’re doing some amazing work. Can’t wait for the final results.
For the average person and even as just a quick test in general Grip strength is an easy marker test.
Great work Askay.
Please keep us all posted.
Thank you Heather
Certainly a whole bank of tests is useful. But if money and time is limited and you are testing people who are already looking after themselves i.e. longevity enthusiasts, then grip strength is not going to tell you much. I am in my forties but my grip strength is greater than in my twenties due to weight lifting. I have manged to maintain a very good HRV as well. My BP is almost as good as in my twenties. But undeniably my simple reaction time has crept up. I am very aware of this as I did a lot of martial arts from my early twenties until my late thirties. You can’t train reaction time back down. Hence why I say that this is the most robust biomarker I know for real rejuvenation.
The other thing is skin quality. But that is harder to benchmark and varies a lot by ethnicity.
@Mark
young.ai has “photoage” test, and it is free. I think it checks skin and eyes to determine age (+/- 2 yrs)
Mark – Steve Perry has been organizing a biohacker group that is using GDF11, and they use reduced reaction time as a key indicator of success. GDF11 is way too experimental for me, but I did find reaction time as an aging biomarker an interesting concept, so a while back I started tracking mine periodically to establish a baseline. As I try new anti-aging approaches, I’m using it as one of several tracking methods.
@Zisos, I tried the photo-age and it thinks I’m -10 years compared to my real age. Nice, but clearly wrong even by my own biased judgement!
@Mark
Hehe… I guess they try to make us feel good. I am 69, and it reported 52 (I.e. -17)
I use a free android phone app that uses the camera and light on the phone to measure HRV, called HRV camera.
There are other areas that are helpful to monitor as well: Vision, Hearing, Inflamation, Lung function, Quality of life, etc……
Hearing is an interesting one. Maybe measuring the highest tone you can perceive would be useful. Of course this varies between individuals but could still be useful.
Have people seen this study?
Evaluation of an oral telomerase activator for early age-related macular degeneration – a pilot study
“The oral TA significantly improved the macular function of treatment subjects compared to controls.”
Very good news for people with a family history of this type of problem.
The study looks very under powered statistically to me. But nevertheless TA-65 does show some tantalizing, if small, benefits. It would be interesting to see what more powerful telomerase activators can do.
from personal experience, after consuming centella asiatica (it contains madecassic acid that has beaten TAM-818 by small margin in some tissues) my macula of retina regenerated visibly and color perception spectacularly returned to what I last seen as young teenager (before it worsened very much). So the result will be very spectacular indeed.
Very interesting, thanks for that anecdote. What type of gotu kola extract do you use and how do you know the active part is the madecassic acid? Typically triterpene fractions contains asiaticoside, madecassoside, asiatic acid and madecassic acid. The two former get converted into the two latter in the body.
I don’t know if this is madecassic acid, it’s just a guess :). What extract? Raw dried leaf (2 tee spoon) combined with veronica officinalis (2 tea spoons) (which used previously alone improved noticeably short term memory), brewed, and scuttelaria baicalensis boiled separately for 5 minutes to 1 hour (varied times), taken in the morning, and repeated this dose after 2-3 hours.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755196/#!po=3.15315
Check Figure 1
KSM-66 is good.
My understanding is that most tumors reach the Hayflick limit quickly and are not a problem. But what if we are constantly promo ting telomerase?
Hi Tom , from what I’ve read its not a problem at least as far as cancer is concerned as cancer cells produce their own version of telomerase , some research labs in the US still use cells from a black woman who died from cancer in 1955 the cells are still proliferating ,
Yes but if we are supplying the tumor with telomerase, won’t it keep growing?
The original cells from the woman that died are still alive they don’t appear to have a hayflick limit
Exactly. They produce their telomerase
I think that the controversy over telomerase arises over the concern that if a cell is damaged then it’s beneficial if the telomeres shorten and the cell becomes senescent. This protects against the development and spread of cancer. Those senescent cells are then mostly removed by your immune natural killer cells.
On the other hand, in the absence of telomerase, telomeres become critically shortened and this destabilizes DNA which also leads to cancer.
Once a cancer develops it’s able to produce telomerase in abundance.
Mark has pointed out that in mice, Maria Blasco had them develop very long telomeres and they lived longer without cancer.
It also seems that mTOR inhibition via rapamycin may not be safe in the presence of very short telomeres ( actually promotes aging).
So at present it’s all very confusing.
Most tumors are not cancers (they cannot produce telomerase). But if we constantly supply telomerase, won’t those tumors continue to enlarge?
You won’t convert benign, well differentiated cells into cancer via telomerase activation, but if you have damage to the genome it is preferable for the cell to go into cellular arrest. In theory, you would be interfering with this protective process by taking something like gotu kola. At least that is the prevailing theory. Even people like Elizabeth Blackburn buys into it which is why she’s opposed to those types of supplements. On the other hand , she’s in favor of exercise and meditation which elongate telomeres via telomerase. Somewhat contradictory.
Once you have cancer then it doesn’t really matter because cancer cells are able to produce relatively large amounts of telomerase on their own. Gotu kola would be like peeing in the ocean.
Most very old people have a homogenous telomere distribution pattern where the very long ones get a “ haircut”, and they have few critically short ones. The general lengths tend to be longer than average. Ashkenazi Jews have very long telomeres and live long.
Right, it won’t convert tumor cells to cancer cells, but with constant telomerase promotion, won’t the tumor continue to enlarge?
Shouldn’t continue to grow like they might under the influence of growth factors like IGF and growth hormone.
The tumor occurs because a cell is damaged in such a way as to have unrestricted growth (but not to produce telomerase) Normally, the Hayflick limit will cause the tumor’s demise.
that’s why the substance that promotes telomerase in healthy cells and inhibits telomerase in cancer cells would be the best. There are few such substances like sylibinin and baicalin, and telomerase promotion is only in few cells types (like liver cells) and only weak (in liver on par with TA65 in skin cells), but telomerase inhibition in cancer cells is much more broad.
An interesting study increased telomerase substially, by intermitently using low dose fluvostatin and valsatran (very inexpensive and widely available)
https://pubmed.ncbi.nlm.nih.gov/26214555/
I sort of recall that study because it gave a very significant improvement in endothelial function. I wasn’t able to get valsartin because I think it had been withdrawn because of some contamination problem, but I may be mistaken.
I’m guessing that you could get a similar improvement from gotu kola, pine bark, high polyphenol extra virgin olive oil , and 100% cocoa.
Yes, the statin and sartan month long experiment increased endothelial progenitor cell proliferation because telomerase was upregulated, and hence rejuvenated the arterial wall. It had to be intermittent, however. It is unclear if this is because the telomerase increase was not sufficient for prolonged proliferation or because other effects of using a statin long term, for example, were counterproductive. Note the most effective dose was very low, probably to avoid the normal effect of statins. Note also that long term users of sartans have longer telomeres.
The amount of telomerase produced by a cell line permits a certain level of proliferation and leads to a certain ‘maintained’ telomere length. Increased telomerase generally leads to increased proliferation, although it doesn’t force it. In general telomerase permits continued proliferation by preferentially locating to and preventing the accumulation of short telomeres, which is why even weak telomerase activators like TA-65 have beneficial health effects.
The concerns around cancer are that a TA might allow a pre-malignant lump that has not yet mutated enough to activate telomerase to grow larger, and hence increase its chances of acquiring such a mutation. Longer telomeres would make such a mutation less likely however, due to improved genomic stability, plus telomerase would also help the immune system to find and destroy cancers. Theories aside, the data so far does not indicate that TA cause increased risk of cancer.
My personal view is that the popular idea that you have to age to avoid cancer is wrong.
Ashwagandha extract KSM-66 is 4 times as effective as TA-65 and far less expensive
Harold and Akshay, forgive me if you’ve already addressed this, but do you expect that—or do you plan to test whether—Elixir/E5 will reduce or reverse (or slow or mitigate) tissue fibrosis and/or ECM stiffening due to AGE or cross-linking as seen with aging? If you are seeing improved organ function in animals in your experiments, would that be at least part of the explanation?
Gary,
Exactly the kind of rejuvenation seen across tissues/organs would not be possible without rejuvenation of ECM. But this is an assumption. In one of our upcoming studies we want to test ECM markers before and after to be able to make a claim. A cell can not remain young surrounded by an old ECM.
Hi Akshay,
My wife and I are both looking forward to trying the Gel when it’s released on Amazon.
Have you decided yet on a product name for the Gel?
It helps finding a product quickly on Amazon if you have something unique in the search string.
Gerard my thanks to you and your wife for wanting to try it. I hope it will delight both of you with its results. Brand name is in the making and I agree with you that a unique name makes easy to search.
I’ve never heard of a benign tumor, such as a lipoma, growing larger in the presence of a telomerase activator, but even so it wouldn’t be particularly concerning.
The real issue is whether a small , indolent malignancy , which occurs in prostate,breast, and colon, would become more active and aggressive in the presence of TA or gotu kola. There’s no good trial looking at that possibility.
We do know with some degree of certainty that rapamycin prevents cancer to a significant extent so adding it to one of those telomerase upregulators would seem prudent.
It is just a theory and as I said probably wrong, that a telomerase activator would give a boost to a benign growth. The only cancers we get to know about are those that are already malign, and can make all the telomerase they want. In fact they don’t want too much telomerase, as cancers need short telomeres so that their mutation rates remain high, so they can evade the immune system and adapt to chemo.
I wonder whether rapamycin is really just dealing with cellular senescence by reducing its worst effects. Ideally, if we could remove or rescue short telomeres we shouldn’t need rapamycin. If this is true, mTOR inhibitors should be regarded as a stop-gap only. This makes sense when you look at the evidence that rapamycin does not give additional benefits when started in younger life; the life extension benefits are fully realised in mice at least, taking it at fairly advanced ages.
As a TA-65 is weak (or not so weak?) anti-cancer agent and it vigorously rejuvenates immune system this is very interesting question… just this answer ’cause of it’ specifically won’t address enhancing/inducing telomerase expression relationship with the cancers.
@Mark “My personal view is that the popular idea that you have to age to avoid cancer is wrong.” it’s just the opposite… while aging doesn’t cause cancer, aging increases the risk of getting cancer and dying of cancer exponentially.
„Senescent cells and the incidence of age‐related diseases”
https://onlinelibrary.wiley.com/doi/10.1111/acel.13314
„[…] We used a conservative approach, by assuming that only 25% of the senescent cells are vulnerable to the treatment […] Treatment beginning at age 60, and given every 30 days, reduces disease incidence by about tenfold within a year (Figure 5a). The incidence curve is shifted to lower values corresponding to an age that is about 25 years younger (Figure 5a). Prevalence of the disease until age 90 is reduced by about 80%.”
While I agree that age related disease is caused in the main by cellular senescence, I don’t agree that simply ‘deleting’ these cells will be helpful. Cells become senescent for 3 reasons:
1. telomere attrition; this can be addressed through TERT and/or TERC upregulation using small molecules, gene therapy using viruses or even mRNA;
2. DNA damage from various insults; some of these cells can be repaired using systemic factors like gdf11, others have to be destroyed (ideally via a rejuvenated immune system through 1. above, but possibly with senolytics);
3. Oncogene activation; we don’t want to mess with this process, but a rejuvenated immune system should clear cells arrested in this way that don’t do the honorable thing and self-destruct.
Addressing telomere attrition is the most important of the 3 above, because it allows for the replacement of cells that need to be disposed of. The human body has a very short telomere length for historical reasons, so forcing it to renew (i.e. using senolytics) without compensating factors will likely cause long term harm.
This is all interesting and raises many important questions.
1. Is the use of senolytics necessary in the presence of rapamycin which is, in itself, a geroconversion inhibitor and reduces senescent cell load? Would it be overkill?
2. Can senolytics cause long term damage as Mark suggests?
3. Since cancer is a matter of growth vs. removal, can we just improve our numbers of NK and T cells ? Perhaps this could be accomplished with modified rice bran, cistanche, and rapamycin.
4. Can indolent, well differentiated cancers , frequently seen with breast and prostate, become more aggressive with telomerase up regulation? How does something like IP 6 cause poorly differentiated cancers to transform into well differentiated types?
No easy answers.
Personally I’d be very careful with senolytics, especially as a monotherapy; without something else to allow for cellular replacement. For example, this study shows dasatinib, a well known senolytic, can cause endothelial dysfunction. This was alleviated by a ROCK inhibitor, which induces a simpler cell structure and telomerase activation: https://www.frontiersin.org/articles/10.3389/fphys.2018.00537/full
It would be fascinating to know if the dog trials have begun yet? Or how the rats are?
Hey Akshay
I just wanted to say I am incredibly hopefuly that this works. I am only 26, but it would be amazing if this could be available for my grandparents (who are in their 60s) and other people (And even me when I reach that age lol)
Thank you to you and Harold for putting the work in here. Would love to know how confident you are and if there any updates for us? (Maybe regarding the dog trials, or the the rat longevity trials?)
Thank you Gordo. Supporters like you make our day. Our Lab is finally set up in California. Next week we hope to make first E5 in US. Lifespan trial all rats still alive including controls. We are confident enough to try E5 on ourselves this year assuming we get our IRB approval. Confident enough to allow an award winning German documentary maker full access to our Phase 0/Phase I trial. Our greatest joy would be if E5 can fully cure diseases onset by aging as that will have direct impact on hundreds of millions suffering from chronic diseases. Pray for us.
Thank you Akshay for the response
That is all incredibly exciting.
Having a filmmaker involved is only a potential positive!
Hearing the rats are still alive is obviously positive information and I wish you all the luck in the world with producing the E5 next week
Good luck and God speed. I cannot wait to keep hearing more
What kind of E5 are you making next week? Rat? Dog? Human? Is there a difference?
I believe it would be the one for rats most likely. Possibly humans. I believe Greg Fahy is doing the dog trials seperate to Harold and his team so he should have already been in possession of elixir (If I’m wrong about this I hope Akshay or someone else corrects me)
Gordo we can’t talk much about E5 nor hand it over at this juncture- we will going ourselves to deliver.
Thank you for the correction. I must have misinterpreted some information I heard or read elsewhere. That’s my bad. I apologise.
Keep up the amazing work
Hi Akshay,
My family and I are all rooting for you and Harold’s success. I was wondering if you could also give us some updates on the blue gel and transdermal patch (has the human trials started yet? And when are you expecting them to be available for the public?). Sorry if this has already been asked.
Akshay
Would love to know how attempts to make E5 in the US went this week?
Thank you in advance
Doesn’t seem to have shown up here yet:
* https://en.wikipedia.org/wiki/Young_blood_transfusion
@Tim Tyler I was not aware that Yuvan was working on young blood transfusions. As I understand it the E5 treatment involves epigenetic compounds derived from young plasma. The difference being that Yuvan would not inject patience with young blood plasma directly.
I meant ‘patients’ – sorry.
Hey Akshay,
Hope everythings gone well with making the E5 and other such tests. Just wanted to let you know that I have faith in Harolds vision and I think you are very lucky to have met him and got involved
Any updates you’d like to give us? Am I right in assuming ‘atomic bliss’ is a potential brand name?
Hi Jordan, you are right I am lucky to have met Harold and our our other core team members. I am grateful for all their contributions and sacrifices to develop E5. Update is the same that I posted recently our first batch is under production in California. No Atomic Bliss is not being considered for branding. Thank you for your faith and support.
Just waiting for the opportunity to turn my support from being faith based to being money based
Very excited at the possibility of ordering some of the blue gel as Christmas gifts this year
Thank you Jordan. I believe one needs to work hard to be lucky. And we are working hard to make it happen. At 76 yrs the other day Harold was 10 hours at our Lab. Our business associates see my mail at 4am and also sometimes at midnight.
Supporters like you inspire us to do this 🙂
Both you and Harold have a commendable optimism and work ethic. 10 hours in a lab isn’t easy at any age. Harold seems very passionate
Thanks for all the effort you and your team put in.
Hello. Despite the fact I do respect to all of you I am still a bit skeptical about E5. If it will be able to become young again, defeat chronic illnesses, cure diseases and etc, why would FDA want that? The global revenue for pharmaceuticals was over $1 trillion in 2014 and Big Pharma and medical device companies make billions of dollars every year. I hope some very interested people will still be able to have a miraculous E5, no matter what the regulations and strict laws will be.
Hello Nanaka,
This is indeed my fear with the path taken by Harold and Akshay. I admire their faith in the system*, but I really hope that, should it appear the system will not allow masses to access Elixir, they will make their formula public.
Good luck to them in the meantime. Hopefully we’re just paranoid 😉
Agreed, was just going to post something similar. The FDA is under regulatory capture. I fear the fda will string them along in bureaucracy until they are drained financially and then go away in order to protect profits for the industry. Sounds conspiratorial but it is a real phenomenon. I wish Harold and Akshay would consider offering their product offshore in panama like all the other forbidden treatments have ended up moving to like stem cell treatment etc.
Honestly the USA would save so much money by curing ageing that it isn’t even a debate
Also there are countless other countries with nationalised healthcare they could in it in the event of worst case scenario with the FDA (The UK possibly could be a good option. The NHS spends a lot of money on caring for the elderly)
I understand the worry around the FDA, but here the financial benefits are unbelievable and I can’t see them stringing it along for any reason.
Also it wouldn’t be a one treatment. So the repeat treatments are where money would potentially be made back
Agree with Gordo
The USA has no interest in saving any money. Tragically they like to spend not save. The gov looks at things and makes decisions based on what will increase gdp versus lower it. So all of the seemingly crazy, corrupt, favortism and awful decisions that are made by the gov finally make sense when you realize they arent making decisions on what saves money or what is good for the health of the americans, they make decisions on what is best for the economy. So toxic foods makes money for big food industry and downsteam health effect boosts the healthcare industry, toxic medications that produce injuries that then need more healthcare and more lawyers, it all finallly makes sense because its good for the economy. Crime, good for the economy, jails, lawyers, prisons all good for the economy. Street drugs, lots of money for the myriad of justice divisions also all the lawyers, prison system etc. Toxic drugs that cause harm, big pharma profits, injuries, lawyers, all good for the economy. Toxic chemicals, big profits for big industry and downstream benefits for sick people that need more healthcare, this is all very good GDP stuff. Its not about creating a nice safe healthy place, its about raising the gdp at the expense of the health and safety of its citizens, its simply to sacrifice it all in the name of GDP. Suddenly the crazy unhealthy unsafe world we live in makes sense doesnt it? So saving money on healthcare for the government is not their agenda, its gdp. So ask yourself, does this product increase gdp or decrease it and you will have your answer on whether they approve it or deny it.
It massively increases it
A crazy amount
Imagine how many people would come out of retirement and go back to work. Or change career and contribute to a new field
Honestly what you’ve written reads more like a conspiracy theory than it does any kind of real breaking down of the situation
Fred those treatments sold in those islands are deemed suspect without clearing the regulatory scrutiny and may have untested risks. FDA has in fact given Fastrack status to more than 50% of the IND applications. If there is reliable data confirmed by doctors that shows even partial resolution of any age onset diseases which do not have any prescription medicine it would be very very difficult for any regulatory body to hold it up. In fact they would support measures to bring it faster to those patients.
Don’t worry, folks. I’m sure The oh-so-liberal Biden administration can arrange to have VPOTUS Harris lash up with Richard Angelo, and form a committee to make sure elders get the rejuvenation that they deserve, despite objections from rogues at the FDA.
Europe Would like that anyway. Its welfare system is overwhelmed by the costs of aged healthcare and pensions. And if Europe wants it this problem for the USA is half solved. Can you imagine having antibiotics in Europe and not in USA?
Akshay,
Now that April is here, I was wondering if you could update us on Blue Gel? Are you still on schedule for an April commercial introduction? Have you given it a trade name so that we know what to look for? What are the unit size and cost?
Thanks,
Rick
April end or early May. We will share the brand name plus look at giving a special discount to Mitteldorf community.. Also expect to see early results of our human clinical trial here.
Discount! I like the sound of that. Either way I’m calling shotgun on the first box of the blue stuff! 😉
Thank you Michael 🙂
Hi Akshay, can the blue gel be expected to help with hair growth for male pattern baldness?
Oliver not sure. We can try and see. In the first human trial we are only testing for wrinkles and age spots. From anecdotal evidence from a colleague in a future trial we want to test for hemorrhoids as it had stopped the pain in one hour and healing in 3 days. When it is launched and someone brings us snecdotal evidence of hair regrowth we will include it in a subsequent trial.
Do you plan on measuring telomere lengths of your test subjects during your upcoming trials??
David no we are not. Do not consider telomere length as an accurate biomarker for age determination. We have Horvath Lab which has developed the most accurate clocks in the world. I would rely on reading of these clocks with confidence.
Correct, Akshay, telomere length has shown little relationship to longevity.
I would hope you use something like GrimAge instead of a clock validated to chronological age. As I keep telling the Deep Longevity guys, I already know how old I am (at least on my good days) – what I want to know is how healthy I am.
Wayne totally agree – Grimage is an excellent reading to get as actual human lifespan data will take decades. But for us epigenetic clock is important as it tells us if biological age has actually reversed. We can have both.
I use Longevity Phenotype to track my progress on longevity strategies. It works great and only requires standard CBC type blood test to work. Also it has been proven in studies to be fairly accurate. Grimage is probably better, but much more cumbersome to use, and more expensive.
@Van: Are you talking about the same PhenoAge clock that I’m thinking of? If so, I would like to point out that it is heavily weighted towards a chronological age input factor. It says that I’m 72, but if I lie and tell it I’m 46, then it says I’m 46. That implies to me that I have the blood profile of a 46-year-old! (I’m 79.) I agree that the standard blood tests being used make it practical for the average person with limited funds, but I think the heavy weighting on chronological age makes the rest of it somewhat suspect. Deep Learning’s young.ai does not use actual age as an input factor, so I like it a bit better. Nonetheless, it, too, is trained to chronological age which I suggest is not what we should be interested in.
As an interesting side note, serum albumin is one of the most heavily weighted parameters in both models. I at first attributed this to the results of the Conboy’s “dilution” experiments with a fixed 5% albumin substitute. I have since learned that there may be different forms of albumin in the aged as well as a reduced serum level. Stay tuned.
https://www.biorxiv.org/content/10.1101/363291v1?fbclid=IwAR0oeUVV3rsLy4unjRemldsodlEwJy8h9Z6uuRRKX_FzZhc35Rf67k6CpAc
@Van: Yep, my comments were about Levine’s clock.
Another interesting side note: Insilico’s predecessor to young.ai, aging.ai, gave me a “bioage” of 46 while young.ai gives me 72 with exactly the same 19 inputs. They tell me this is due to the much larger database used by young.ai.
I believe that all epigenetic “clocks” are not yet quite ready for prime time. One reason I say this is that even the DNA methylation clocks don’t consider the many histone modifications that may be even more directly causative. Meanwhile, I suspect GrimAge or its ilk will prove very useful for determining the direction of change if not a precise magnitude.
Agreed. Histone modifications seem like they likely have important interactions with DNA methylation in terms of determining biological age. Interestingly, in 1935, Alex Carrel explained in his book “Man, The Unknown” that he was able to calculate a rough biological age for dogs by calculating how much its blood plasma restrained (or not) the growth of a cell colony.
Most of you guys here are scientists or at minimum have a scientific background. As a lowly engineer my perspective is this: If there is any rejuvenation then it should be blatantly obvious. Meaning the subject should look and feel younger, athletic performance should increase, better sleep patterns, more energy during the day, better rest at night, etc. etc.
I’m always surprised when I hear some of you go to great lengths to actually measure your biological age. For scientific purposes I completely understand and you want to know if a particular compound is working. But as Yuvan is now nearing the release of a commercial product (the blue gel) more practical measures will be required.
In other words: it’s great if some lab test shows that I have gotten five or ten years younger. But if my bathroom mirror or my wife disagree it’ll be a tough sell 😉
There needs to be a distinction made between the usefulness of measuring telomere lengths in certain cells with the methods currently commercially available, and the importance of telomeres as they actually are for aging… Of course telomere length is vital in aging. But the methods to measure it are not very good, hence the large scatter in results…but even so the biggest factor in the variation in TL is age. I am hopeful better methods will be available soon.
I note that GDF11, a purported systemic rejuvenation factor, upregulates TERC and restores telomeres in both mesenchymal and neural stem cells. The following paper is for MSCs.
https://www.biorxiv.org/content/10.1101/2020.03.30.008722v1
@ Wayne and Kerry
Man did I call that one right, re: albumin; see upthread on November 17th!
And more on albumin – it might not even be necessary to add ‘undamaged’ albumin. With age albumin blood concentration falls (with a correlation value of >0.98). You could make a great aging clock ONLY MEASURING ALBUMIN CONCENTRATION.
read nearly every post here going back a year. As a layperson in his 60s it’s amazing to find many refreshing ant-aging ideas and more. So when can I buy your gel or patch and when will the Elixir method be available?
Thanks for thinking of life before luxury.
Yes Mitteldorf’s is probably the most eminent science blog for anti-aging enthusiasts. Gel should be available in the next 45 days. Patch either Christmas or early next year. E5 as we call Elixir now will take much longer as it has to go through FDA regulatory review.
Hey Akshay, when you say E5 will take much longer as it has to go through FDA regulatory review, are we talking 2 years? 5 years? 10 years? Or no idea yet? Best of luck – I’ll definitely be snapping up some blue gel as soon as it’s released! 😀
Thank you Oliver! If in the preclinical stage or IRB Phase 0 human clinical trial we are able to reverse any disease onset by aging like Sarcopenia which has no medicine available then FDA may fastrack E5 review. This can take 18 to 24 months. If it isn’t fastracked then it can take 3 to 7 years.
@Akshay
What are the requirements to participate in clinical trials?
In our IRB E5 Trial we are giving priority to our investors who wish to volunteer. They should be above 65 ideally with a pre existing condition like atherosclerosis, type 2 diabetes or sarcopenia.
Thanks, Akshay. Sadly, I just fulfill the age requirement.
What is the minimum investment, and do participants need to travel to California?
Regards and best wishes for the outcome of the trials.
James only accredited investor can invest. We will provide air travel and accommodation for the trial.
Akshay,
Can I make a suggestion that you use kidney function as a therapeutic target for your clinical trial and getting E5 through FDA approval? It has several advantages: testing is easy, clinical endpoints can be clearly set, there are no other treatment options and you achieved significant kidney function improvement in your mouse study. Also, if E5 could get patients off of dialysis, or prevent them from going on dialysis, Medicare would probably pay for the treatment.
Rick thanks – that’s a good suggestion. I have seen many die due to kidney malfunction and once it begins to falter its like having a timer in a bomb being activated. I have to discuss with our team as to what non invasive assays and tests can be selected which can be pass through peer and FDA reviews.
The dilemma, it seems to me, is that specifying a condition then requires a trial population with that condition. I, for example, could not participate because my only clinical condition is age. Mayo clinic has used Chronic Kidney Disease for D+Q and fisetin senolytic trials. But what percentage of your older investors are stricken with CKD? Most of us have a degree of sarcopenia, or at least dynapenia, but I doubt the FDA considers it as having no current treatment. Diagnosis of sarcopenia is also a problem – closest thing in most old folks medical files might be frailty.
I’m thinkin’ Dr Fahy may have hit on the ideal solution. ALL us old folks have thymic involution, and there is no treatment! (How he got past the FDA puzzles me.)
Dr. Fahy is a respected scientist with a great body of work. Thymic involving is directly linked with collapse of T-cells which does cause immune related deaths in the elderly. The presentation may have convinced FDA of the benefit of such a prescription as there is no medication available to restore thymus clinically. Sarcopenia is a condition that affects all adults as they grow older. I have not come across medicine that is prescribed by doctors to remedy sarcopenia. FDA has approved drugs for early stage of alzheimers or dementia. So hopefully similar evaluation outcome may come through. Atherosclerosis is also quite common as we grow older. Anyone that is prescribed statins is eligible. Our studies have shown LDL go down to normal levels and HDL go up. Statins manage the condition. E5 can hopefully cure it.
Akshay: No medicine available, but treatment with strength training is very effective for sarcopenia. Perhaps the dog trials will measure the effect on the thymus and, if positive, you could use it as a primary outcome. I note that the secondary outcomes in a lot of clinical trials are often as important as the primaries but would probably not qualify for a clinical trial on their own.
It suddenly occurs to me that a discussion of trial criteria here is of little value. After all, you are already in close collaboration with Dr Fahy – a master at it!
Thats true and we are working with ex FDA regulatory consultants who will ensure appropriate application.
I think that the important concern here is getting E5 through the FDA process as quickly as possible. To do this you need to qualify for breakthrough status by having a treatment for an FDA recognized disease that has no viable alternative treatment. It helps if it is also a deadly disease. Whatever disease is chosen for clinical trial, it should be the one that gets FDA approval the quickest. There are several options in E5s case, but I think that Chronic Kidney Disease (CKD) is the most viable option.
Diagnosis of CKD is straightforward, often being diagnosed with a single blood parameter, creatinine. This simplifies the setting of clinical end points and tracking during clinical trials. Since the results are all hard numbers, tightly correlated with kidney function, success of the trial won’t be spoiled by the vagaries of questionnaires (Unity’s UBX0101), or a dependence on indirect measurements.
CKD should be a less expensive trial to run. You would want to run more tests than creatinine to get a full picture of kidney health, but I believe that they are all inexpensive, non-intrusive, routine blood and urine tests.
Key for many will be getting insurance to pay for treatment. Medicare currently pays for the vast majority of the 500K people in the US on dialysis at $100K per year. They would be highly motivated to approve any medication that would rescue patients from dialysis or remove them from the 100K on the transplant list. Johns Hopkins estimates that over 50% of seniors 75 and older have CKD. If E5 is inexpensive enough, it would probably also be approved for these people as well.
Once E5 is approved, and has an acceptable safety record, it can be expanded to many other indications. Of course, this depends on E5 being able to resolve fibrosis and inflammation in an aged human kidney as well as it did a rat’s.
@Rick Davis: As a non-scientist layman this strategy makes a lot of sense to me. Start at the most favorable scenario and work yourself backward. Let’s make it happen!
CKD sounds good, but I would first want to know if enough investors wanting to be trial participants have it.
Wayne the Phase 0 and Phase is more about safety rather than any particular condition. We plan and will need to have many human trials as there is a lot we need to find out about E5 in humans. Besides safety the big ones are dosage and frequency. While targeting conditions for regulatory approval will come later in the Phase 0 for investors I will like to find out about change in any underlying conditions.
Rick I know you have mentioned CKD before and I agree that it is a good target condition. I will be bringing it up in our strategy discussions with our regulatory consultants.
Akshay, how can I get my name put on your email list for the gel?
Hi Kevin there is no email list right now. We will soon launch a website which has a way to submit your email for updates. In the meanwhile you can write to me at atomicblissventures at gmail dot com
Hi Akshay,
I was wondering how the rats lifespan study was going on. Are the rats still all alive? In both groups? I’ve been told that in the Argentinian experiment, some rats already died. Are there differences between the two studies?
Have you seen the Buck Institute researchers article about the oxylipin biomarker as a mean to assess the senecent cells burden? I don’t know if it could be applied to rats. But it seems to me simpler than a biopsy and could spare rats life.
https://www.genengnews.com/news/biomarker-discovery-could-aid-development-of-senolytic-drugs-against-age-related-disorders/
Patricio all the rats are alive in both groups. Argentinian trial is by another group led by Dr. Goya. They are not injecting E5.
I did see that paper from Buck with interest. Have to check with Harold and our principal investigator if we can incorporate it in any of our studies.
Hey Akshay. Despite the fact I do respect to all of you I am still a bit skeptical about E5. If it will be able to become young again, defeat chronic illnesses, cure diseases and etc, why would FDA want that? The global revenue for pharmaceuticals was over $1 trillion in 2014 and Big Pharma and medical device companies make billions of dollars every year. I hope some very interested people will still be able to have a miraculous E5, no matter what the regulations and strict laws will be.
It would be interesting to see the effect of E5 on CDC42 because it has been reported that the inhibition of CDC42 improved hematopoietic stem cell function, improved immune function and extended life span based on middle aged mice. The CDC42 was inhibited by CASIN using a single dose.
Moreover, a company analysed blood proteins of each blood of paired parabionts and discovered an extracellular protein called HAPLN1 and they believe it may play a crucial role skin rejuvenation observed in old mice paired with young mice.
Finally, can E5 carry out cellular reprogramming like OSK treatment in a mouse model of Glaucoma where vision was restored.
Hi Ghalib,
CDC42 is a protein with important functions. Nature has a system to regulate how much of any protein is printed, active but in aging this ratio goes awry. E5 may not directly inhibit CDC42 but may reset the production to a ratio that existed in a younger environment. I continue to believe there are no bad proteins. 100s of millions of years of refinement by evolutionary selection would have cleared any detrimental protein. That is why when we are young all systems work so well. Aging skews the ratios thereby creating harmful effects by oversupply or undersupply of certain proteins.
My answer to your second question is probably not. That was an extensive reprogramming done on specific cells whereas E5 is systemic reset of epigenome to a more youthful signature.
Dr. Horvath has been busy, coauthoring more published studies than there have been weeks in this year! This one particularly impressed, finding “Bat longevity results from augmented immune response and cancer suppression.”
https://www.nature.com/articles/s41467-021-21900-2 “DNA methylation predicts age and provides insight into exceptional longevity of bats”
Peer review comments and responses were informative:
Reviewer #1 – “Developing an aging clock that works for a diverse set of bat species is a spectacular achievement.”
Reviewer #2 – “This is a tour de force study.”
Replies to Reviewer #3:
“Difference in recorded lifespans between three long-lived species and two short-lived species that we used to identify longevity DMPs [differentially methylated positions] is 20 years or more, even though they have similar body sizes (20-40 g). The three long-lived species [maximum ages 29.9, 30.5, and 37.1 years] also represent three different phylogenetic lineages.
CpG sites that undergo hypomethylation with age do so largely at random. In contrast, sites that undergo hypermethylation with age are highly nonrandom, and as has been noted before, are near genes associated with development. So yes, we believe there are predictable methylation changes with age.”
Hey Akshay,
I am joining my voice to the numerous questions you are asked, sorry about that.
Any update on the peer-review of yours and Harold study?
Thanks
Hi Raphael,
We were going to submit to a well known journal but some co-authors wanted to add data. Should be submitted anytime now. I am expecting publication this year.
Could anyone tell me what effect should E5 have on teeth? Very interesting.
These are exciting results! May I enquire into the progress of the gel product?
I don’t imagine it will have much difference to be totally honest
But having fake teeth is relatively common already
I’ve always had bad/soft teeth and half of them have already been replaced. But I would not be that non-chalant about this. Implants and root canals are very invasive procedures that have high risks on the endocrine system. My thyroid issues may have been caused by a series of root canals I had to have done the year prior.
Now that said, I did see some research about two years ago where researchers were able to grow new teeth in animal experiments – I think they did this via stem cells. Still not fun to lose teeth but definitely an alternative that would be long term sustainable.
I agree. To be honest making your teeth and gums strong is easy with the changing of the diet but regrowing new teeth is truly an amazing thing. In fact, we can consider it as a program. Rats like to use their front teeth to nibble and gnaw at food and so have front teeth that keep growing. Alligators can make new teeth whenever they need and sharks have rows of teeth that they replace all the time. They get a lot more sets of teeth than us.
There is one insight that kind of intrigue me concerning E5, and it is its posology.
To make it clear: Dr Greg Fahy managed to reverse age, slowly at first and much faster during the last three months of his trial, increasing the signal of two important hormones and controlling insulin and diabetes drived from increase in GH, so modifying 3 factors in the environment of the body. To achieve the results it took one year of continuous daily dhea+metformin and Gh every other day. Yet the results were great, and perhaps would have been more impressive if they have continued some more time, as the rate of rejuvenation shown in the clocks was speeding during the last months. At least is what I think. In the second trial, if people are alright, they intend to prolonge the period 3 to 6 months after the initial year, to see if things work like this.
Dr Harold Katcher and Akshay managed even more impressive results with 4 doses every other day in rats. Which is a very mild treatment compared with the continuous treatment of Dr Fahy.
The Conboys managed also very good results just with ONE 50% of plasma replacement.
BUT
Having followed closely the Grifols trial on Alzheimer (unfortunately two relatives of mine are going through the disease), in which patients had a huge volume of their plasma, beyond 50%, replaced by albutein, and this being done weekly during a month and a half, only to show a mild slowing of their condition, but nothing similar to rejuvenation or age stopping, let alone improvement of their cognitive ability).
This makes me wonder if the plasma “cleaning” is effective in humans at all. Could be that it had worked in rats, but not in humans. This happens all the time with rats. Things work better in them!
The other way around, Dr Fahy trial makes obvious that adding young factors or signals, makes the body young again. So I am quite optimist that Dr Katcher has found something really impressive.
But also makes me wonder if E5 will require, just like Dr Fahy intervention, a long continued treatment to show effect in primates like us. Let’s say, 500ml of elixir every three days, during 3 months?
It would be great anyway.
Yes, I know that with rats it took just some few shots. But we’re not rats. And rats were able to become young again with a single plasma replacement, and that didn’t happen to the Grifols patients.
I’m looking forward how it works in dogs and in Dr Katcher himself!
Ines very good insight. We are thinking the same that the dose curve may be much longer with humans but it is something we have to find out from the human trial.
I have again and again posed the question of the relative therapeutic times between species. There seems to be an assumption that the ratio would be that of relative life expectancies. I offer that relative metabolic rate makes more sense. I have yet to get a specific response or any references. If this question is not answered, how do we know how long to continue a human study?
One good thing when considering the rat study: blood levels were clearly improving after 30 days. This would translate to about 6 months if my metabolic rate theory is correct or nearly 2 years if life expectancy is controlling. As for the frequency and duration of treatment, I don’t have a clue where one would even start!
Thank you Akshay, I am really curious about the process.
Furthermore, I wonder if in the first E5 trial will be women included. That’s a point, because most of trials are done in male mice and rats (I don’t know if this was the case in your first trial), and as it happened to Dr Fahy, is fis TRIM trial was with 9 male subjects, and now it turns out that the dhea hormone should be perhaps restricted to women in the TRIM-X trial. There is an aspect that really is a youth/age factor, which are the sexual cycles of women, as during those females produce Estradiol and Pogesterone among other hormones, which are the key pieces to avoid Alzheimer disease (women are twice more likely to develop AD) and osteoporosis respectively (and many more other nuisances that come with menopause, like arthritis, decreased libido and others). In man there is not such an abrupt post reproductive cliff, so it is something really interesting to see, not only because of the fertility issues attached, but because of feminine health itself.
So, that is my question.
A recent study showed pretty conclusively that the age of the albumin in plasma makes a huge difference. Until this is explored further, I am not going to put much credence in plasma dilution.
As for Fahy, it would be nice to know what the mechanism of action is in changing DNA methylation. Is it direct, or does it work through activation/inhibition of transaction factors, or what?
I turn 80 tomorrow, and I have a son who is 8. The answers to these questions and a resulting clinical therapy are extremely important to me.
Any man who sires children at over 70 years of age has my deepest admiration 😉
Any man who sires children who’s over 70 has my condolences ,
I also have a daughter age 19. Parenting has been the most rewarding thing I have ever done. I’m in fairly good shape, and I can still sometimes beat my son in an uphill race. I fully expect to proudly watch him graduate from college even without E5!
Yes Wayne but you were a lot younger when you sired her than your 70s I have two in their 30s both went to university and got degrees , but now I’m in my 70s I wouldn’t want to go through all th e nappy changing night feeds junior school senior school college then uni again , If E5 works , then I might change my mind but for now i’ll enjoy my retirement doing what I want , there’s a big world out there that I want to explore
Question for Akshay or Harold: Since it’s early May, is your Cupertino lab getting any closer to releasing the ‘blue stuff’? My wife wants it and she wants it now! 😉
Michael answer is yes. Once we get our trademark registration done we can complete our packaging design and launch the product. We pray for many more who are like your wife in their desire to try something new to improve their skin. At the same time we must manage expectations: The effect isn’t overnight. It would take 1 to 2 months of regular application to see the full benefit of the gel. We have filed our IRB application for the blue gel human clinical trial. We should have the approval in a few days. We are conducting a trial with 25 volunteers. We will be sharing data here as the results emerge. It will give us better clarity on how soon We can discern the change to the skin by the naked eye. The hi resolution ultrasound scans will show us what is happening in other layers of the skin. For example We expect collagen thickness to increase.
Just a question Akshay , the blue stuff , has this anything to do with the other work done at Maryland uni using methylene blue to reverse skin cells ageing ?
John no that is something else.
Thanks for the reply Akshay , knowing it’s not 1MB has eased the one concern I had having already used the the mb in homemade face cream ,
So here is a request to all enthusiastic community members. Blue gel although developed by Pharmaceutical PhDs in a Lab vs cosmetologists it has been deemed to fall under cosmetic category by FDA due to its safe profile. Could some of you purchase blue gel when it becomes available and apply on entire body – skin area twice daily for a month? You are requested to take a blood test measuring IL-6 and TNF-a before the first application and after 30 days of application. Each application should require 3ml each bottle of blue gel is 30ml so you may require to purchase 3 bottle for this. As per this UCSF trial you could have normalized and youthful levels of inflammation which as you know comes with significant benefit on various age related conditions. The logic the UCSF scientists took is that since skin is the biggest organ if one is able to calm the chronic inflammation on skin one would not only have youthful skin but also make a big impact on overall chronic inflammation in the body:
https://onlinelibrary.wiley.com/doi/abs/10.1111/jdv.15540
You can email me your results or post them here.
I would be happy to do that , but to get the blood tests done means I would have to get my doctor to agree to the tests and arrange them due to our NHS doing these tests , getting blood tests done privately may be difficult over here ,
That’s the big benefit of living in Spain. All I have to do is to see my doc and he’ll just write me a script. It’s all free and I can easily do it one month apart.
I’ll even put it on my dog if you want me to! J/K – but yes I’m absolutely game. My skin isn’t very old – I’m only 55 – but I have noticed more sagging around my knees and elbows. So I was already planning on buying it by the case load and using it everywhere.
Can’t wait to actually try it.
Sure, I’m in. I’ll include IL-6 and TNF-a in the annual physical preceding application.
That study has an interesting chain of citations.
Thank you PRice. I agree. I found that study quite interesting. Hope blue gel can do even better than what they did. That would transform it from an anti wrinkle to true systemic anti aging. Chronic inflammation is a precursor of almost all the diseases onset by aging. How many of have felt the soothing goodness of applying winter cream all over. So feel good, look good and get better inside everyday. Thats a lot for $35 🙂
Not sure that I’d be a good trial subject. My IL-6 last June was already at a negligible 1.0 pg / ml, one-fifth of the referenced study’s Baseline Young group’s 5.1 ± 0.9.
Congratulations not only not qualify for this test but also set you up for a healthy years ahead. Could you share with us your anti inflammatory regimen?
Thanks Akshay! That IL-6 measurement was taken on Day 70 of eating a clinically-relevant amount of microwaved 3-day-old broccoli sprouts everyday. My model was clinical trial “Effects of long-term consumption of broccoli sprouts on inflammatory markers in overweight subjects” https://researchonline.lshtm.ac.uk/id/eprint/4647168/
That’s the main treatment for 14 months now. Last week I switched to equal amounts of broccoli, red cabbage, and mustard seeds using the same protocol. It tastes better, but isn’t evidence-based in that I haven’t found a study on 3-day-old red cabbage or mustard sprouts.
I’ll participate as a blue gel user without officially reporting results. Analytics would probably kick them out anyway. 🙂
Akshay,
Am I missing something here? Three ml is a very small amount, maybe enough to put on your face or hands. It would seem that it would take more like an entire 30 ml bottle to cover a complete body. Does Blue Gel need to be diluted before application?
Rick unlike a lotion or cream it needs to be spread very thinly. Instructions will be on the product website and inside the packaging. After application try to keep it without anything else touching it – like towel or cloth – for 5 mins. Of course the amount to apply is not a major factor in the study just an indication. The actual amount would vary with body size. When you actually use it do give me feedback on amount required for you along with your height and weight.
Akshay, you have already my email and mailing address!
Yes I do Stephan. Hope you can participate by taking baseline and 30 dat cytokine reading?
Akshay, I let you know early next week whether this can be done up here.
The timeline will be an issue for me too since I’m leaving for a 1000 km solo expedition in Nothern Canada on June 28, 2021.
Am I right that the Blue Gel will be not available on Amazon anytime soon?
Hopefully it should be available soon. 1,000 km expedition in Northern Canada sounds amazing.
It will be a physical challenge at the age of 66.
I admire your spirit.
@Stephan: Make sure you take along a few packs of NMN or NR and you will blaze through it – no problem. My wife and I have been on NMN for a year now and the difference is stark.
@Michael
I have used different NAD+ boosters based on NR, NMN and Niacin for 2 years. To be honest, I haven’t noticed any difference.
My hypothesis is that exercise and fasting, which I both practice, raise NAD+ levels so I might have reached already a plateau.
Indigenous people in Northern Canada and Alaska have survived 15,000 years in these harsh environmental conditions with a nomadic lifestyle and foraging.
And that is what I’m going to do.
Dear Stephan I have some good news. You have been a role model for this anti aging community with your discipline and regimen. I also know Covid has stopped the tourism – your livelihood. So on behalf of all the Mitteldorf community members and blue gel brand can we be one of the sponsors for your expedition? Of course we are a small company so can only be a junior sponsor. I will also try to send you box full of blue gel which you can apply all over every night before you sleep. I hope it can power your expedition. In return if you do see any difference or benefit do mention in your documentary on the expedition or a video that we request. If you do not feel any difference then you do not have to.
That’s very generous Akshay. Great idea too! Stephan: You should definitely bring a video cam to record your excursions and report on how you are doing. Just don’t get eaten by a bear!!!
Dear Akshay,
I’m deeply touched by your generosity!
Any sponsorship, even the smallest, is much needed and appreciated.
As you know, I’m eagerly awaiting the Blue Gel to try out. In return, I can offer to spread the word:
I have secured commitments from several international adventure magazines to publish the story of my trip.
I have permission to post the progress of my journey on a Facebook group called “Yukon History & Abandoned Places” which has an active membership of over 16,000 people, most of them age 65+. They are also very active in sharing content with their circles, so there is a chance to reach a magnitude of prospected clients for your products.
Be assured that I document the progress of the Blue Gel application.
If you have a company logo and decals, I will prominently display them on any media produced and my gear.
OFF-TOPIC:
Anyone interested in the historic background of my solo expedition, please consider watching the following video:
https://www.youtube.com/watch?v=KGxHHAX1nOY
or contact me at stephan at bardubitzki dot com. I also encourage you to follow my journey on Instagram @klondike_stampede.
Thank you Stephan. What you offer in return is of much greater value so we should be thanking you for the opportunity. One of the many good things lost in our modern world is great adventures. Your expedition brings it back. I will move this conversation to email to take it forward.
“t the same time we must manage expectations: The effect isn’t overnight. It would take 1 to 2 months of regular application to see the full benefit of the gel. ”
Hi Akshay – great news!!! But I had to laugh when I read the above sentence :-))
You clearly have not been marketing products in the beauty industry. To give you an idea: 10 years ago a popular economist and writer called John Maulden (mauldeneconomics) sent out an email advertising LifeLine Skin Care. My wife and I were among the first clients and have used the stuff to this very day. That’s a decade of paying ~$200 per month plus minus as the price has come down a little since – you do the math because I don’t want to.
The benefits have been there, especially in the beginning. But they took a LONG time to materialize and in recent times I wonder if we should even continue. So when you are talking about 2 months I sort of have to giggle as this would be considered RAPID progress in the beauty industry.
Michael LOL yes knowledge of beauty industry is low. That would be good if 2 months is not considered a long duration 🙂
Follow up question for Akshay from my wife: She wants to know whether or not one should also see an improvement with lipids in the skin. You mentioned collagen but without lipids that sagging skin and hollow eye sockets would probably not fill in.
Yes we expect all the layers of the skin to improve- it should feel and look younger as that happens.
This could be a treatment that actually works for Rosacea , which would be fantastic , all those on the market so far are only half effective ,
That would be wonderful John
Michael:
The collagen alone should prevent sagging and provide moistness.
From the article:
When collagen levels are high, the skin is soft, smooth, and firm. Collagen helps the skin cells renew and repair themselves. Collagen also helps keep the skin moist. This is why collagen has been seen as a very important ingredient for skin care over the years.
…Collagen gives skin its healthy and youthful appearance. As people age, they lose collagen. Their skin becomes less firm, and wrinkles and lines develop.
https://www.medicalnewstoday.com/articles/317151#Ways-to-boost-collagen
Collagen scaffolds are used in tissue regeneration, whether in sponges,[14] thin sheets,[15] gels,[16] or fibers.[17] Collagen has favorable properties for tissue regeneration, such as pore structure, permeability, hydrophilicity, and stability in vivo. Collagen scaffolds also support deposition of cells, such as osteoblasts and fibroblasts,
Akshay, thanks for all the info you post here.
Will the blue gel be available by subscription?
You’ve mentioned Amazon, but there will be a run on it unless you have a purchase limit. With a subscription it would be easier to pace sales and arrange your production to meet supply.
Yes Nick we do plan to have subscriptions as an option.
@Nick Westgate
While I would love to see a “run for it”, I very strongly doubt it will happen. I am not pessimistic about the effects of Blue Gel. I am pessimistic about the adoption rate of ANY new cosmetic product promoted by an outsider to compete in such a high-stakes industry. Having been “burnt” by various false claims in the past, they tend to doubt newcomers. Needless to say, I hope that I will be proven wrong. The success of the Blue Gel will be a great ambassador for quick approval of E5. It will also provide funds that might be very necessary for Yuvan at these early steps. So, let’s hope that there WILL be a “run for it”.
Zisos you are right. Even if we have a great product it will be challenge to stand out in the clutter. But of the hundreds of thousands of products on Amazon 99.99% wouldn’t have IRB quality human trial data. Plus we hope to make available the high quality hi res ultrasound scans of before and after through a website and through a press releases. I am hoping our Medical Director who is ex Harvard University faculty and is good looking will get some television interviews especially once the trial is published in a high quality dermatology journal. We will try our best to let people know that such a product is available. After that the product has to do its own work to get word of mouth support.
Those of us who are skeptical about topical application having a systemic effect might note the following:
https://doi.org/10.1111/jdv.15540
AND, it’s a human study. AND, in only 30 days. AND, available on Sci-Hub.
The reductions in serum inflammatory factors were almost as astounding as the 155-day results of E5, if my initial scan of the article is correct! (I turned 80 today, so do your own analysis.)
I originally planned on saving my money for the E5 patch or injection, but I obviously need to rethink that. Even with raising two kids in retirement, I should be able to find time for twice daily whole body application.
Last I checked, my local clinic could not obtain IL-6 or TNF-alpha lab results. hsCRP is iffy for me, as just having a cold will explode it. I think my best inflammaging check is NLR (Neutrophil Lymphocyte Ratio). Others may want to consider it also, as it is readily available and cheap (CBC and Differential test – do your own division).
I have no doubt that Ashkay will ensure that the blue gel will be formulated properly for skin absorption.
A lot of substances are absorbed through the skin.
Sometimes a small amount of DMSO can further facilitate absorption of some substances.
From the Link: Factors influencing absorption[edit]
Along with inhalation, ingestion and injection, dermal absorption is a route of exposure for bioactive substances including medications.[2] Absorption of substances through the skin depends on a number of factors:
• Concentration
• Molecular Weight of the molecule[3]
• Duration of contact
• Solubility of medication
• Physical condition of the skin
• Part of the body exposed including the amount of hair on the skin
https://en.wikipedia.org/wiki/Absorption_(skin)
My wife and I use DMSO all the time – mainly as a pain killer but my wife also uses it to take NMN for better absorption. Now if that damn stuff wouldn’t just smell so bad!!
I also take NMN but in capsule form , along with Pterostilbene
and what I’ve found to be the best supplement out of all those I’ve tried over 9 years C60 in olive oil
The substance was designed to hydrate the stratum corneum, and the mechanism of action as I understood it was the resulting improved barrier function. None of the ingredients to my knowledge are anti-inflammatory. Perhaps I misunderstood it.
“That IL-6 measurement was taken on Day 70 of eating a clinically-relevant amount of microwaved 3-day-old broccoli sprouts everyday.”
How did you get a consistent source of broccoli sprouts over such a long time span?
I grew them while working from home. Current practice is pint Mason jars with plastic strainer lids. Soak seeds for 12 hours, rinse sprouts three times a day. Time adds up to about an hour a day.
How much sulphoraphane do you think you are getting a day? I think Rhonda Patrick says you need about 40mg but thats off the top of my head. Do you think you are getting more than that?
Hi Fred! I got an estimated 52 mg sulforaphane daily for 13 months with microwaved 3-day-old broccoli sprouts.
Don’t have evidence for more than 17 mg daily now that I cut broccoli seeds by two thirds to add equal amounts red cabbage and mustard seeds this month. Red cabbage’s main glucosinolate is also glucoraphanin, but haven’t found 3-day-old red cabbage sprout studies.
Mustard’s main hydrolysis product is allyl isothiocyanate. Haven’t found 3-day-old mustard sprout studies, but there’s evidence that mustard’s myrosinase enzyme is thermally labile. It probably contributes to hydrolyzing glucosinolates released by microwaving. I let sprouts sit for five minutes after microwaving before eating them.
Since you have experience with doses, what have you noticed with the difference between say 10, 20, 40, 60mg? Is there a threshold that you need to hit and then there is diminishing returns? Or is it progressive in nature?
This paper explored dosage:
https://www.sciencedirect.com/science/article/abs/pii/S1043661820315917 “The phytoprotective agent sulforaphane prevents inflammatory degenerative diseases and age-related pathologies via Nrf2-mediated hormesis”
But they missed the usefulness of performing sulforaphane dose-response experiments in contexts that are physiologically unachievable with humans.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118069/ “Biomarker Exploration in Human Peripheral Blood Mononuclear Cells for Monitoring Sulforaphane Treatment Responses in Autism Spectrum Disorder” said:
“There was no concentration-dependence in induction of any genes examined, with the higher (5 μM) concentration of SF even showing a slightly diminished effect for induction of AKR1C1 and NQO1. Although this concentration is achievable in vivo, more typical peak concentrations of SF (and its metabolites) in human plasma are 1-2 μM.”
Thanks, I just meant your personal experience with various doses. What do you feel? Does it give you a boost in anyway?
I feel fine now that inflammation is gone. I eat them twice daily. Sulforaphane is so reactive that I don’t eat anything else with them, or an hour before and after.
It isn’t a panacea, though. I apparently waited too long to properly address arthritis and tendinosis. The damage isn’t repaired yet, so I can’t play golf or dance.
After 35 days I changed from a starting amount of broccoli seeds of one tablespoon to two tablespoons (10.7 grams). The doubled weight must have been what I needed, The Weeks 6-9 period was noticeably transformative, physically and mentally.
I ate 65.5 g average twice a day, each microwaved to ≤ 60°C (140°F) to get an estimated 52 mg sulforaphane.for 4+ times longer than any clinical trial. I’ve probably plateaued, but keep going per Dr. Katcher’s environmental signaling paradigm of aging.
PRice you are successfully activating Nrf2 the most powerful repair pathway in our body. No wonder you have managed to tame the precursor behind all age onset diseases: chronic inflammation. Remarkable achievement. I can imagine the physical and mental transformation this made. You have minimized a lot of the risk factors that arise with aging.
Thanks Akshay!
I work as a software developer, a young person’s field. The experience has been like the study’s Barnes maze test results. I occasionally surprise younger coworkers. 🙂
A correction: 10.7 grams average is one tablespoon.
I have several questions:
a) Growing sprouts is time-consuming. Why do you prefer sprouts, rather than seeds? Is it because of the taste, or does sprouting increase the sulfuraphane content?
b) if someone chose the seeds would it be possible to grind after microwaving, so that chewing will not be necessary?
c) After microwaving sprouts (or seeds), can they be stored in the freezer for future use? Or would that negatively affect sulforaphane?
Hi Zisos! I think you’ll find discussions of a and b if you search “microwave broccoli seeds.” Sulforaphane degrades quickly, so I haven’t done c.
Akshay Atomic Bliss
on May 8, 2021 at 3:06 am he said:
… we plan to have subscriptions as an option.
:
1. I am over 86 years old.So – can I already queue to subscribe to e5 purchase?
My IL-6 and TNF-alpha already in testing
2. I propose, with the consent of the buyer, to add 1% to the price for those who cannot afford to buy e5
GREETINGS!
Bogdan Cho
Hi Bogdan the product available for subscription this month isn’t E5 but a topical gel. You make a good suggestion but without charging any extra to the customer we are initiating a program to ‘adopt’ elderly who are completely without any support or insurance. We will be posting their happy smiles on our product website.
What is the subscription price per month and how/where do you go to sign up?
Linda product price for subscription should be around $30 to $35 for a months supply for targeting wrinkles. For full body you would probably need 3 of those – depends on your size.
It is not yet available but should be available soon. Will make the announcement here. Thank you for your interest.
Akshay – can we place bulk orders? I’m not kidding – both the wife and I plan to do the whole body treatment for at least three months. Probably longer. Also what’s the shelf or refrigerator life?
Michael,
It stays stable for 4 weeks plus without refrigeration but to ensure full potency its best to store in your refrigerator once it arrives. We are using air conditioned warehouse for same reason.
I find it interesting that E5 gets no media coverage, whereas others with much less potential get all the coverage
https://www.smithsonianmag.com/innovation/in-search-to-stall-aging-biotech-startups-are-out-for-blood-180977728/
It’s called Marketing and is everywhere in our society including churches, charties, etc. Just as David Sinclair, lot’s of Marketing, but no substance.
Thank you Zisos our low profile is by design. You must have read Josh’s latest post here. Although they did mention us as Nugenics in the article and referred to Elixir.
I feel like you probably don’t need to spend a ton of money on marketing, or spend a lot of time in interviewers, this early on. Or maybe even ever. If/when it works it will be effectively self marketing. Right now all a mass marketing push would do would be to engage surface level hype for a month or so and then people would forget because the internet has an extremely short term memory
From a marketing standpoint it’s probably much better for to wait, prove definitely that the product works, and let the miracle market itself.
Fully agree Gordo. Thats how we think.
Once I receive my Blue Gel and permitted it demonstrates noticeable improvements on my skin, I would love to become an ambassador of Yuvan Research to spread the word.
Thank you Stephan. I hold in great esteem as an anti ager just from your discipline and what you have achieved. So we hope live up to your standards and have you as our ambassador.
If this works as we hope , everyone who uses it will become an ambassador , sales from word of mouth will rise exponentially ,people will be fighting in lumps to get hold of it ,
From the human trial we will soon have high quality data and imaging to show us how much it worked. We pray that it works for everyone.
@Gordo
I fully agree with you that there is absolutely no need to either spend money or time to promote something that is not yet ready.
I still find it interesting that there has been huge mainstream media coverage for interventions of much lower importance and even questionable benefits (I.e. hyperbaric oxygen therapy).
While at this point mainstream media coverage (and social media) is not absolutely necessary, it will be extremely valuable in the future. Both: To attract customers for the Blue Gel, and investors for helping to finance the development of E5.
Word of mouth is for sure effective and can be exponential. However, “exponential” is very slow at the beginning. For those of us that are convinced of the effectiveness of E5 and want to be “ambassadors” we could start now. Making people aware of the possibility does not mean hype will be immediately created. In my opinion, media coverage would be useful even now. Of course, it is extremely difficult to convince the mainstream media to “stake their reputation” (as Josh did) on something so seemingly impossible.
Will it be available in the uk and europe from amazon?
Dean initial launch is on Amazon US. You probably can order it but the shipping may be quite expensive. In a few months it will also be available in Europe.
Akshay – shipping won’t be cheap but that won’t be the issue. The real issue are customs and you guys will need to be smart about how you label the product. My suggestion would be ‘beauty gel’ and it should pass through just fine. Also you may want to reduce the price on the shipping label which will affect customs.
Lol , I have to agree with Michael on that , I’ve ordered a lot of things from abroad on both Amazon and EBay and the value and description declared on some items especially from China is a fraction of the actual cost and not what was I’m the parcel I’m amazed that I’ve only had two items where the value was anywhere near to true cost and I’ve had to pay import tax on them
Michael and John,
We won’t be able to undereport the price but the product is in itself inexpensive so I doubt whether it would attract import duty.
Your correct Akshay about the gell , but I still shake my head at the descriptions on some of the packages I’ve received from abroad even low cost items where the description and postage didn’t add up to the cost of a first class stamp for a letter ,
Ha! You clearly have never dealt with Spanish customs officials – they make the Gestapo look like amateurs – LOL 🙂
That may change hopefully when we have high resolution scans from an IRB study.
@ashkay Thank you for your reply. I for one would be prepared to pay for international shipping, especially when compared to, say, the one.skin and korean logically-skin product price and effectiveness.
Dean yes one.skin is quite expensive vs blue gel but someone I know had positive feedback after using it. We will check with Amazon to see what best rates they can do for international shipping.
I agree with Dean , the shipping cost from the US is secondary it all comes down to ordering and paying for it from outside the USA and it says that on the item on Amazon due to the different systems in place to order and pay , and if Amazon will actually set up a method via PayPal for foreign orders ,
I have a UK Amazon and PayPal account but it still depends on how Amazon set up orders and payment from outside the US
I am sure Amazon US should allow international shipping to most countries. Just in case it doesn’t we will set it up in our product website.
Hi Akshay , thank you for your reply and that it will be set up to accept payments from overseas buyers , I’ve also bought quite a few items from the US but also there have been times where when I’ve gone to pay its been refused and I’ve been unable to purchase the item , once again thank you , Regards John
@Akshay, are there any measurements on bluegel’s effect on TEWL?
TEWL is the gold standard for measuring skin barrier quality, and high TEWL is generally associated with poor skin quality.
I’ve used many skincare products over the last 20 years. Some of them do a decent job, but I’m hoping bluegel will be the game changer many of us have been waiting for.
Ole I will have to check with my Principal Investigator. We are using even more accurate assessment tool: High resolution ultrasound scans.
I live in Spain and have ordered a few products from Amazon.com in the US. They are all set up for shipping overseas. They know the Customs fees per country and have reasonable shipping costs. Had no problem getting any of my ordered products thru customs.
In that case we should be able to
I live in Spain as well and agree. Amazon, albeit not cheap, has international shipping down to a science.
Thank you Akshay, I am really curious about the process.
Furthermore, I wonder if in the first E5 trial will be women included. That’s a point, because most of trials are done in male mice and rats (I don’t know if this was the case in your first trial), and as it happened to Dr Fahy, is fis TRIM trial was with 9 male subjects, and now it turns out that the dhea hormone should be perhaps restricted to women in the TRIM-X trial. There is an aspect that really is a youth/age factor, which are the sexual cycles of women, as during those females produce Estradiol and Pogesterone among other hormones, which are the key pieces to avoid Alzheimer disease (women are twice more likely to develop AD) and osteoporosis respectively (and many more other nuisances that come with menopause, like arthritis, decreased libido and others). In man there is not such an abrupt post reproductive cliff, so it is something really interesting to see, not only because of the fertility issues attached, but because of feminine health itself.
So, that is my question.
Ines for that very reason our current lifespan study is all female rats. And you are right the response to E5 is a little different than what we had seen with male rats. But the mechanism and tools are highly conserved across species so should also be across gender. Will there be gender specific version of E5?: Maybe.
What you mean in a little different response, Akshay? Percentages of the biological age reduction? Apparently most of the longevity supplements including Calcium AKG works better in females but in my opinion special fraction factors should not have gender. TRIIM is something different which involves hormonal dimension but as a strict supporter of Harold’s theory of the aging process I believe E5 will be the same for both genders.
Hello LEo, TRIM is not that different. There you’re changing the signaling in the periferal blood, with hormones and working with m-tor. E5 is an amount of other different factors, we don’t know which, but perhaps some can be hormones as well, why not, perhaps they are specific molecules, factors that also change the signaling, it seems that much more radically, but the basis is the same, cheat the body through changing its signaling, and telling the cells, “Guys you’re acting like a 70 year old when the information here say’s we’re 30! Let’s change our rate of reparation, we still have to reproduce!”. At least that is what it seems to me.
Ines you have a good understanding:)
Leo in the lifespan study with all females the effect/reversal of few markers we check was lower than what we saw in males. It is still quite a strong effect just overall marker readings seem different from males. We are still analyzing the results and also sending DNA samples for rat clock measurement. As we do more gender specific studies we will get more data to form an analytical conclusion.
Wow, that’s awesome Akshay. Thank you and it’s very interesting what the results show.
And thank you Akshay for your always quick answers, the process is amazing in itself, just keep us updated. Kind regards
Hi Ines, The TRIIM-X trial is more focused on a thymus gland regeneration from the fattier tissues to the young one again. Since thymus is a part of the immune system that declines markedly with age, and regenerating it may prevent or reverse key aspects of immunosenescence and potentially prevent or reverse key parts of the aging process more generally. Although, on average, trial volunteer epigenetic ages were lower than their chronological ages at baseline, epigenetic age was nevertheless significantly decreased by treatment based on the results of all four epigenetic clocks.
Either way I like Dr. Fahy, he is doing E5 trial with dogs which is the most interesting thing to me. As I know he was hospitalized so Dog trial has not been started yet but hope he is okay very soon and continues his great job with our star Harold and outstanding Akshay!))
It doesn’t stop amazing us even now. We have seen in mammals what it does with age. Now we are very keen to see in NHPs what it does on specific disease. Hopefully in 2nd half of the year we will get to see what it does in humans.
First of all, I want to thank you for sharing all the updates and the amazing research you are doing.
I have a rather personal question. Currently, I am 21 years old and very interested in expanding my lifespan as much as possible. From what age will it be best to start using treatments like E5 and blue gel? (or any rejuvenation treatment for that matter)
Also, what are the chances of my age group to experience enough technological advancements in our life that we can live for 300+ years? I know it is a guess, still, I am very interested in your ideas.
Kind regards,
Rino
Dear Rino –
My advice is to trust your youth. Stop worrying. Stop optimizing your long-term future and engage fully in the present. You are sure to live into a time when better remedies than E5 are freely available, if only we as a collective survive and our culture remains viable.
– Josh
Hello Josh. May I have your thoughts why do not you consider E5 as an universal phenomenon as injecting just 4 times is able to reset your biological clock? I mean what do you consider as a better remedy which may be available in the future?
Leo,
I would agree with Josh. E5 seems to be a breakthrough intervention but that does not stop scientific evolution. I have no doubt we should see even more advances in age intervention technologies. For example the Gingko Biloba tree seems to freeze its gene expression pattern after reaching its prime enabling youth for thousands of years. Humans should be able to figure out how it does that and may invent a similar intervention. This is the wonderful side of us humans: our collective intelligence keeps evolving. I can’t begin to imagine what technological marvels we will have 1,000 years from now. Hope all of us are there to see them 🙂
That’s good to imagine but if we consider the progress rate in this dimension I do not think we will have such things in the near future. Would love to have it, of course but… a bit skeptical. I also agree with Josh that “If only we as a collective survive and our culture remains viable.
I agree with Akshay , when I first became interested just after reading the Baati rat study in 2012 there were just 4 labs doing ageing research that’s now grown to over 200 our medical knowledge is doubling every 3-1/2 years
That’s awesome but how many of them are doing the right job? Marketing, Marketing and Marketing everywhere. New “Miracle” patented supplements like an ordinary astragalus, curcumin and etc. However I am happy we have Dr Harold and his team and several other outstanding people doing truly an awesome things.
The research is in basic medicine genetics biochemistry not marketing , all marketing is is trying to sell many treatments and products , if what Harold and Akshay are offering does work there will be another golden statue erected in Amritsar alongside the temple thats there,
Hi Rino, happy to see someone so young conscious about aging. I curious how you began looking at aging research. I can’t speak about other interventions but it seems E5 could be considered in your late 30s to bring you back to your 20s assuming it has that potency in humans. If regular treatment resets the biological age to youth than one could hope for such long lifespans theoretically but we won’t know that until we reach that milestone. Whether in future humans will achieve 300 years? I am confident we should be able to achieve that level of scientific knowledge to reach such an age. There are other species that do.
Dear Akshay,
Thank you for your reply with the given timeline. So, if I am reading your message correctly there is a fair chance for us all, which is great to know!
I began looking at ageing research a month ago since I struggle with my fear of death for a year or something.
The reason I am so conscious about it at my age is that I feel that death has no logical reason (and being very afraid of it if I am completely honest). I never want to lose my consciousness (aka die) because life is too great.
I look forward to the future posting about E5 and wish you all the best!
Rino
Thank you Rino. You are absolutely right we humans have outgrown the need for recycling and death. Aging is cruel and makes horrible changes. What are you studying? hope you study biology – we can use a motivated young man like you.
Dear Akshay,
Thank you, I am studying Economics and planning to get into Investment Banking / Private equity.
Hopefully, I can get into the longevity field in the future using my expertise to build out the treatments commercially.
Until then I will keep up with the latest research.
So, despite not studying biology (very sadly afterwards), I hope that I can contribute in the future!
I am sure you will. I have observed that autodidacts bring a different approach/perspective to research.
Hi Akshay, being this my first post here, thanks for your generous effort put on your quick answers, providing us with such valuable information about your promising research.
I am following your team work since some years ago but from a couple or three weeks ago an idea is swirling around my head and I want to subject it to your judgement. It relates your rejuvenation research based on plasma fraction with that of the Conboy team, working in the area of plasma dilution. To make two long stories short, and if I recall correctly, your findings clearly lead to an average 54% rejuvenation in many age markers by adding, and therefore notably increasing the presence of, some rejuvenating or anti-aging plasma factors in blood flow. While the Conboys experiments show the rejuvenating effects of reducing the concentration – and presence – of pro-aging factors in blood flow by diluting it with albumin and other additional compounds. To be taken into account the Conboy’s consequence of reducing, too, the presence and/or concentration of ‘rejuvenating or anti-aging plasma factors in blood flow’, though this fact is notably outweighted by the positive effects of lowering the concentration of pro-aging compounds.
As my thoughts’ shortest resume: on one hand, your works increase the presence of rejuvenating blood factors, while on the other, your colleagues decrease that of both pro- and anti-aging factors to get their beneficial results. And my questions is: could some sort of sinergy be expected if both treatments were implemented simultaneously, obtaining a reduction of pro-aging factors while an increase of anti-aging ones?. And a last and natural question, has this potential and collaborative point of view being considered so far?.
Thank you, Mr. Katcher and the whole team for creating such a promising future for us all.
What can be a better thing when you inject something, just wait and becoming younger everyday, instead of older.
Mr Akshay, if it turns out that E5 works same in other bigger animals, will we be able to inject it several times and extend the lifespan up to 5 times? If I inject it to the cat, will she be able to live 50 years or more?
P.S I realize it’s a complicated thing to be answered but I mean if only E5 works same as in rats.
Thank you in advance and thanks generally for what you are doing.
Thank you Azza. Its like if you take a vitamin D pill and your vitamin D levels go up there is no reason why that should not happen everytime you take it.
That’s incredible to hear. Thank you for taking the time answering me.
So it’s the end of the May, can you tell me if you have already started manufacturing E5 and started Dog trial, Mr. Akshay?
E5 likely won’t be manufactured for 3-5 years. FDA approval etc.
Dog trials I’m not so sure about
Akshay said the blue gel should be available at the end of this month/early next month I believe
Thank you Gordo that answers Nanaka’s questions. Nanaka I will add that yes we have manufactured E5 at our California lab. The first batch is under testing on rats to check its values.
Thanks Akshay. I meant manufacturing the first batch for testing. What about trials?
We hope to do 2 third party rat studies, dog study, non human primate study and IRB human clinical trial for E5. Timing depends on various factors but hope to start all of the above this year.
Any updates on the gel? I know you were shooting for May to start selling it on amazon.
Yes will announce soon
Thank you for the information.
With all due respect to you, Mr. Josh, I think you are tarnishing the whole reputation and authority of E5 with the land and not valuing it accordingly. And yet, do you feel any better today? What David Sinclair suggests in 20 years, Dr. Katcher has already discovered and will offer day by day. Maybe I overestimate the capabilities of E5? Maybe your desire for immortality is so great that you do not consider the possibilities of E5 and you aspire to the mechanisms of Ginkgo biloba?
Just Akshay agreement what Josh said above made all this passionate desire, as soon as I could, to do E5, faded away and now I perceive it as a normal dietary supplement, such as NMN, AKG, etc. I do not want it to turn out like an ordinary “Longevity” supplement because it’s the only serious thing ever been existed on the planet Earth! I want to hear more about this and change my mind back to the way full of passionate desire of getting it ASAP and become younger every day.
Azza can you clarify as to what Josh said and I agreed to that you did not like? Josh has been the most supportive to E5 and Harold.
Yes, I can. “ You are sure to live into a time when better remedies than E5 are freely available”. You answered an example of Ginkgo Biloba, which has an average lifespan of 3,000 years and which can freeze its gene expression pattern after reaching its prime enabling youth for thousands of years.
The reason why I do not agree with this comparison is the experiment of Professor Vera Gorbunova, who found that naked mole rats produce a special molecule that prevents them from developing tumors. It is a thick, sugary substance called hyaluronan, found in the spaces between their cells. Even if the cells mutate, the hyaluronan stops them dividing further, like a gloopy protective glass.
Despite the fact this may all sound very promising, we should not get too excited about preventing cancer just yet. The problem is that we don’t know if any of these treatments will work properly in humans.
Naked mole rats are very different to us, so we don’t know how extra hyaluronan would affect us. There may be a reason we have less, says oncologist David Vail of the University of Wisconsin-Madison, US. Such high levels might prove to be toxic, for example.
The same is true for genetic manipulation. The way our body expresses genes has evolved over hundreds of thousands of years. A gene that helps a naked mole rat fight cancer might cause a whole other disease in humans.
This is not a theoretical problem: we know it happens.
A 2002 study genetically engineered mice to have numerous copies of the p53 gene. The change did increase their resistance to cancer, but the mice also aged more rapidly and could not produce offspring at a young age. Some of their internal organs also became significantly smaller.
We need to understand the basic biology, otherwise, there’s no way to intervene when things go wrong, However, Lynch remains cautious about what extra versions of this gene would do to humans. If the extra copies were beneficial, evolution might well have already produced them, he says.
So to conclude, that’s the reason I consider Blood fraction reintegration in our body and becoming younger biologically is the best and the safest thing to live loong and happy lives because The Horwath clock is the universal across all species and from Naked Mole rats to Bowhead whales, all share the same CLOCK!
What do you think, should we consider other species and even trees life hacks as a good intervention in the human body or just trust the universal clock and reverse the aging process for several times we want? The fact the Harold found out the thing in our Era does not mean it’s a weak intervention. As Harold said E5 works about the same as Shinya Yamanaka factors and while it was on a targeted area like the eyes, E5 is the whole body rejuvenation( if it turns out to work same in larger species, of course). David Sinclair is claiming to have Four Factors therapy in 2-3 decades and Harold has already found out the thing. That’s impressive to me, I do not know.
Azza I think you’ve totally misunderstood what Josh was writing about , he was simply pointing out that there are things in nature that are outside the norm , bristlecone pines being one another is coy carp that are classed as immortal they all die from disease not from ageing ,
E5 is the equivalent of a model T Ford but compare that to a modern Ferrari there’s no comparison eventually more research will bring better versions of E5 ,
A number on here have mentioned that living longer will also increase the chances of getting cancer and I agree but after reading the Baati rat study I’ve been on C60 in olive oil since autumn 2012 , without going into detail all the rats on that died from old age and when they died had no disease in their bodies whatsoever , rats are cancer factories 75 to 90 percent die from cancer the rest from the other diseases we get in old age , about two years ago my doctor sent me for a full set of tests after finding a small amount of blood in my urine , MRI scan X Ray spirometry tests , the blood in my urine was from bleed through in a large vein in my urinary tract which I already knew about from a previous test but everything else was in good condition the only anomaly was what they thought was modules on my lungs another MRI scan and it was found to be scar tissue from bronchitis when I was in my thirties , I also had a small amount of emphysema , but the C60 had stopped that from progressing , and the symptoms I had have gone and not returned , so I’m keeping my fingers crossed that what worked for the rats in regard to disease will also work for me once the E5 is taken and the age reversal starts ,
First of all your text does not answer my question and I would appreciate to know Akshay’s and Josh’s thoughts about it. Then, sorry but I can not trust anyone who has been on commercial C60 because it causes nightmares, nervous system damage and etc. This blog is not dedicated to this scam molecule but I will try to explain a bit more and please, if you will have questions about C60 direct me.
So, people vary widely in their ability to detoxify hydrocarbon solvents.
People who are already compromised in their health would be wise to avoid adding to their toxin burden by consuming a C60 product with known hydrocarbon solvent residues (which is EVERY C60 product on the market right now, despite manufacturers’ pronouncements that they are “99.99% solvent free”~ they are NOT ~ except for Greska’s).
For C60 and all nano-size particles, size does matter but the shape matters too.
All nano-size particles entering the body, ranging from viruses to bacteria to foreign material, are surveilled by the roaming cells of the immune system. These cells are the first to “see” and interact with particles of C60. The SIZE and SHAPE of a C60 particle are critical factors in determining HOW a person’s immune system responds to C60. Friend or foe? Inflammatory or anti-inflammatory? Useful or not?
Solvent-extracted C60’s have NO consistency in the size and shape of the crystals they produce, and therefore can vary widely in the types of responses they induce in the body. This, in addition to the solvent residues and other impurities in these C60’s, make them unpredictable and unreliable in biological applications and why they have not been exploited further for their pharmacological potential.
C60 had properties known as “solvatochromism” which means it can be a variety of colors depending on which solvent is used. Pure non-aggregated molecules of C60 in sunflower oil is clear. The published Russian research has shown this. If it is purple, it is because it is crystallized in a face-centered cubic structure, which is not as single molecules of C60, but aggregated crystals of C60 which can be a variety of irregular, non-spherical shapes and sizes, not all of which can be assumed you be safe and biocompatibile.
Bob Greska HAS provided proof of safety testing on his product, as well as the purity of the carbon in it. Most reassuringly however is the results people are reporting with his product without suffering the stomach issues, nausea and headaches with solvent extracted C60.
I am not trying to promote any brand here, I want to repeat that I do not take even Greska’s C60 because I do not have enough safety Data but if you insist taking C60 molecule, please, just do more research, never take any other brand and ask for 3rd party testing and other ones available on Greska’s page.
REMEMBER: The solvents in C60 are not something like the ones we do inhale or ingest from every day life. It’s bound in a cage like structure of C60 and therefore is directed right at the mitochondrial level. That’s why it causes pain, nightmares, arthritis like symptoms and many more. It’s extremely hard and I have been detoxing for more than year from the solvents in my body.
LoL Azza , you read a lot and understand very little , your talking rubbish about C60 , first of all there are no toxins in C60 it’s totally inert and none toxic , it’s filtered through touline and the American drug agency allow more touline in a litre of drinking water than you would find in a litre of C60 in olive oil which would last well over a year compared to a couple of days for water those things you mention as being symptoms of taking it are lies put out by people with their own agenda , or are paranoid ,
The immune system doesn’t even enter in to it try other forums where C60 has been discussed and taken by thousands of people and none I repeat none have had any bad results for taking it all have had positive results including endurance hair growth , I’m 76 years old and have never suffered from any infantry condition what so ever , you talk of different crystalline sizes , sorry it’s not crystalline it’s 60 atoms of carbon in the shape of a soccer ball , there’s not even room inside to get more than two atoms of water ,
I’m not sure what have you the arthritis like symptoms and having to detox but if I was you I’d look at the other things you were taking first before blaming C60 which you obviously know very little about ,
Azza you make good points and who knows you may be right. I would be happy if it were obviously but science and technology continues to evolve. Our forefathers couldn’t even imagine that airwaves could carry Crystal clear moving images and display in our home. Or hand held phone would connect a relative within seconds even though he/she may be on another continent. We are discussing about things yet to come so just like our forefathers we are clueless about them. But what is important is to be alive hundreds of years in the future if one wants to witness such innovations and for that right now you are right may be E5 seems to be the only safe, ready to use, systemic means of reversing age phenotype.
Hi Akshay:
First, let me express my appreciation for your willingness to engage us to discuss our concerns and keep us apprised of progress. Obviously what you are doing has our rapt attention due to the potential impact on our lives and the lives of everyone on the planet.
I do have a question which likely cannot be completely addressed now but will be of much interest, at least to me.
Being 76 years old, I know that my physiology is quite different than at 25. Some of these changes I can easily imagine will be reversed, over a period of time, with E5. Such as muscular potential, level of energy, etc.
For others I have my doubts. Such as the flexibility of the lens in my eyes, the amount of cartilage in my knee and so forth. Do you have any comments on what E5 can address and what will have to await other medical interventions? It seems to me that the earlier one can arrest aging the better off one will be.
Thank you Ed. You are right its difficult to answer that as I do not have data as evidence yet. So anything I say is just an opinion. But we will soon find out.
If E5 will not repair the wear and tear of aging, and you are interested in a future technology that might, you should follow the work of Dr. Michael Levin at Tufts. Dr. Levin’s specialty is morphology, specifically using bio-electricity. Among his accomplishments is getting a frog, a species that does not normally regrow limbs, to regrow a rear leg. Amazingly, he did this using FDA approved drugs. Regeneration of tissues is one of his goals. He has recently started a company, Morphoceuticals Inc., to commercialize some of his discoveries. Following is a link to what I believe is his latest presentation, well worth a viewing: https://www.youtube.com/watch?v=Z-9rLlFgcm0
I hope you will find my answer, Akshay. In this mess…
Azza yes I did and I did reply to that please scroll up. I will share one highlight about the E5 platform. Our biology is fascinating. We are a collection of cells each with the same book of instructions. Each also marked to open certain pages and keep closed the others and that marking keeps changing with time. This gives the cell its phenotype and function. On top of this the cell produces proteins and secretes regulatory instructions to enable various complex systems to manage our energy, mobility, strength, immunity, etc. The language used by Nature is quite similar to our basic computer language of 0 and 1 using which complex computer software programs are made and function. The regulatory elements are grammar of this language. If we take x and y axis: spatial organisation allows for various mechanical, biochemical, electrica, etc. processes to be executed and temporal organisation dictates the time when they have to be executed. Recently Wyss-Coray’s papers gave evidence of temporal organisation of aging. The temporal organisation works on what meter we don’t know yet. Is it cell division or circadian clock or something else? All this complex self organisation runs our body day and night on autopilot. E5 uses Nature’s own tools to change the temporal organisation. Any technology not using Nature’s own tools is like wading against a current. Including something as powerful as partial Yamanaka factors. Going back to the software analogy its like another less gifted (than Nature) author adding code in the middle. That doesn’t mean it can’t work but it changes the risk of stability. It will take us many lifetimes to continue to improve upon the platform of E5 but we did have a great start to indicate that we have identified a powerful set of tools. And it is a as safe and stable as all other of Nature’s engineering in its prime.
Akshay, I’m not a scientist but a former software engineer and your explanation makes a lot of sense to me.
I have some good news. We are soon doing a soft launch of blue gel. I have kept aside 1,000 units for our community members. You will be able to buy online. I will share the link. On human trial of blue gel have made the application to IRB. Expecting approval any day now. Will start trial after that. Anyone who wants to wait to see the results can buy after we share early results in a month.
Great news Akshay! Count me in!
That makes sense to me too. Do you have a set of protocols that you will need for us to use after receiving the blue gel?
Congratulations!
Thats very good news now, Akshay. And even better ones in a month!. I wish you, Dr. Katcher & team the best luck.
Hello . You explane it beautifully Akshay. Please, post the blue gel link as a comment at the end of the comments. Otherwise it may be lost among our chat.
Kind regards.
Thank you Ines. Will do as a new comment.
Akshay,
as you mentioned the language of life as a digital software engineering project, I thought you might like Bert Hubert’s tweets about DNA as a very long term software project:
https://twitter.com/PowerDNS_Bert/status/1355567505788571652
Hope to get your link for Blue Gel soon,
best, Gerd
Gerd please do share such papers. Its absolutely fascinating. Imagine a nebulous collection of software code directly or indirectly managing trillions actions all happening with incredible fidelity. The coding enables a complex self governed autonomous system. This paper brings out the mathematical and architectural beauty of this coding.
Sorry that should be inflammatory not infantry (my kindles changing words ),
Ok, I said I am not going to turn the blog into C60 topic but all I can say is good luck! I am glad I only took 2 bottles of it and I am pretty detoxed now. You just do not understand that toulene in the water is not same as in cage like structure of nano particle which irritates the mitochondrial, directly. actually direct observation and personal experience should be the cornerstone of any person’s research. Only then should one look for studies that corroborate it, and those too should be evaluated for confirmational biases, flaws in methodologies and other short comings. Please stop reviewing a molecule which is off topic here, I hope Akshay will be able to find my question and worries. Have a nice day.
I wasn’t reviewing it I simply suggested that as the rats in the Baati trial had no disease it was worth looking at by those who had said cancer if we lived longer was a concern, your assertion that touline can get inside is also wrong , there’s no room between the atoms of C60 that allows that it’s simply used to filter the C60 from the rest of the Carbon that forms when it’s manufactured now your trying to blame me for this whole thing , as I said earlier you read a great deal but lack understanding , including how C60 works ,
This will be the last I’ll write about C60 in this part of the blog ,
Good luck. Hope Akshay finds my comments about the topic the blog is intended to.
Any more updates re Blue Gel please?
Hi, would you mind sharing with me any new info that’s been posted here during the last few days? I have the same problem but I didn’t subscribe so I didn’t receive these new comments as emails either.
Akshay Atomic Bliss
I have a question that I haven’t seen answered elsewhere…
The original research was on a blood derived product, but speculation was that the product could be synthetically created.
Will your treatment be using the blood derived product or a synthetically derived product?
Thanks.
Akshay has told me that they have contracted with a lab to create E5 (not extract it from blood), but he gave no more details.
Thank you Josh. We missed your visit to our Lab this time. Hope you can visit this summer. People will appreciate that not only do we have something that has immense promise of reversing to a younger biological phenotype in the same cohesive manner that Nature designed but also second discovery is a way to not create a slave trade for young blood which probably is as important as the first discovery.
Akshay, that’s an excellent ethical point about the “slave trade” in young blood.
I have a possibly frivolous question (while we wait with bated breath for blue gel news ; – ) about the name E5. I can see why you did it, but did you choose 5 by the same old IT method that produced i18n (internationalization), l10n (localization) etc? Just curious!
Cheers,
Nick.
My guess is that i5 stands for “Hi Five!”
Actually, my sources (and by “my sources” I mean my overactive imagination) tell me that three names were in contention (after they decided against youthenizer) and they were E5, I5 and Ehaw! Unfortunately, they went with E5.
A take on aging
Multi cellular organisms are governed by gene networks right from embryogenesis till death. I say death because i feel aging is also controlled by a gene network, which comes in to being at puberty. I also feel that morphogenesis does not end at birth, it continues till the end of the pubertal phase. Morphogenetic pace not phase varies across species with varying intervals of growth pace.
A gene network has function not individual genes, an individual gene can be part of many gene networks in the same organisms(for e.g serotonin). it is the gene network that morphs at various tissue growth milestones or organ boundary milestone and acquires different forms and function at those milestones. It does this by inhibiting some of its member genes and/or adding new genes to its network.
Aging is one such network which is activated at the morphogenetic milestone of puberty. The activation of this network, results in a program which controls
1 the repair functions of the cell at the individual level, such as autophagy,dna repair, protein digestion, mitochondria repair etc.
2 the recruitment of the immune system in response to cell damage and
3 the renewal provided by resident stem cells.
The gene network which was in control of the above functions during the growth and the final morphogenetic turn at puberty, is modified by activation of some unidentified genes, which in turn inhibit some genes, which played a key role in the previous iteration of the network. Due to this, the whole network modifies itself to implement the aging program.
And therefore, various genes which were found to be beneficial in the previous avatar of the network turn deleterious in the new network, leading to the so called phenomenon ‘antagonistic pleiotropy’.
Various supplements which have proven to be beneficial are just perturbing small parts of the overall network. However, with the epigenetic clock showing lock step epigenetic modification across various organs and tissues in the organism. the presence of signalling factors in the communication medium can be hypothesized. Hence plasma exchange/dilution are probably effective because the perturb the whole network.
Also according to me partial reprogramming is an unnatural way of changing the dynamics of the aging gene network by introducing elite transcription factors, which supersede the key transcription factors controlling the aging network.
Any news about when the human trial will start? It would be interesting to see Harold Katcher in a follow up interview on Youtube a few months after treatment. By the way, is it reasonable to assume that larger animals will have to wait for longer to see the effects of E5, as compared to rats?
Longer, yes, but how much longer? I have many times asked for informed opinions and references on the subject of relative therapeutic times in different species. I have received zero replies. Articles that I’ve read mostly assume that the relative lifespan of the species is informing. This would mean that the equivalent results in a human to that of a rat at one month would be about two years. I argue that relative metabolic rate makes more sense, but few agree with me. If true, it would mean the above two years would become about six months.
I again invite knowledgable responses to my basic question (including references).
Wayne we will hopefully find out in the next 12 months with actual human clinical trial data. My hunch is that the answer lies in how long does it take for a global epigenetic change to occur? Let’s say you do CR. CR shows its benefits via epigenetic changes. So how long does it take before we can see the effect of CR? Second would rate of turnover of cells. This spans from 2 to 9 days for stomach to 10 years for bone.
We hope to file an IRB application in the 2nd half of this year. Then it depends on the IRB how long it takes. Their review will take months. We still have to find out how long will E5 take to show effects in humans. Our study with larger mammals like dogs and non human primates should give us an indication of the same. Another important question: how long do they last – that is time between doses.
Thank you for the answer, this is really fascinating to follow. However, as there is a long tradition of self-experiments in science, I must ask: will Dr. Katcher use E5 on himself before any proper trial? I think he (or you) said that he feels like he doesn’t have much time left and wanted to try to rejuvenate himself this year; or that may have changed? I assume he may want some data from larger animals than rats before doing that.
He is a responsible scientist. He is carrying a big responsibility on his shoulders that could benefit hundreds of millions suffering from age related conditions. So even though its very tempting to try it asap He prefers to wait a few months till the larger animal studies are done and the human clinical trial is set up. Before he starts there should be a bank of E5 so that he does not run out. You wouldn’t want to become young only to again become old. Even I am excited to see a much younger Harold soon 🙂
@Akshay
Recently there has much media coverage of this study;
https://www.nature.com/articles/s41467-021-23014-1?utm_medium=affiliate&utm_source=commission_junction&utm_campaign=3_nsn6445_deeplink_PID100062364&utm_content=deeplink
It concludes that due to gradual loss of resilience, there is a hard upper limit to the human lifespan of 120-150 years.
Questions:
In your opinion, Akshay, would E5 have an effect on this loss of resilience?
If so, would it be possible to prove that experimentally?
I assume that a similar limit exists for rats. Could the lifespan study with E5 in India offer the possibility of proving that the loss of resilience in treated rats has been reversed?
Assuming treated rats do live longer than untreated, and also the “loss of resilience” of the treated has been reversed, we will not only have an increase in lifespan but might also have possible reasons for the extension.
Similarly, if the human studies show that resilience loss is reversed, we might draw conclusions about the extension of the upper limit of human lifespan.
The predictable wave of changes as shown in Wyss-Coray’s 2020 papers are deliberately effected in the epigenome by regulatory factors. As Morimoto, Issa and Medelsohn have shown there is an epigenetic drift that leads to progressive loss of functionality. They also show the plasticity – these changes are reversible. Rapamycin for example has led to lifespan increase in mice (Bitto 2016). In perspective Prof Richard Dixon found that a 1,000 year old Gingko Biloba tree had less than 5% difference in the gene expression pattern versus a 20 year old tree. A 1,000 year old tree was as fertile as a 20 year young tree, autophagy, immunity, photosynthesis were as efficient as in the young. It was able to replenish its stem cells. Somehow the tree was able to freeze the epigenome thereby becoming immortal in a young state. According to Prof Dixon the trees do not age and die due to environmental catastrophe. So an intervention that can reverse the epigenome to its youthful signature and maintain it there in every cell should potentiate the possibility of significantly longer maximum lifespans.
Zisos, like the media, you are misunderstanding this study. It is actually a very nice study, whose main contribution is to show that in addition to the slow decline in a given biomarker (whether this goes up or down) with age, there is also a medium term increase in the time for an oscillation in the given biomarker to return to its long term average/an increase in its variance over time. This is like a rubber band being stretched over and over again, and gradually losing its ability to return to its original length. The study merely extrapolated such changes, finding a complete loss of hysteresis by ~age 120-150 depending on the biomarker used. This is the same as found based on telomere attrition (~120 years) found by Blasco et al. It means this is the absolute limit if nothing is done to change it. But we know much can be done, as the paper also acknowledges.
Thank you, Mark.
It is possible that I misunderstood the study, although I don’t think so. Because the excellent explanation you give is pretty much what I understood in the first place. But it is not important if I understood it before or after your explanation.
I DO agree with you that this study can be extremely helpful. I probably did not phrase the last sentence of my original comment properly. So, maybe I can expand on it here:
The authors of the study use the metric “resiliency loss” (the loss of elasticity of the “rubber band” in your example), to calculate the upper limit of human life.
As you mentioned, there are things that can be done to change the upper limit I.e. reverse the “resilience loss” (or restore the elasticity of the rubber band).
Assuming we can measure the new resiliency, and using the exact same method that the authors used, we can now calculate the “new” upper limit. In effect, if the method used by the authors is correct, we have probably found an indirect way of calculating the effect in the upper limit of an intervention, without having to wait until the test subjects die.
Already Yuvan is running the Lifespan experiment with Rats in India. It would be interesting to use this methodology to see if the predicted lifespan using this study’s methodology, will be near the actual lifespan of the treated Rats.
For sure there is much extrapolation here. But it would be extremely helpful to have a method to estimate the new “upper limit” of humans as a result of a drastic intervention (I.e. E5), by just measuring some biomarkers (resiliency).
Sorry, Mark:
Automation sometimes can result in errors.
The reply by “Komputron Monoprosopi Ike”, is actually mine. The email was fillled automatically, and I did not catch it
Thanks for replying and sorry for the slow reply, I only noticed by chance that you had responded. Yes I agree, using the paper’s methodology could be very useful, although they do not tell us their exact methodology, other than it is based on blood counts. They also find it is (roughly) equivalent to step counts from wearables. So in theory many different biomarkers like HRV, resting HR, BP, etc., could be used. From monitoring my own biomarkers I can see that there is a slow periodicity and maybe over a few months you could calculate increases or decreases in variance that result from an aging treatment.
Hi Akshay, are there any updates on the blue gel? Is there any website or social media account I can follow?
And I want to thank you very much for your work.
Thank you Greg no social media for us. We may make it a membership that way everyone interested can feel part of the community and get regular updates. We did receive our IRB approval so we hope to start the human trial soon.
Congratulations for your IRB approval. I ordered a Il-6 and TNF alpha before using the blue gel, as you requested, should we send it to you when we got the results or do you prefer that we send the data before/after altogether after 8 weeks with the gel?
Kind regards.
Confused, you have already started on the blue gel?
I didnt realize it was released yet.
Yeah I don’t quite understand that either. What human trials? Wasn’t the gel supposed to be available for purchase on Amazon because it’s categorized as a cosmetic product and thus doesn’t require much in the way of FDA approval?
I’d assume that Akshay misread my question and was talking about E5.
Greg, Yes blue gel falls under cosmetic category as confirmed by FDA. But as we are not a cosmetic company but a biotechnology company we want human clinical trial results of our gel backing our product.
No, Akshay asked for a Il-6 and TNF alpha before we started, and after 8 weeks, to check changes from the baseline, of course I don’t have it, but I wanted to know how to proceed when they start selling it.
Hi Ines,
Day before you start applying full body 3 times a day and after 8 weeks.
A very interesting paper by Vadim Gladyshev’s group: Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging.
https://advances.sciencemag.org/content/7/26/eabg6082.full
Ghalib indeed one of the most important papers this year. Vadim Gladyshev has been doing amazing research: Till recently we believed germline did not age but apparently it does. The reset to the most youthful state ‘clean slate’ occurs during early stages of embryogenesis. And then aging begins even as we develop. No wonder Nature wants to recycle us. To keep cleaning the slate everytime. If we can find out what is it that Nature does to reset to minimal biological age and thus at one stroke remove all accumulated damage and errors, we could perhaps adapt it to reverse to a youthful state and remain there. This would preclude the need for death and recycle.
As always, very nicely explained answer. Thank you Akshay! May I ask if the single dog trial has already started? Have you already injected the first dose?
Not yet Leo. When we do this forum will be the first to know.
Thank you, looking forward!
Agreed Akshay, very eloquently put. Knowing and understanding the rejuvenation event that occurs in early embryogenesis might be a game changer, I wonder if it is similar to the systemic E5 epigenetic reprogramming and can it be applied to adult cells.
Ghalib it would be much more comprehensive, elegant and powerful. After all its been designed by Nature, an incredible engineer and architect. The design and engineering at the macroscopic, atomic and subatomic level, the fidelity of trillions of processes running on autopilot, thermal, mechanical, biochemical, electrical, phase change, etc. etc. is mind-boggling.
As an update on the blue gel availability: We are waiting for our sales tax registration to go through and our lawyer is figuring out under what t&c we can sell to a community. Should resolve soon. Thank you for your patience.
Good Luck!
Sooner, the better, I feel like a child waiting for Christmas day.
Hi Akshay,
What is the relationship between the Blue Gel and E5? I understand it is a topical product rather than an injectable, but does it contain any of the same molecules?
Thanks
Mark no completely different products. Blue gel is a peptide that is highly beneficial but goes down with age whereas E5 is as you know young plasma derived fractions that has shown ability to reset epigenome to a younger signature.
Does increasing 1 of the ~30 peptides that decrease with age decrease any of the ~270 peptides that increase with age?
Tom no idea. Haven’t come across any study on that . This peptide is supposed to reset more than 6,000 genes to a younger profile when its systemic levels are restored to those found in the young.
But are you sure this peptide can cross the skin barrier?
Patricio for that we have a transdermal patch that’s going to follow the gel. The gel is for topical application the patch is for bringing up the systemic level of the peptide.
Akshay,
Do you have a study that you can point to that supports the claim that the peptide in Blue Gel resets 6000 genes to a “younger profile”?
Yes I do and its conducted by the most eminent Institute in USA. Unfortunately I can not share it just yet as we want to keep the peptide confidential till we launch.
I just watched a new interview of Harold Katcher on YouTube, where he says E5 will be more like an infusion rather than the injection. To be honest, as the new episodes come out, the less optimistic I become to E5. It’s going to be something like a dilution when you take out the blood and then take it back, how are you going E5 to change the mankind and be affordable to everyone while it will need too complicated things and procedures, nurses, professional doctors, equipment and etc? We all knew it was a combination of the factors and what was making it different from the dilutions is the fact that it’s concentrated like in ampoules. Sorry for the criticism but more and more I become sure all the claims and effectiveness of it, like 54% reduction, simplicity and etc were just for the attention. What do you guys think about it?
It wasn’t a claim of 54%. That figure comes from Steve Horvath’s epigenitic clock which evaluated the effects of the treatment on an experiment using E5 on laboratory mice. It was reported in a paper which Steve (a very well respected scientist in this field) was a co-author. I presume that as you understand more of the complexities of the technology you are being taken aback by it. My problem is that, like all medical research, it is taking longer than I would like. I simply urge you to be patient and follow the progress so that you can make your evaluation with more data. As a 76 year old I am impatient as well.
Azza,
As I read it, the administration of E5 was by tail vein IV. No blood was removed. You might wish to read the article:
https://www.biorxiv.org/content/10.1101/2020.05.07.082917v1.full.pdf
I am not currently worried about the means of administration. Other means of administration may prove effective (patch, nasal, sublingual, etc.), but even if IV is the only vehicle, I would gladly sit through a few dozen of them in order to see my son graduate from college. (I am 80, he is 8.)
I wish you very best but please watch a new episode of the interview on Modern Healthspan channels. That’s exactly what I am writing about, we all knew it was an injection, now turns out it’s an infusion because of the mass of it.
“It’s going to be something like a dilution when you take out the blood and then take it back”???
Azza, I dont think you have any idea what an infusion is, not sure why you are coming here to try to tell people what the E5 procedure is going to be when you have no idea. Maybe you should do some research or learn more or even ask Harold what it is going to be before making an assumption and then attacking someone for a false assumption on your part.
Before replying here, watch a new episode. Watch and listen carefully instead of teaching others what to say, where to come and what to write. Harold said it’s an infusion and it’s a Richard’s reply, not mine, by the way.
What do you think an infusion is?
You think it involves removing the blood
It doesnt, you are incorrect.
I tried to tell you this but you ignored that.
Infusion vs Transfusion – MedicoRx® Home Infusion Pharmacy
https://medicorx.com/infusion-versus-transfusion
As both an infusion and a transfusion are given through IV drips, it can be easy for people to assume that they are the same. Infusions essentially refer to when an outside substance is administered directly into the bloodstream, while transfusions refer to when the same substance, just from an outside source, is administered in the same manner.
So, when Harold said “infusion” in Richard’s latest video I suppose he meant, instead of a needle injection, a patient would be connected to an IV bag containing E5. The difference essentially would be the time to administer the E5 (Needle = short; Infusion via IV Bag = longer).
I’ve received a dozen infusions last year when I had issues with a hyperactive thyroid (now all back to normal – thank God). Anyway, it’s not a big deal. A little prick and you just sit there watching a movie or reading a book for an hour or two depending on your metabolism and health (slower is safer).
If that procedure is too much for Azza to bear in exchange for the prospect of significant rejuvenation then I’m more than happy to take his place 😉
You just can not read or do not understand what I wrote. If it were ampoules and an instant injection, then anyone could buy it abroad but when it comes to a massive infusion bags, it’s no longer as simple as people could imagine. Not to mention it’s price, it can dramatically increased and even become more expensive than regular HPE, since more people will be needed for the procedure.
Azza, what exactly are you getting at here?
On the one hand, you potentially have the CURE FOR AGING – something only dreamt of by millions of humans over countless millennia of time! And on the other hand, you have a minor inconvenience and cost.
What’s your point? Shouldn’t you just feel happy and excited and hopeful that E5 is everything we are hoping it can be?
Why would you be concerned about how it’s delivered or packaged or even it’s cost?
I am a first supporter of the Yuvan research, I am happy with it. I just said it’s May can not be as simple as seemed to be. You may need to learn how to analyze the sentence.
It appears your understanding of the subject matter is even worse than your manners.
This is not brain surgery Azza: You take out the E5 with a syringe and then inject it into a bag of saline solution. Which you can buy at pretty much any pharmacy in the world for relatively low cost.
Yes you need to know how to set up an IV drip. But every nurse on this planet is capable of doing this. See this guide: https://www.youtube.com/watch?v=KmyAksAo0RY
Your perception of the realities involved seems to clash with that of the rest of this group. Maybe that should give you pause and before you submit another response.
I just want you to learn how to analyze the written. Have a nice day.
And I want world peace. Unfortunately we can’t all get what we want 😉
I agree with the overarching sentiment here: Let’s be patient and as supportive as we can of Harold/Akshay’s efforts. Maybe we’ll all be proven wrong but if we’re not the future shall be glorious.
As the old saying goes: Patience is bitter but its fruit are sweet.
I agree, Azza should definitely take a pause. He not only seems uninformed and is jumping to conclusions, he seem irrational and hysterical and has lots of complaints. I have seen people like this before. They like to yell and scream, throw accusations around, just general bad etiquette.
I am not he, I am she you fu**n stupid.
Female? Well that explains the irrationality then. Listen, you are just a young teenager. Why dont you sit down and let the adults discuss things and stop being rude?
I am not a teenager. And I do not think why such a sexist should live more!
I think it’s due time for us to ignore the trolls. Nothing can be gained by engaging in useless dialog and accusations. I propose we simply focus on conversing with the productive members of this group moving forward.
My deepest thanks to everyone who jumped to our defense. I am really touched by your support 🙏. Azza did not seem negative to me. From the interview it seemed to her that the costs would be high. Let me reassure her that Harold and I have a stated goal to have E5 available for all. It will require administration under medical supervision but as someone said here IV drip is a routine procedure that any qualified Nurse can handle. We expect E5 cost to be $5,000 per treatment which is much lower new drugs costing $100,000 per treatment. Harold and I have different estimates on how often a dose will be needed. He feels it could be in years whereas I feel it could be in months. But in future version all we may need is applying a transdermal patch which may make it easier to have constant steady state levels of E5 in us.
Thanks Akshay, you completely understood what I meant, I am your supporter. Why do you have such a different expectations? Harold thinks it will be needed once every 8 years while you think in months.
Azza it’s a complex biological question. Harold feels that at some point the gene expression and epigenome are reset to how they were at a younger age and so aging should begin again after treatment from that point. Whereas I go by the half life of the components of E5 and feel that the regulation of the aging program may be independent of the gene expression pattern and epigenomic signature. So we would need to keep hacking this regulatory onslaught. Anyway we will find out by next year. Either way is fine if it can keep you in youthful health perpetually.
Thank you for the explanation! What can you say, will it be available for those living outside the USA? How you plan it to be sold on the market?
Yes of course. It should be available across the world. The timing of availability will depend on local regulatory approvals and our financial and management bandwidth.
Yes of course it will be available worldwide. The timing would depend on local regulatory approval and our financial and management bandwidth.
Hi Akshay, it seems you have an approximate expectation how E5 will be administered, how frequently and etc. Have you thoughts how it goes with a dog?
Leo we have to find out. Once we infuse by IV we will do blood draw and conduct cytokine assays at 7th day, 15th day, 30th day, etc. and based on these readings decide timing of next dose.
$5000 every few months may sound like much but one easily forgets that the value of seasoned professionals is high. Meaning someone in his/her 40s and even 50s is easily able to command a high six figure salary. Also let’s not forget the effect of compounding interest which, if done correctly and early enough in preparation of future need, would outright pay for the treatment and then some.
Yes in the beginning that may leave out deserving people in low income nations but again – we should not be focused on the early stages. Given enough time I am convinced that the treatment will become affordable for nearly everyone. That’s the vision, so let’s work toward that goal.
Thank you Michael. Hopefully Harold is right and so it would be $5,000 every few years.
Yes right! It’s no big deal, and according to Dr Katcher, it only needs to be done about every 8 years to maintain your youthfulness. Such a small price to pay to the ultimate (!!) gift of life and time. And of course, over time the technology and research will continue to improve – who knows, maybe some sort of mechanism involving nano robots or something to automatically maintain the correct “signal” to your body to tell it to stay young.
Let’s just be thankful that after millions of years of evolution, we are all possibly the luckiest humans alive because we were born at the same time as E5 was developed … fingers crossed 🙂
Let’s hope it’s approved and fastracked, no doubt Harold is a genius!
Hi Fred: I think that the confusion comes from the interview itself. The interpretation of infusion requiring plasma removal and re-injection was by the interviewer, not Harold. My daughter does infusion therapy all the time. A simple process.
You are right but Harold agreed, that’s why I do not like Richard’s interview, horrible quality.
Richard isn’t a professional interviewer, but he is persistent and has interviewed many doctors and researchers in the anti-aging field. I for one appreciate his efforts very much! In fact, it was through Richard’s channel that I first learnt about Dr Katcher’s incredible work and led me to Josh’s site here.
As someone who has received a ton of them I can confirm – infusions are not a big deal at all. Anyway Akshay, Toby, Fred, et al.: it may be time for some mock latin: Illegitimi non carborundum :-))
Akshay, do you have any idea about the intensity of injecting E5? I will write an example to make it clear, so, if you are 10 years old and with the help reversing the age by about 50% you become 5, will you continue to age from this 5 years of biological age or will you need to inject it regularly to stay on 5?
Nanaka from the 2 doses in rats we saw that after the peak of the first dose there was aging again. But after the second dose there was a cumulative benefit with a deeper peak but the aging was much slower then after the first dose. This is the only data we have as reference right now but in August we will be administering a 3rd dose in our lifespan study. This will tell us more. We will also need to find out the dose response curves in larger mammals and humans which may vary from the rats.
I know I’m impatient and dealing with bureaucracy time but….Another month has gone, are we any closer ?
Michael it gladdens my heart to know that there are so many supporters who are eagerly waiting for our first product 🙂
We received the sales tax registration. Unfortunately our lawyer is unable to guide us regarding starting a community membership so we are going with the mandatory label as required by FDA. Its in the works. It is quite normal for product launches to take longer than expected especially since its the first launch and we would want to ensure everything is in compliance. There is no deadline so we would rather be safe than sorry. Final tasks are being completed to prepare for a soft launch with 1,000 units of 100ml bottles with pump dispensers. If after the 1,000 units there are still members of our community who need more we can double that with another 1,000 units. This is our small gesture to our supporters: they will always get first opportunity to buy before it opens up for public. To the first 100 who order we are planning a surprise gift. 🙂
I dont know if my reply to Michael which was also an update was published here so adding here once more: Michael it gladdens my heart to know that there are so many supporters who are eagerly waiting for our first product 🙂
We received the sales tax registration. Unfortunately our lawyer is unable to guide us regarding starting a community membership so we are going with the mandatory label as required by FDA. Its in the works. It is quite normal for product launches to take longer than expected especially since its the first launch and we would want to ensure everything is in compliance. There is no deadline so we would rather be safe than sorry. Final tasks are being completed to prepare for a soft launch with 1,000 units of 100ml bottles with pump dispensers. If after the 1,000 units there are still members of our community who need more we can double that with another 1,000 units. This is our small gesture to our supporters: they will always get first opportunity to buy before it opens up for public. To the first 100 who order we are planning a surprise gift. 🙂
How do we get on the pre-order list?
I will post the link here
Can’t wait for it!
Can’t wait!
Thanks Akshay,
Funny, its only been 14 months since Josh first posted about the breakthrough but it seems so close and yet so far away. You have had to deal with lawyers, covid and
bureaucracy as well as the science (sucks to be you).
I would like to preorder for my wife and self, I’ll happily prepay as well if it helps.
All the best,
Mike
Thank you Michael. Yes last year has been challenging for everyone. No need to preorder. Once link is posted here you can order as many units as you need.
I’ll take 500 of those bottles and bathe in the stuff until I look 25 again 😆
We are rooting for you Akshay! Keep up the good work.
Thank you Michael! Blessed to have friends like you.
Ashay, I hope you still plan to ship to Europe. They charge 21% VAT tax on everything in the entire EU, but cosmetics is no problem. Thanks for all your hard work and I am anxiously waiting to order the spray to start.
Thank you so much. Mostly signing up with USPS and hoping they ship to Europe. If not I have friends in EU who can stock and ship. Will surely figure out something.
Yes UPS is a big shipper here in Spain. They will know exactly how to handle it. Thanks
Hey Van – I also live in Spain. What I’m a bit more worried about are customs. They have been extremely strict in the past year and almost every package I receive is being slapped with excessive import charges.
UPS knows the law and will attach a sticker to package showing VAT paid.
From your mouth to God’s ears 😉
Since you’re Spanish I better translate that one. I mean to say ‘I hope you are right!’
.
Congratulations on the release of Dr. Katcher’s book (title: The illusion of knowledge: the paradigm shift in aging research that shows the way to human rejuvenation, available at Amazon).
Wonderful read!
“E5 On Dogs Project: Validating The 54% Reduction In Epigenetic Age”
https://www.youtube.com/watch?v=vGK4L3-_XnI
Congrats to the whole team!. Another step ahead. Nevertheless, dogs don’t seem to show enough correlation with humans in test results yet.
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-1976-2
That’s true. Dogs are very challenging for a study like ours but we love our pets and so worth a try.
What you mean when you say it’s challenging?
Do you mean the amount of E5 needed for it? I suspect shorter lived animal(dog) rejuvenation should be easier than the humans.
Nanaka there are very few age related assays available for dogs.
What is the “blue gel” everyone is talking about and where can I find more information about it? Thanks.
Yes, it’s right but evolution has already made human and dog very similar not to mention E5 should be something working across most of the species.
Sorry, this was for Akshay.
Yes it should be but we need to provide evidence via good quality assays. In rats we ran 30 tests. In dogs we will be lucky if we can do 5.
That’s interesting, so what’s purpose of doing it on dogs and primates if it won’t help humans? Does not Steve’s test show rejuvenation on dog study?
Yes Steve’s test would be the main reliable one. As a scientist one would test E5 on non human primates. But as dog andvcat lovers we would like to see if E5 extends healthspan and lifespan.
Dad and I have been following this blog since it started but we have been unable to get a post to come up approved. Maybe this will be the first? The way I understand it, the blue gel is a peptide gel that is supposed to help with external signs of aging. Originally we had hoped it would be available on Amazon in May, but September is fast approaching and still nothing. This is expected to be followed with a dermal patch which would help with aging on the inside. (The ultimate help would be the E-5 but that seems to be years away.)
Toby, Shay has covered it correctly. Merely product being ready is not enough there are a lot of compliance we need to complete before we can sell it. I misjudged the time it takes here. Professionals are handling them but we have to live by their schedule. We are a new company and first launch does take its time I hope to have your understanding. As Aristotle says Patience is bitter but it’s fruits are sweet.
Thanks for your replies, Shay and Akshay.
Akshay, how much have you tested Blue Gel on human skin? Have you actually seen it reverse aging? Have you seen it remove wrinkles and lines etc from skin?
I’m quite interested to know more about this product.
Thank you very much
Sincerely
Toby
Toby there has been one human trial where it increased collagen layer by more than 50%. Collagen is 70% of our skin and shrinks significantly as we grow older making our skin brittle instead of supple and Subject to wrinkle and lasting photo damage. We are ourselves conducting a human trial which will include ultrasound high resolution scans to confirm andcmeasure any improvement. So hopefully there should be plenty of evidence versus conventional skin care products in the market.
A 50% increase in collagen? Wow, that’s just mind boggling. One does not need a medical degree to realize the implications, especially on a long term basis.
Hi Akshay,
NEEL, any progress?
https://uspto.report/TM/90738472
If you look further down on that report you can see that it has been filed and is still being processed. The status is shown as ‘pending’.
Thank you Michael. Stephan we continue to work towards a launch as soon as possible. I have one more update: Harold’s book launch is on 4th September at Book Passage book shop in Ferry building, San Francisco at 2pm. So anyone who can attend could consider doing so. On Amazon his book debuted at no. 1 and has continued to remain in the top 5 of biotechnology books new releases..
Awesome – that’s one of the rare times I wish I still lived in the Bay Area. Can you please post the URL of the book so I can purchase it? Thanks!
https://www.amazon.com/Illusion-Knowledge-paradigm-research-rejuvenation-ebook/dp/B09C7JNB64/ref=zg_bsnr_13518_1?_encoding=UTF8&psc=1&refRID=QH19TCGEXTPYRXBJY1F9
It’s called The Illusion of Knowledge by Harold Katcher
Dr. Katcher interview (new today)…
Thank you for the link, Stephan! It looks to me like we may see the Blue Gel on Amazon in December or January. That is really not bad time wise for a maiden launch! And then a Dermal Patch sometime in 2022? Wooohooo! Good job, Akshay Atomic Bliss, and all involved in this! -Shay.
Hello, I just incidentally discovered this community and am so happy about it! I devoured Dr. Katcher’s book only a few days ago and wanted to warmly congratulate him, Akshay and their team for their work. Harold Katcher’s personal determination (and dream) is very inspiring. As for his approach of the theory of ageing, it illustrates a remarkable capacity for thinking outside the box (or the cell in this case) despite not being the mainstream approach in the longevity field. “E pur si muove !” comes to mind. Allow me to express much gratitude for everything you’ve already accomplished and to wish you good fortune for the next steps. Looking forward to your future announcements.
Dear Maxime your kind words truly made our day. It does get difficult when giving birth to anything as any mother will agree so such encouraging words help you on those difficult days 🙂
Thank you very much.
I’d also seen Maximes post and looked on Amazon and bought the book and expect it to arrive Wednesday and I’m looking forwards to reading it so thank you Harold and all others involved in its production ,
Harold thanks John for purchasing the book and hopes he enjoys reading it.
Hi Akshay, why did you decide to go for an IV bag instead of injection?
Obviously we have 200x the plasma volume of rats, but you’ll now be adding saline and albumin, so by definition you will be doing dilution, as well as the (confounding/but likely beneficial) effects of pristine albumin, which makes this a different experiment to that done by you and Harold several times on rats.
Could you not just increase the concentration of E5, or are you worried about safety so you want to add it more slowly?
Thanks
Mark IV is only with Saline. No albumin. The volume requires IV otherwise it would need too many injections.
Hi Akshay, would this then be similar to a dialysis process?
Hi Qin so you could post successfully 🙂 No not dialysis. Just IV drip.
Just purchased a digital version of Harold’s book from the Amazon. After reading the first chapter I have to admit that it really goes into my reading testes. As a person interested in ancient history and even prehistory I really appreciate that Harold started with a historical background. The other thing is that it is very well written and I really enjoy reading it. As I am a bit slow reader when it comes to texts in English I will definitely have few nice evenings with The Illusion of Knowledge.
I hope that this publication will reach as many readers as possible and will spread the awareness about your wonderful work.
Dear Adam thank you so much for such a nice review! I request anyone who has liked the book to please leave 5 star reviews on Amazon. Apparently that is important in the success of a book.
I’m still in the process of reading the book and I wish Dr. Katcher and his team all the best in research and upcoming rejuvenation products.
However, success comes with the danger of an aggressive takeover by a big pharma or super-rich billionaire to extend their power to control humanity.
Hi Akshay:
I have just finished reading Harold’s book and have watched various interviews with Harold discussing his results. It seems to me that Harold is a bit like Isaac Newton and his formulation of the three laws of motion. He built on the work of others before him (such as Galileo) and his unique background enabled to appreciate and synthesize their work and his understanding in such a way as to enable an integrated approach to understanding nature. In Harold’s case of course it is understanding the mechanisms enabling rejuvenation. I heartily commend him and look forward to him realizing the dream of his youth. But not in 400 years.
I presume that when Harold mentions the treatment he received in India that it is the peptide skin treatment? If so, his improved health sounds quite exciting on its own!.
Thank you so much Ed. Harold will be really pleased to read your post here on his book 🙂
I am aware that in many areas of the country private firms exist that perform infusion therapies at home. Vitamin injection, NAD injection and the like. Have you considered contracting with them to deliver E5?
Ed upon FDA approval E5 will be prescribed by doctors. They may want to administer it themselves at their clinic.
Hi Akshay , you mention 5,000 dollars as if it’s a small amount , it’s not also use the excuse that it’s still considerably less than the amounts for some drugs that’s true but those drugs are for serious conditions that effect just a small number of people and has had to undergo human trials , whereas E5 is really just a mix of hormones ,
I feel that using the saline solution and IV drip means that it cannot be injected by the user , whilst I can understand that there are millions of diabetics who have to inject as much as four five or more times a day for their entire life ,
I get the impression that far from Harolds hopes that this would be as cheap as possible for as many as possible it’s unfortunately turning into something only the well off can afford ,
John as E5 will be prescribed for a medical condition your insurance should cover it. E5 is not a mix of hormones. It will have to undergo same number of human clinical trials as any of those expensive drugs in the market. So if we succeed in getting pricing to $5k Harold would have fulfilled his goal at 5% cost of typical new drugs.
Hi John
In my opinion *any* amount of $$ would be worth it to (a) live as long as I choose and (b) live in the body of a 20 year old.
I wouldn’t worry about the cost because as production and distribution increases, the price will naturally become lower over time.
This is the ultimate product – pretty much every person on the planet will want it, hence it’s a massive market that will drive the price down through basic economics.
All good points Toby. Thanks.
I am sorry but this reasoning does not follow the natural laws of supply and demand. If there is a product or treatment that everyone on the planet wants then it will implicitly increase its value and thus its price as opposed to reduce it. Askhay and Harold may have good intentions but at some point shareholders, delivery partners, and other 3rd parties will hold the reigns when it comes to the pricing and application of the treatment. The whole idea that Yuvan will be able to control the entire delivery chain over the long term is short sighted IMHO. Just my 2 cents FWIW…
Michael if we are able to retain majority control then we could control pricing of our products. But if forces beyond our control influence it then your prediction may be more accurate. We can only try our best.
Hi Toby , I agree but how long will that take , I don’t fancy living on bread and potatoes for the next 20 years until it’s price drops to a level where everyone can afford it also how long will insurance keep paying once they know what they are paying for , also most people in England and places in Europe don’t have insurance that would cover this (i’m in england) and they will only prescribe drugs that have been past by the group that advise the govt , Akshay says it’s more than hormones that’s not as I’ve read it over the time I’ve been on the site , it’s 10 signal hormones perhaps he can explain how they differ to any other hormones considering the fact that every hormone in the human body is made from just 21 amino acids and can be printed out easily and relatively cheaply
John as one of the co-developers of E5 I should know that its not what you think it is. If it’s prescribed for a chronic condition I don’t know why insurance would not cover it.
It seems to me that $5000 is a quite reasonable cost for a revolutionary drug that will allow you to live the life of a young person again. Particularly a drug that requires dramatic insight into human biology, extensive clinical trials and the willingness to preserve through the myriad challenges of commercial interests, legal issues and scaling up for production. I commend Ashley and Harold for this. When I researched the cost of obtaining a very small amount of a blood protein (gdf11) some years ago (only one protein not five) the cost was quite high. I think that if it can be obtained for anywhere close to 5k initially that will also be an outstanding achievement.
Haha I think everyone is trying to make Akshay say what E5’s components are by intriguingly mentioning
hormones, one protein not 5(E5) and etc.
Thank you so much Ed.
Hi John
It’s a bit too early to really speculate on the pricing etc. Dr Katcher believes it might be one treatment every 8 years (which would be quite cheap), whereas Akshay thinks you might need several treatments per year. Therefore the cost range at this stage is quite varied. Further testing is needed to determine the optimal frequency of treatments.
I imagine, there might even exist some sort of money lending service where folks might trade their treatments for some loan repayments plus interest, or perhaps even trade for their labour for a period of time. I’m just wildly throwing out ideas here, but really, I’m sure there’ll be lots of options for folks to obtain their E5 treatments.
I’ll gladly pay any amount to keep my parents and myself rejuvenated. The question is less of how much and more of when?
Getting any new product out especially that requires regulatory approval takes many years. But fortunately it’s much faster now than even a few years back. For all believers there is one more option: As our human clinical trial moves to Phase II and III it will need thousands of volunteers. Qin you could consider enrolling your parents. Best part is it will be free.
I will! Thank you and Dr Katcher for all the hard work!
Thank you Qin
Involvement in the Phase II/III … that’s a wonderful option! Please keep us posted here for that Akshay 🙂
But is this a discrimination? What a hurt for those of us who live in Europe, I would gladly take part in the trial my only mother who may not even be able to attend the E5 release.
I also don’t live in the USA … I’m sure some trials could be organised in other countries through some local research or medical organisations.
But how soon can it happen? Aging is the most complicated and the most cruel thing, my mom may not show a rapid degradation but because of the evolution program, she may just die.
Hear hear!! (shouting from Spain). My mother is 77 with various small afflictions that are robbing her of much quality of life in her retirement. By the time E5 arrives in Europe she will most likely be long dead, which would be tragic as she would miss this fantastic treatment and may end up one of the last people having to accept what is at least currently considered a ‘natural’ lifespan (which by all intents and purposes has already shifted significantly over the past century).
Anyway, I know that Akshay and Harold aren’t able to perform miracles but if there’s a way for us Europeans to get our hands on E5 – somehow somewhere – it would be massively appreciated. I say that especially in consideration of the renewed travel ban that prevents many Americans from going abroad or Europeans from traveling to the United States.
All I can request is be patient. Take care of your loved ones. Try to see if there a good quality natural interventions that can ensure they remain in your loving care for the next few years. We will try our best to fastrack E5. I know that Phase III will be in multiple countries around the world as regulators want to see it work across different races.
I understand completely, Akshay and also must remind myself to appreciate your position. The curse of success comes with creating something that everyone wants but cannot be given to all, which in turn produces much frustration and additional pressures on the creator. My hope and pray that modern medicine will be able to maintain my mother’s health into her mid eighties by which time she may be able to benefit from E5.
I’m not a scientist but have personal experience with natural lifestyle interventions that keep me still very healthy – physically and mentally – in my late 60ties. I will do a write-up and share it here for those who are interested.
Not sure if my reply has been published. You are right, one pity thing is when you lose your mom and think it’s a natural thing to age and die and second and far more pity thing is when you know something is existing which can save your loved one but because of the living place you are not able to help. I know Akshay wants to make sure it’s safe, but do not understand if someone in USA is able to join the trial, why could not we? It’s a discrimination, I think Akshay should have a discussion with team members and with a “regulator” man.
Nanaka – as much as I appreciate your situation I would caution against making ad hominem attacks along the lines of claiming intentional discrimination, especially in the current political climate. There are simply limitations that are part of the process and as much as we may contort ourselves in regards to morality or hypothetical possibilities it won’t change the outcome or the process Yuvan must follow in order to bring a viable product/treatment to market.
Akshay and Harold are the last people on earth who would be engaged in active and intentional discrimination against any other human being. Let’s just all cool down and remain patient – I know it’s difficult to face the death of a loved one but this is the REALITY, so let’s deal with it. Heated accusations or even questioning the moral fortitude of others, let alone Akshay and Harold, is a slippery slope that should be avoided at all cost.
Thank you for your understanding Michael and Nanaka .
Oh no, I did not want to mean it. I mean general discrimination, which we have to feel. I just adore Harold and Akshay, I think Akshay’s role here is the first and the most important. I would just appreciate if he could review this with his great team.
Of course Toby. We will never forget the support given to us by the community here especially Josh, Zisos, Mehlre, and many more. The publisher of Harold’s book Nicolas and his wife Nina have volunteered to maintain an email registration web page. To all emails registered there we will send regular updates, photos and videos. Nicolas will share the link here soon.
Yes please – do share the link. I have purchased Dr Katcher’s book and would definitely like to be added to the mailing list! Thanks Akshay.
Nanaka – we must all just be patient and hope our loved ones can hang on for a few more years until E5 is proven to be safe (that’s the first phase that the FDA requires before moving to new phases).
I am humbled to see my name mentioned in such esteemed company. Wish I could do more but until at least the blue stuff is available my ability to promote the brand and product remain somewhat limited. Until then I will remain in eager anticipation of the first launch of the topical gel. Which IMO is key in financing E5’s long term future and viability as a widely available treatment. Quite frankly speaking if it wasn’t for the topical product launch I would have been a lot more skeptical about Yuvan’s prospects and funding opportunities. I congratulate Akshay/Harold for having had the foresight to focus first on a quickly available treatment which addresses several hurdles young pharma companies traditionally end up facing (i.e. years of burning through investor cash until first product launch).
Thank you Michael 😊
“When because as production and distribution increases, the price will naturally become lower over time.” ? I am not sure why you would say that. The price is whatever Akshay and Katcher decide it to be. They dont have to lower it at all over time and it certainly doesnt naturally lower by itself, heck, they are free to increase it if they want as long as they have a patent.
Fred to be fair Toby just mentioned what could be possible and as someone who will be involved in the decision making – unless big pharma gets us – I can assure you Harold and I would choose to lower the price when possible.
Yes right. And it might even just be the lowering of costs for manufacturing, packaging, shipping etc as the volume of sales increases. This is something that happens with many products. But of course, you are correct, Dr Katcher and Akshay, given they would be the only legal producers of E5, could set whatever price they want.
But as Akshay points out, and so does Dr Katcher in several video interviews, their aim is to make a reasonable level of profit to reward everyone’s efforts, but not to over charge excessively (which would slow down the rate of saving people from age related death).
I’m the first person to spot a scammer, and to the best of my ability, Dr Katcher and Akshay do appear to be genuine and fair, with the goal of bringing the ultimate gift to the world.
And we only have a few short years to wait to see if E5 is effective and safe, and to prove that those involved are honest.
Akshay – could you please explain a bit more about your comment regarding “big pharma” … do you mean there might be a chance big pharma could buy your company or something like that (I sure hope not) ?
Toby E5 if it succeeds in humans the way it has in rats many big pharma might get affected. We could expect some kind of move by them. Plus Harold and I wish to go back to the world of education if we are blessed with youth. I hope to do a PhD in Astrophysics. Harold too has many interests. So we have to pray and plan for the worst while we hope for the best.
Why can not you just go back to Mumbai and then anyone in the world could participate without waiting to FDA until it approves? I do not know how many years will it need to let my mother join phase III trial. Do not you plan any other way for a very eager participant? It’s have to, not my wish. I worry she may not be alive by this time.
Nanaka I would myself like E5 to go through the strictest testing before we make it available for the public. Therapeutic development is not as easy as it sounds. I do admire your love for your mother. If she is in otherwise good health write to me and I will share my suggestions for natural supplements that you can check with her doctor to bolster her health till E5 becomes available.
Hi Akshay
One thing I’ve been wondering is this…
Unfortunately, many treatments that seem to work well in rats and mice, do not end up being effective in humans.
So far you have only tested with rats (with amazing results), but what gives you confidence, if any, that E5 will also work with humans?
Or is it really just waiting and seeing the test results in humans?
Thanks!
Toby very good question indeed. The statistics of drugs that work well in rats and translate similarly to humans is dismal. We won’t know for sure until it is tested in humans that’s my honest answer. But the fractions we are using are highly conserved across species. The difference between the genetic make up of rats and humans is surprisingly small. We both share the same program by which aging is implemented in our bodies and the factors that reverse in rats are also factors that would reverse in humans. This is fundamental biology and what gives us confidence. Of course there is a lot to find out even if it works similarly like how long will it take to give the benefit, how long will it last, etc.
Thanks Akshay, that makes sense … the next 1-3 years are going to be very exciting watching the test results as they come out!
I think since rats lifespan is too short, E5s factors are worn out quickly, maybe it will last longer in dogs and cats, longer in monkeys and even longer in humans.
You may be right. Harold thinks so too. We will soon find out.
I second the thought of a clinic in Mumbai which administers the drug at all-in cost for those who are of an age or otherwise need the treatment sooner than the completion of the whole process is likely to allow. The results of the clinic might supplement the clinical trials.
Ed I wouldn’t feel morally comfortable doing that before a thorough examination and approval by FDA. If I was so inclined Harold would have received E5 by now. There is a procedure laid out for introduction of a new drug and I would like to follow it.
The fact that the new aging clock clock works across mammals seems to me to increase the probability that a treatment (E5) that resets the clock in rats has a good chance of doing the same in humans. Of course, only actual experiments can determine this for sure. Thank you for your patience in answering questions.
Thank you Jim
Thank you Akshay, I will email you. I do not mean it’s availability, I mean just letting us join your trial. Since it has zero side effect on the immune system and is generally considered safe, as well as created by a nature, as you say, then I would most definitely get my mother involved but that’s exactly why I am asking you to find out a way for such an exceptions, maybe you can think about it and find out a way for the EU resident to take part in without moving the USA.
Nanaka if she can travel I don’t see a problem
I do not know Akshay, she is 93 years old, we do not have viza and etc, it’s very complicated to make her flight. I am still hoping your team will find out the way for us to join human trials.
Which city is she in?
Athens, Greece.
Nanaka I would like manage your expectations. It takes a lot more to enroll in a trial than my desire to help. I can’t say right now if Athens will be one of the trial centers. Also there is screening of volunteers done by the medical team and principal investigator.. At 93 she can be quite vulnerable. But it also means she has a good set of genes and has lifestyle factors suiting a longer lifespan. Let’s hope for the best.
Akshay – you can have your degree in astrophysics. I for one will be going into space!! 😉
Harold will probably join you 😀
That according to him is the biggest advantage human civilization will get from longer lifespans: travel into space.
I agree , it’s one of the things I’d like to do going to a habitable planet round another star , also my apology about the price in an earlier post , I didn’t know you were doing human trials , as far as I’d read you had just done them on rats and dogs and that you weren’t doing the full FDA drug approval , which I now see you are ,
No worries John. Yes space travel outside our solar system would require hundreds of years.
Hi Akshay , it may not take that long , NASA are already working on FTL travel based on a Mexican physicists work who’s already done the maths and physics , it will still be years but it’s closer than most people think
Wow! Can you share the name of the Physicist? I know Harold would love to read his work.
Hi Akshay , I would have mentioned it in my post but forgot how to spell it , I think it’s Alsabere just do a search for faster than light travel and the name , even if I’ve spelt it wrong the search engine will give the correct name
The Albuquerrie Drive is undoubtedly interesting. Maybe the prospect of a Physicist having a very long lifetime and preserved brain plasticity is what will allow it to come into being. Maybe Ashkay himself in his Astrophysicist career.
Thanks Ed , I knew my spelling was wrong but thanks for correcting the name ,
You know Ed my kid like wonderment at science and technology is what drove me to aging research. I was too naive to know that you can’t just try to solve the most complex mystery of biology. I could have wasted many years of my life. I know my family used to wonder if I lost it when I would choose to research and study on many hours on weekends after a hard week at my day time job. I did that for 10 years before I had my Eureka moment and destiny brought me Harold who had a similar journey thousands of miles away. I think this thirst for science and technology will always remain for both of us no matter how many lifespans we might get blessed.
The advent of E5 may bring about the full potential of the human species. An unlimited lifetime allows unconstrained possibilities
A wonderful thought.
Sorry Alcubierre
I have to admit that this strikes me as a bit academic. Over here in Spain it would take many many years – perhaps a decade – until a E5 would be approved and supported by most insurance companies. Now I personally do not have an issue as I can afford the $5000 once or twice per year but it does put a crimp into being able to administer it to e.g. the average Spaniard who makes about €1000.- per month. A whole generation of people here subsist on even less, and many of them may have the greatest need.
BTW, I am not trying to be over critical and it’s a non-issue for me personally. I simply feel that relying on the approval of insurance companies in particular as a strategy is a long shot.
Case in point: A year or so ago I was considering to get on a newly approved drug that would have helped me with a thyroid induced eye condition. The cost of that drug was in the tens of thousands for a single regimen and although it is being selectively administered in the U.S. its approval here in the EU is still many years away.
Michael those things may be beyond our control. We will on our part hire the best consultants to fastrack any approvals needed for insurance. You must also not underestimate the power of the voter in a democracy. If many desire a speedy approval it would be difficult for the elected politicians to ignore that.
Hi Akshay,
for people like me, who have taken good care of their health, who have no known conditions and never have been a burden for the healthcare system, no insurance company will cover an E5 treatment.
Also, it would be interesting to learn whether there are the same rejuvenation effects for participants with pre-existing conditions and people in good health.
The reasoning for that is my experience with NAD+ boosters, which didn’t provide any noticeable benefit for me.
Just my 2 cents.
Stephan NAD+ is going after a single symptom and that too if it does reach the cell and mitochondria. Whereas E5 is a systemic resetting of every cell to younger phenotype. It would be very difficult to miss. Regarding insurance for example however fit you are you would still qualify for sarcopenia.
Dear Akshay,
over the years, I have learned from you so much about balancing my lifestyle intervention and supplementations. That builds trust! Also, I can’t thank you enough for your efforts to help Harold’s dream to become true. I have the most respect for you!
However, in my experience, healthy people are not a business model for big pharma companies. They do not just influence universities, physicians, health care systems ( I better should say “sick care systems” ) etc, but also insurance companies.
In my opinion, your assumption that E5 treatments will be covered by insurance is an illusion unless Yuvan Inc. gets swallowed by big pharma.
For people like me, who are experience financial stress, this is not a good scenario.
I hate to be negative on this end.
No it’s a genuine concern. I hope we can get insurance to cover our treatment like all other prescription medicines. In your case you don’t have to worry. You are in great shape and can easily make yourself available for our Phase II which will be free for you.
Thanks, I will be available anytime and you have my contact information 😉
Forgive me if I don’t know much about US health insurance, but generally, people who age and die stop paying health insurance. Insurance companies might want to help out with E5 somehow to keep their paying customers alive.
Do not worry guys, before the E5 is being studied and approved by the FDA, we will have a genuine breakthroughs from David Sinclair and other scientists working on reprogramming. It’s a hot news came from David that they restored electrical activity of old human brain cells through reversing their age, aka “rejuvination”, cellular reprogramming. They expect that the diseases of brain will be cured by making it young again. Also, yesterday, David mentioned they will do Yamanaka factors on human in about a year. That means we will soon be able to reprogram our whole body and as David said, he is going to make an achievements not only for “rich” people, but for everyone. We will be able to reprogram our entire body as simply as we are taking NAD booster molecules today. So at least, it’s a bad strategy and the conception your team has decided, Akshay. You could commercialize it as soon as possible but you decided to wait 10 year, where other reprogramming solutions will be available far sooner.
Nanaka you are unaware of regulatory laws in this country. Do you think a therapy like yamanaka reprogramming which has led to cancers in all rats after treatment is going to be available in 1 year for humans without FDA approval? I wish you all the best. My desire would be for your mother to get whichever rejuvenation treatment that comes out first. If reprogramming is available good for her and you. My best wishes.
No Akshay, I have not said that. I said what David mentioned yesterday that in the beginning of 2023, they are going to treat first humans with Yamanaka factors, like they did on a blind mouse. Not to mention Calico labs and Jeff Bezos generous gift to altos labs. I mean what David says. Citation: “I am an optimistic person and I knew everything would go fast but even I could not believe so rapidly”. You can watch his podcast, published yesterday in YouTube, the newest one. Not to focus on David only, my comment is more like to find out why you have chosen this way. No doubt other reprogramming treatments will be available until FDA approves E5, if at all it will.
Nanaka try to speak to someone who is familiar with FDA regulations. No such therapy can bypass FDA approval process. So all of them will take similar time. As I said if a systemic rejuvenation treatment is available before E5 I will be most happy as so many can begin to benefit. The number of potential customers/patients is so large that any one therapy won’t be enough.
Akshay, I am not trying to discredit any work done by your amazing team. I am just saying what it is. We could not imagine if reversing the age was possible just 5 years ago, today, plenty of lab is working on reprogramming with a safer ways, successfully. If anyone want to get what I am saying, please watch Mayim Bialik interview with David, uploaded 2 days ago. It’s David’s main wish to reprogram an entire body and activate it with a simple antibiotic. I also understand what you are saying, that you can not commercialize E5 without the FDA.
Not only that Nanaka I am also saying David can not commercialize safe reprogramming without FDA approval as well. You can ask him. His first human trial is expected to be in 2023 ours is expected to be in 2022. We have had no adverse effects so far: zero. Reprogramming has led to genomic instability and terratomas. Which doesn’t mean a safe way to do it won’t be discovered. But it too will have to go through FDA scrutiny. David, Calico and Altos are big names. We are a small company set up by two misfits. It will be interesting to see who comes out with a prescription therapy first. Your love for your mom is cute 🙂 Hope every mom gets a daughter like you.
Thank you and good luck. If we have a safe Yamanaka reprogramming, then we will need to do it after we age again, not once every few months. I hope E5 is meant to act like these factors and we won’t need to infuse it monthly to maintain.
And I forgot to mention, where there are billions of dollars invested, FDA can make it approved very soon.
It’s not supposed to work like that but you may be right. FDA process speed is dependent on whether the application qualifies for fastrack and if any safety issues come up during any of the trials. Only 14% of the applications win approval. Most of them applied by multi billion dollar Pharma companies. Main reason for failure: adverse reactions or lack of efficacy. If there are safety issues even billions can’t win an approval as human lives are involved.
I hope E5 is fastracked as soon as possible. I do not think anyone wants it more and sooner that me 😀😀
What is the fastrack duration you expect Akshay?
Thank you Nanaka. Difficult to say but it can be just 2 to 3 years instead of 7 to 10 years. You may like to know that 70% of new applications last year qualified for fastrack.
Now I understand why you are so calm: No side effects, curing literally anything, including Sarcopenia, a very good experience from the last year. Let’s hope it’s fastracked as this 70% you mentioned.
Fingers crossed 🙏
🙏🏻🙏🏻🙏🏻
By the way, when are you going to request for fast track? As I know, you are going to be answered within just 60 days upon requesting and it can be done during the developmental phase.
Next year after first data from our Phase 0 human clinical trial comes in
@nanaka: Not to speak out of turn (and please correct me if I am mistaken Akshay) but what has not been mentioned in your exchange is that Yuvan’s blue gel may (or may not) have slight rejuvenating effects on top of the expected cosmetic benefits (e.g. younger looking skin due to an increase in collagen/elastin and other rejuvenating effects. Akshay has advised all of us to draw a blood panel to measure IL-6 and TNF alpha before starting on the first regimen. There are no guarantees but it’s worth a shot. If I was you I would get your mother on that as soon as the topical gel is available, which hopefully will be sometime this year (again Akshay, please correct me if I am too optimistic here).
Right on all counts Michael
I will but it’s not a rejuvenation. Blue gel is a peptide, maybe copper peptide based, Why to wait for the gel when we have AKG? NMN? Sirt 6 Activators? Spermidine? I understand what you mean but…
We don’t know that yet. We may need E5 every few years or every few months we will soon find out.
Akshay,
So appreciative of your willingness to keep this group informed and provide us with answers to so many questions. Sincere thanks!
A lot of people have voiced concerns about “high costs” and “big pharma” interference w/ E5. I personally don’t share those concerns. In addition to Nick’s insightful comment on insurance companies having a vested interest in keeping paying customers alive and paying, here are some additional thoughts where I’d like to get your opinion:
Low/Scalable Material and Manufacturing Cost – Some drugs have high costs in these areas, but you’ve mentioned E5 does not. This should, over time, minimize cost-of-goods for E5.
Addressable Market – Many drugs justify high costs due limited market size. There are not many markets larger than all humans over the age of 45. When markets number in the billions of consumers, speed to market penetration (before something else hits the market) is critical to maximize long-term gross profit potential (think: E5 version 2.7, E6, etc.). High consumer costs will slow/limit market penetration and will be expressly avoided with a market this large. (Example: free/subsidized cell phones)
Breakthrough Routes to Market and Disruption- Traditional distribution models are cracking and/or already dead. Books, cars, music, supplements, and a host of other products are sold to customers via new processes/routes. Big pharma is ripe for disruption and I think there are some incomprehensibly rich people behind Calico and Altos Labs that would love to pick a fight with big pharma. A product like E5 with a huge addressable market would fit nicely into their future plans/portfolios. (Think about how Bezos has been so maniacal in his efforts to drive out cost and reduce prices to Amazon customers – essentially the antithesis of big pharma).
New Wealth Models – Peter Diamandis has done a good job helping people understand that, in today’s world, the fastest way to become a billionaire is to change a billion lives for the better, in even a slight way, and charge $1 to do it. Harold is going to need a big bag of money to achieve his space travel goals – the best way for him to get that will be to ensure E5 has maximum market penetration (i.e. benefits the most people possible) with very modest per-transaction profit goals. (This model will also work out nicely for the early investors.)
Akshay, do you think I’m off base on any of these, in terms of their possible applicability to E5?
Don you are absolutely on the mark with all your comments. I bet you must be quite successful in your work. That is indeed our strategy.
Hi Akshay. Can we have your thoughts about X39 patch? Do you use it?
Azza not sure – have to find out more. From what I have seen a small patch generating a particular light reflecting human Infrared which activates a single enzyme or peptide in sufficient quantum sounds far fetched. Also the studies cited do not seem to be IRB approved clinical trials and just says improvement dies not specify before and after levels of the target. I wouldn’t spend my money on this until I see good quality trial data.
That’s why I asked it to you, thanks! I have seen attaching it on a horse and pain is gone in a second. We all know there is no placebo for horses.
When you said we will keep a steady levels of E5 with the help of a patch, didi you mean this kind of thing?
No not this kind. They actually do not have any medicine that is transferred transfermally through the patch. They just claim to emit a light which is a modulated reflection of human Infrared transmission to elevate one specific target. I have doubts on the mechanism and the efficacy. But will change my mind if I see Hugh quality clinical trial data. Our patch would have E5 that would be released in a sustained manner transdermally.
Very interesting 😲 So E5 will need to always be with us to maintain its effectiveness. Is this proven or we have to find out yet?
It would be a more effective delivery but we would need to find out via multiple human trials.
Thanks for the info!
FDA approval of a new drug takes 12 years and costs a billion dollars. And that’s when you have a specific condition you’re targeting. They don’t even acknowledge aging as a condition that needs treating. And that’s for a unique drug that doesn’t exist in nature. I don’t expect you to tell us what E5 is Akshay, but we know it’s natural, you said so lots of times: it already exists in the plasma. So what is being patented? Assuming that none of this is insumountable and approval goes through, that kind of investment in time and money will necessitate a far higher price than $5000, just to cover costs, regardless of what Akshay and Harold want it to cost.
Or you sacrifice some credibility, go offshore, start curing human aging, and in a few years the FDA doesn’t exist anymore.
I agree with you, Mark. FDA does not control supplements, since your E5 is synthetically made and does not contain a real plasma fractions, which could be illegal to sell, then why just do not sell it as a supplement? You can cost it any price you want, including 5000$. We have some supplements which cost 1000$ a month, for example Japanese made Fucoidan (liquid form). If your aim is totally based on altruism, then why you need to wait for the FDA? In this case anyone could buy your “supplement”, no matter where they live.
Mark the days of FDA process taking 12 years are over. For example for breakthrough therapeutics they have initiated a fastrack system. Which can get a new drug out in a few years. Last year 70% of the IND applications qualified as fastrack. We are consulting with the best and most experienced regulatory experts so whatever I say here is based on their guidance. So let us hope for the best with regards to timeline. Patents are for various aspects of a technology even if it is sourced from endogenous molecules. Try to check Alkahest patents. Even if it’s highly safe and endogenous one is generating major changes in our biology. FDA is a highly regarded and tough regulator so it is important for own peace of mind to pass all their exams. It is a question of human lives.
You could just sell it in health clinics as an IV therapy for aging, like NAD+.
I just think it’s crazy you’re trying to get fast track FDA approval for something that isn’t a drug and doesn’t treat a specific disease.
But good luck anyway. If Harold suddenly starts looking much younger I’ll know you changed your mind and decided not to wait!
It would have saved hundreds of thousands of humans, including my mom. If FDA does not fastrack it in 2 years, then we will have to wait for 5-7 years, I doubt.
Absolutely! For example, Greg Fahy is completely open to his protocol. He is very rational when is taking about the FDA. Under a professional supervision, we can easily do a TRIIM. Why wait to FDA? The same should be happening to E5. You would have become rich more rapidly and would have saved plenty of people.
Mark and Nanaka it’s not an option. It’s not a supplement. It’s probably the most powerful therapeutic ever developed. It’s going to make changes to every cell. You have to bullet proof it. FDA does not allow such infusion. It shut down Ambrosia even though it was just infusing young plasma. What you are proposing to go outside the law without falling understanding the therapeutic. Anything so powerful must be thoroughly tested before it can be prescribed. And we are applying IND for individual diseases and not for aging. Just be patient and let it run its course of trials.
Akshay, no doubt E5 is a revolutionary treatment, but I still think everything is a campaign. NAD drips are also changing every cells and have a potential to not as dramatically as E5, but slightly increase the lifespan.
Trust me Nanaka you can’t compare NAD+ supplements with E5. NAD+ does not reset the epigenome or gene expression in every cell its hopefully upregulatong one key element that goes down with age. It’s like applying a bandage when you need surgery. Plus since most NAD+ supplements are taken orally I have reservations on how much is actually absorbed in every cell and its mitochondria..
I take sublingual NMN twice or thrice per day and do feel a difference. Recently I went on vacation and a few days in I kept complaining to my wife that I kept feeling tired and I had no idea why. Like a week in it suddenly dawned on me that I had completely forgotten to take any NMN the entire time (it was tucked away in some suitcase). So I took some and I almost immediately felt a lot better and more awake.
BTW, I did not respond as strongly to NAD+ and in general the response seems to be very subjective to each individual. For some reason it’s manna from heaven and other do not feel anything. I’m 55 by the way, and at least for me personally it’s makes me feel 20 years younger. Just my 2 cents based on three years of personal experience.
I have had good results with NMN I started with tunnel vision in my right eye it got so it was llike looking through the tube in a toilet roll and a loss of hearing , since taking NMN my tunnel vision has gone and sight in my eye is back to normal and hearing almost back to normal , my own reading on this also indicated NAD has only 1/5 the bioavailability of NMN so I’ve not tried it to see if there’s any effect , I’m 76 years old and the only thing I suffer from is a small amount of BPPV due to calcium in the inner ear kept under control with the epley manouvour
John and Michael It’s good to know sublingual NMN is working. Restoring any one deficiency out of a 100 would still make you feel better as everything in biology is connected. But as you know it can’t be compared to a systemic rejuvenation therapy. But your feedback is valuable as readers here can benefit till any systemic rejuvenation therapy is available.
Of course you cannot compare NMN, NAD+, or NR with what you guys are working on, which boils down to bonafide cellular rejuvenation. That’s holy grail stuff while anything is more akin to bandaids to prevent the wheels to come off a failing machine. I merely wanted to share my experiences as it may buy some participants here valuable time until E5 is available. Which – let’s be clear – is still several years away in my estimation.
On the other hand the combination of e.g. NMN, good nutrition and diet, vitamins, exercise, restful sleep, and of course the blue gel may just arrest enough of the aging process and buy us sufficient time until all kinks with E5 have been ironed out and it’s widely available. At least that’s my plan and I’m only 55.
BTW, tell Harold to keep exercising – he owes me a space walk! 😉
I totally agree with you Michael and will pass on your message to Harold 🙂
@Michael
Is there a specific brand of NMN you are taking? If so, where do you get it from?
I have taken commercial NAD+ boosters such as TRU NIAGEN, TIME+ as well as Niacin for over a year but couldn’t experience any improvements.
My reasoning is my high level of physical activity and fasting practice, both are known to improve NAD+ productivity.
Yes intermittent fasting (at least 12 hours every day) and regular exercise probably do their part as well. Since I am in Spain finding a EU vendor for NMN was difficult. The one I settled one was donotage.org where I order pure sublingual powder. This vendor seems to maintain a good reputation on Reddit and I personally seem to respond well to it.
Given the fast improvement in grip strength of old rats treated with E5, sarcopenia might be a specific disease you could target. But I’m not sure that would qualify for fast rack status.
Hello everyone. I’m one the publishers, together with my wife Nina, of Harold Katcher’s book, “The Illusion of Knowledge”. Nina and I are starting a newsletter to inform people in general, with regular updates, about the progress of Harold’s and Akshay’s company, Yuvan. You can subscribe to the newsletter on https://www.ntzplural.com/newsletter .
It is a great honor for me to be mentioned by Akshay as one of the supporters of his efforts. For anyone who has followed this blog, it would be hard NOT to be a supporter. Thank you, Akshay !
Zisos there are supporters and there are supporters that become early investors. You and your family are in the latter group and will always be close to our heart.
How has “The Illusion of Knowledge presentation gone?
I see it’s scheduled for September 5, instead of 4?
Nanaka it was on Sep 4th and went quite well 🙂 Harold read from his book and then spoke extempore and everything that Harold says is interesting. There was Q&A followed by book signing. Someone bought 15 autographed books 🙂
Nanaka it was on Sep 4th and went quite well 🙂 Harold read from his book and then spoke extempore and everything that Harold says is interesting. There was Q&A followed by book signing. Someone bought 15 autographed books 🙂
Thank you and good luck! Akshay, do you know if something like an antibiotic will be required after infusing E5 to activate the genes like it needs to be done on Yamanaka factors reprogramming?
Nanaka there is no antibiotic required after E5 administration. Also it’s mode of action does not involve yamanaka factors.
But it does actually make a similar thing, reprogramming whole body to the younger state, right?
Yes but the mechanism is different
Congratulations everyone then, if it’s action is the same but without a “side effect”.
Yes that’s the beauty about E5 there has been zero immune response or any other side effects so far – we have tested 30+ biomarkers. The secret is that we are using what Nature has created.
Awesome!!!
Hi all, i just went to the website showing NEEL. Does it mean that we have to wait another 6 months before blue gel can be allocated to someone to approve it for distribution? Its status is confusing!
It will be launched on Amazon by November but you will have to wait until May-July-2022, for the distribution.
May i know the difference between a launch and a distribution?
Ah yes, I meant distributing to the European countries.
Any word on Josh’s recovery?
Does it need to be a resident of USA?
No. Phase III will be in multiple centers around the world
I would like to suggest that everybody leave Akshay alone to work on patents, trademarks, financing, etc., instead of answering questions about future unknowns. That way, we will have a better chance of having our dreams realized sooner.
Thank you Wayne 🤗
My Dad and I each bought a copy of Harold’s book on Amazon. They should arrive in about a week. We cannot wait to devour them. If the blue Gel is available on Amazon in November, we will be buying that, too, for sure. I would love to get my parents enrolled into E5 human trials eventually. They are 77 and 80, but as Dad says (they are): “Still Upright and able to take nourishment.” Haha. -Shay.
Loved everything you said Shay. You and your parents are awesome 🙂
Akshay, I suppose the E5 tests will be on a disease and the volunteers you need will have to have the disease. Although there is also a phase to detect possible side effects and that requirement will not be necessary there and surely you need people of different age ranges. I am from Spain and my 86-year-old mother has lost mobility, she can no longer leave the house and going from bed to the kitchen is already hard for her. I’m afraid it won’t come to the day when E5 is available. For my part, I am 55 years old and have some back problems, lumbar canal narrowing, which I think the E5 would cure, since it is somewhat degenerative; otherwise, excellent health, and I would love to participate in the tests to be able to be. Are you going to announce the selection of candidates in any way? How can I be aware of it?
Thank you very much, I admire what you are doing.
Thank you Felix. As you must know we have no dearth of volunteers.. We are giving first preference to our investors and then specific target diseases selected by doctors. But next phases are much bigger.
Ha! We seem to share a few things in common, Félix. I’m 55 myself and I also live in Spain. Although I do have some back issues I keep them in check via regular exercise. If you’re not already doing that I would strongly recommend you get started on that as it can slow down further degeneration until E5 will be available. ¡Saludos de Valencia!
Thanks, Akshay. I will try to be vigilant in case my mother’s illness or mine in phase 3 is one of the targets. I suppose that participation as an investor in your company will now be limited and not public offering.
¡Saludos desde Valencia, Michael! We also share the city :))
Hi Akshay!
I don’t post very often here but I’m following your works for a long time now as many with great interest. Beside the launch of the blue gel and the human trial next year (we cross fighers!) I was wondering how was going the rats lifespan trial. Maybe it’s too soon the ansewer yet, I don’t know. Are they still all alive? In both groups?
Beside that, my interest for the aging field and the reading of many very skilled people in this forum led me to try to learn more about human physiology by own. So I bought a book of general physiology, which is a good first step. Do you have any suggestion of other books to deepen this subject?
Hi Patricio, the rat lifespan trial is ongoing since Jsnuary having crossed 3rd dose of E5. Both group rats still alive at 31 months of age. Their avg lifespan us 36 months. Encouraging cytokine and grip strength results continue but this time we also could see some physiological differences. Our friends Nicolas and Nina who are publishers of Harold’s book will soon share a link where you can register your email for regular updates from Yuvan. In latest update they will share some photos and video and biomarker results from the lifespan study.
I personally enjoy reading research papers on biological discoveries. My favorites are papers by Richard Morimoto where he shows us the collapse of efficiency of ubiquitin proteasome support system just after puberty, Jean-Pierre Issa who wrote about epigenetic drift, Professor Hayashi from Tsukuba University who showed us that rate of damage is the same between young and old what changes is rate of repair and also that this damage is reversible, Richard Dixon who unraveled the permanent youth of Gingko Biloba trees for thousands of years, Vera Gorbunova for her brilliant discoveries of unique mechanisms which support long lived species, Mina Bissell who showed that a cancer cell turned into a normal cell in a young ECM, Greg Fahy for his human trials showing reversal of thymic involution,Tony Wyss Coray who has designed fabulous studies to show that changes occur in our proteins at certain life stages in a predictable manner, all of the many many papers of Steve Horvath who hopefully will win a Nobel prize soon for his pioneering work on biological clocks being able to predict age accurately from any DNA sample, Michael and Irina Conboy for reigniting the young blood experiments and of course Harold Katcher’s two seminal papers on aging and heterochronic plasma exchange. I read only two blogs that I find very incisive of Josh Mitteldorf and Vince Giuliano.
This is the link for Yuvan Research updates:
https://www.ntzplural.com/newsletter
Thank you for this update and your counsels.
I’m eager to know what it ‘s going to happend. Do you intend to administrate a fixed number of dosis and see how much longer they live after that or do you plan to regularly administate E5 ad vitam aeternam so to speak?
We plan to continue to dose every 90 days.
Hi Akshay. Do you have anything to respond to ineś regarding the ovarian function?
I’ve just received the first update of your trial by NTZ. Thank you for sharing intermediary results. They are very encouraging.
I compared the figures with your preliminary work and the last article with Horvath and I noted some points:
– Body weight: rats in both groups follow the same curve but in the pictures and the video, the treated rat seems clearly leaner. If the difference is representative It would be interesting to measure the ratio of fat tissue and muscule if possible.
– grip strenth: in your preliminary work, th grip strenth of the young rats was about 10-12 N. Here the treated rats are clearly beyond that (18 N). Don’t you fear that E5 have a doping effect?
– IL-6 and NTF-alpha: the drop of those two cytokines is not so dramatic in the current trial. Even after the third dose they don’t reach the young rats level (from the last trial). Did you change the dosage?
Patricio we made the same observations. We are trying to figure the best way to measure fat to muscle ratio in rats. Grip strength should be taken for comparison between treated and control in sane study as reading may vary depending on the particular grip strength meter used. Even we were expecting further drop in cytokine levels but our Medical Director said that the levels flattening out at healthy is ok. We haven’t kept young controls in this study and we can not compare with young control of another study as kits change so readings should be only taken from same study to compare. I will ask our Lab to see if they can measure young rats next time.
I would like to start congratulation Dr Katcher for the launch of his book, which I am enjoying right now. Not only the information, but the literary quality.
About E5 in females.
After having exchanged a few short mails with Akshay, concerning the rejuvenation of the tested female rats, my main question was about the rats fertility. Any young female mammal needs estradiol and progesterone, not only for reproduction, but for brain activity (no estradiol leads to Alzheimer,one thing where many of women agree is that menopause onset is the hallmark for intellectual difficulty), for bone turnover, to avoid sarcopenia, and to change fat accumulation patterns, without sexual hormones released by the ovaries, female mammals go through the same symptoms as women go through menopause.
Nevertheless the tested rats seem pretty lively in the video. But have no ovarian response.
According to Dr Izpisua Belmonte (Salk institute), the menopause’s onset is regulated by the epigenetic changes in two especific genes (at least in the ovarian aging of the monkeys he used to map that aging). So as Dr Katcher states in his book, that fertile window in the life of a mammal that starts after puberty is part of the “life program”, and the reproductive period is also driven by an epigenetic clock.
According to Akshay the rats don’t show ovarian function right now, after at least two doses of E5. And this is remarkable, as this means that the equivalent rejuvenation of a woman lets say, 65, would perhaps bring her back to her 50s, which when you are in your 60s is really great, but would mean a partial rejuvenation. And that for some reason the “demethylation” would affect some set of genes, but not all of them.
So it is not that I don’t feel optimistic, and It is not that I don’t consider Dr Katcher’s job outstanding, no one had done such a thing before, and his contribution is a major milestone in biology.
It is that the translation of the results into human females seem partial.
Something that intrigues me, is that in Dr Fahy’s trial, some functions like the kidney function that in principle should never improve to a youthful level, were clearly improved, and even improved after the treatment was halted. Both Dr Fahy and Dr Katcher change the signaling (just like dr Izpisua, he also rejuvenates mice by exposing them to pulsed yamanaka factors, or like Dr Vittorio Sebastiano, he rejuvenates cells of old mice in vitro with yamanaka oskm +2 extra factors and infuses them in back to the old mice, and that part of the tissue gets functional again).
I wonder if something similar to what KM Elias is doing with damaged ovaries, infusing IPSC must back up female age reversal
https://www.biorxiv.org/content/10.1101/697532v2.full
It will be difficult that someone believes he/she is young if he doesn’t feel virile/fertile. And this has nothing to do with having offspring. It has to do with the functioning of the body of a young mammal, A Young mammal is not is not in post reproductive period.
Hi inès, May I ask how do you know “lifespan study” rats ovaries have not been rejuvenated dramatically, yet? Even NMN is able to reverse the menopause…
I understand your kind of disapointment about the effect on ovarian function. But keep in mind that:
1) the trial is still ongoing, we dont know yet the effect of multiple repeated doses
2) the paper of the previous trial mentioned that, according to various epigenetic clocks, the rejuvenation varies with the organs. Liver was rejuvenated by 73% while the brain only by 11%. So the effect of E5 may not be an homogenious reset to a some younger age, but rather a shift to some new kind of state.
3) E5 may not be the ultimate holy grail. Maybe we can still improve it.
Hello Patricio, I don’t enter the forum that often.
I am not dissapointed! The facts are amazing! Who did such a thing before? and on the top of. it without side effects! Harold and Akshay managed to rescue rats from decrepitude! Just restoring some peptides/molecules that were present in plasma when they were young!
Of course it is important that trials are done in females as well, we have (slightly) different biologies, despite the main physiological processes are the same, very often I see the female biology is disregarded in research. And of course the abrupt and many times terrible cliff that menopause means in a woman’s life is sort of dismissed as “natural process” (many age conditions are as natural and we fight them).
In fact some of the phisiological changes that Akshay mentioned they were seeing, could be ovarian activity (ot other things).
I hope that he will post if they record such a thing, I know they are being extremely kind to share results and we are very lucky, who can almost chat and beg Akshay for the results of ongoing trials and third party validation.
But if those physiological changes are not ovarian activity, just as you say, it may be possible to add or to intervene in a way that brings back that ovarian activity, making perhaps an E5+ other factors with the key molecules for female.health.
I am not pessimistic because, first of all, Harold’s discovery seems to agree (and increase the effects) with Dr Fahy simple recipe of signaling change HGH+DHEA+Metformin +zinc ticking the epigenetic clock backwards. Just that Harold’s recipe seems faster and almost without latency period in rats.
Without Dr Fahy precedent, perhaps I would think, this is something that work on rats but not on bigger mammals. But I think there will be an effect in humans. Hopefully very important, as just other 3 mollecules were able to run back the clock without being “rejuvenating specific factors”.
The key is to know the dose and perhaps the latency period (the fact that rats don’t have that doesn’t mean there isn’t one for humans).
And I can’t wait to see the results in male dogs (and their female counterparts).
There seems to be a lot of ignorance around reproductive function amongst life extension enthusiasts. The logic seems to go something like this: it is believed genetic mutations are not life limiting to a human, therefore rejuvenating a human being will not need us to correct any mutations in the genome.
But mutations in the genome of the germline are absolutely ongoing throughout life – in males sperm accumulate mutations, and in females eggs only divide in the fetus and therefore just run out (regardless of NMN; I predict this benefit will be transitory).
So we may live to walk around as healthy, youthful, sexually active 300 years old. But we absolutely won’t be able to have babies. Not the normal way, anyway.
I choose to look at this with a forward looking perspective. IF we will indeed still be talking to each other 100 years from now, and assuming of course we survive a century of rapid cultural and political changes, then I am fairly convinced that we will have the means to address the question of human reproduction at old age. This especially in the face of the fact that male sperm counts have been falling precipitously every single year at the rate of ~1% (last stats I recall – please correct me if I’m mistaken).
I’m not a bio-engineer or scientist but I do know that many of the things we are doing right now would have been deemed to be impossible just half a century ago. In other words: let’s not worry about it too much for now and cross that bridge when we get there. As they say here in Spain: Poco a poco 😉
Yes, no doubt it’ll be possible. Providing civilisation doesn’t collapse first, etc. But it won’t automatically happen just because methylation changes have been reversed, telomeres have been elongated, etc…
Well, I don’t enter this blog that often, but now I see you make a bunch of statemens out of ignorance, I will up date your ideas from that Solomon’s Zuckerman dogma according to which there is not postnatal egg generation in mammals. LEt’s start remembering that back in 2008 Jonathat Tilly et al measured apoptosis in ovaries, found out that the rythm of apoptosis on egg cells in the ovary was so fast that if no generation of eggs was done there, women will reach menopause around 17 years of age. I’m sure you know it is not like that. Investigating forward they found OSC (oogonial stem cells) and cutured them till he got immature oocyte like cells. Despite he was mocked by many people in the scientific community, Evelyn Telfer, from Edimburg University closed many mocking mouths when she reproduced Tilly’s results. Now it turns out that there are other than OSC, there are VSELs are epiblast-derived pluripotent stem cells corresponding to primordial germ cells that persist in very small numbers in adult female gonads . Evidence shows that while Oocytes derive from the above mentiones OSC, those oogonial stem cells derive from VSELs, which are scarce, but present in the ovary during the WHOLE life of a woman. So potentially the oyaries could be rescued just like the thymus has been brilliantly by dr Fahy.
As you can see, the eggs of a 40 year old woman don’t accumulate 40 years of mutations. Simply their quality is less because of the misfunction of genes IDH1 and NDUFB10, genes that have to do with ROS and antioxidant qualities in cells. Solving that would mean the recovering of ovaries. How do I know that? Well, I am a fan of dr Izpisua Belmonte, from Salk institute, I read his amazing papers and follow his research regularly.
Here I enclose you one of the many papers that deal with the de novo oogenesis in the postnatal ovary in mammals (among which women)
I am afraid that your statemens concerning other people ignorance only shows that you are not fond of scientific journals.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940822/
I think Izpisua Belmonte is such a well known scientist that I don’t need to refer a link to you, you can find him easily in the web. His brilliant study on ovaries too.
Ines and Nanaka have you read about Matt Krisilof’s venture Conception? They make eggs for pregnancy out of blood. They raised $20 million.
Thank You Akshay for sharing this. I read MIT Technology Review’s article about it. Blood is truly a miraculous staff. I wonder why E5 has not shown reproductive rejuvenation. You are ahead of the time, definitely. I know despite the fact that the mechanism and the manner are different between E5 and Yamanaka factors, they both do the same thing, reprogramming body to the younger signature, where E5 needs to be only in vein and the blood river takes it literally everywhere, while a partial reprogramming is far more complicated thing, local injections, side effects etc, and it’s not even possible for Harvard to fully reprogram the body. “Blood alone moves the wheels of history”, that’s the quote for Akshay and Harold 😉
Thank you Leo. I like your quote 🙂
Wow, what a news, And they say it will be available in about 15 years. It will make gay couples lives easier and not only. Akshay, I have replied this to Ines, how have you found out female eggs are not rejuvenated? By Horvath’s clock?? And what does it mean???
One of the main questions is regarding to hematopoietic stem cells and thymus. They are resistant to the rejuvenative effects of plasma-based therapeutics. Akshay is there any hope E5 can affect them?
We have to find out. But we have the brilliant living scientist amongst us: Greg Fahy who has already achieved one of the miracles: reversed thymic involution. So just in case plasma based therapies are not significantly rejuvenating the thymus combining it with Greg’s therapy will do it.
Thanks, got it. Harold mentions cytokines in one interview. It is associated with thymus activity and cytokine storm is mainly characterized by the IL-1, IL-6, and TNF-α, among which the serum TNF-αlevel is negatively correlated with T cell function by downregulating the expression of CD28. Since E5 showed all these factors regulation to the youthful level, can we presume it may rejuvenated the thymus gland too?
Harold thinks so but we can’t be sure unless we check.
Hi Akshay, sorry, I saw this just a couple of days ago! I’ve been looking in the internet, and it seems they are trying to reproduce the work of Katsuhiko Hayashi, who built mini mice ovaries in the dish and produced and matured egg cells there.
It is super interesting, specially for women without ovaries or eggs, cancer patients and for same sex couples.
But the point is that despite being very promising, it can take decades and that an eventual ovarian recovery would not only provide an egg supply, but crucial hormones for women, which is what really interests me and I think ovay it has been simply dismissed during medecine history, considering it no more than a bag of eggs that can be exhausted during many decades, Thak God this is changing. And it is a part ofwhy I am so interested in the evolution of your trials. Of course E5 is a major breakthrough, I still wonder if the rats will at some point show some ovarian activity.
In any case thank you Akshay, any of your tips is always interesting.
“IL-6, a marker of inflammation, was restored to low youthful levels…”
For an upcoming blood test, I’m going to ask to get IL-6 and TNF-alpha readings.
However, I’m confused about the importance of IL-6 reduction in the context of the E5 trial. According to Wikipedia:
“IL-6 has extensive anti-inflammatory functions in its role as a myokine…Following exercise, the basal plasma IL-6 concentration may increase up to 100-fold… The exercise-induced increase of plasma IL-6 occurs in an exponential manner and the peak IL-6 level is reached at the end of the exercise or shortly thereafter. It is the combination of mode, intensity, and duration of the exercise that determines the magnitude of the exercise-induced increase of plasma IL-6…”
Thanks for any clarification.
Hi Stephan, IL-6 is an inflammatory marker. Inflammation is needed and used for immune function and repair. When we are young Inflammation is triggered but then it is also resolved after its task is completed. As we age it gets triggered but does not fully resolve. So there is what is called a state of chronic inflammation. This is shown in thousands of studies as the precursor of almost all the diseases onset by aging.
E5 does not eliminate inflammation. It brings back the youthful ability to resolve it to normal healthy levels once it’s task is complete.
Thank you, Akshay!
As you know, I can still enjoy hiking steep mountains and do extended canoeing trips in my late 60ties. I have my regime of lifestyle interventions and I’m getting more and more convinced that one of them rules them all. Of course, I’m not getting younger, but I would be interested in knowing my biological age.
Do you have any suggestions?
>So if we succeed in getting pricing to $5k
>Harold would have fulfilled his goal at
>5% cost of typical new drugs.
Akshay,
The dermal patch sounds interesting.
Is possible that the some of the ingredients in E5 may
not be critical in the rejuvination process?
Also, the original test involved urbal supplements any chance that
you might also sell these as a lower cost option?
Just wondering what your thoughts are on the above?
>So if we succeed in getting pricing to $5k
>Harold would have fulfilled his goal at
>5% cost of typical new drugs.
Akshay,
The dermal patch sounds interesting.
Is possible that the some of the ingredients in E5 may
not be critical in the rejuvination process? Another
way to reduce the cost.
Also, the original test involved urbal supplements any chance that
you might also sell these as a lower cost option?
Just wondering what your thoughts are on the above?
Gerald we will work hard to ensure lower cost. Natural extracts did show great results but not as powerful as E5. So current focus remains on E5. We haven’t done any further research on the natural extract mix. May be in the future we may relook to see if there is any complimentary role or as you said lower cost lower power alternative.
Hi Akshay.
As Steve Horvath has informed us, Interventions that affect epigenetic aging, do also affect proliferative capacity/lifespan but not vice versa. Does is suggest a very small percentage (11%) epigenetic reversal in hypothalamus may not be as important in terms of LIFESPAN?
Leo brain is a very different organ. It may not need major rejuvenation if no neurodegenerative disease has begun. For example Harold is 77 but his brain is functioning very well versus other organs and tissues. He has the sharp memory of a 20 year old. But we have lots to analyze and understand as we get additional data.
Thank you Akshay, I appreciate your explanatory answers as always.
Akshay: About one month ago Modern Health Span did a YouTube interview with Dr. Greg Fahy about a dog trial (one older dog) of E5. Even though it is a very limited trial, validation on a second type of mammal is very exciting. I suspect it would greatly heighten interest in and of itself.
Is the test underway? What are your plans to release results to the general community?
Ed you know that we do not shy from sharing results.. yes Dr. Greg Fahy has been a great help and inspiration for the dog study. It has not yet started. The dog facility where it was planned is shutting down for renovation so the dogs are going to be shifted to some volunteer who is helping to host them. There seems to be two options already so the shift is imminent. Greg has also introduced us to Dr.Richter who he considers America’s number one Veterinarian doctor. So we have him and his team ready to help out. Fingers crossed soon things will fall in place.
Akshay shared with me yesterday that he and Harold are desining a manufacturing facility that can create E5 in sufficient quantity for larger animals and humans.
That’s great news Josh. I have this 6 foot tall pet rat who would make for an ideal lab animal. It’s potty trained and even cleans its own cage! 😉
Rattus Humanicus I presume? I have the same pet! What a coincidence!
What are the odds? They may be related!! 😉
In the interim I’m keeping my fingers crossed for a blue Christmas.
It was real pleasure to chat with Josh yesterday. His spirits are high and he is back! What a fighter! Josh all your multitude of followers will be delighted to read your brilliant posts again 🙂
Hi Akshay, it’s great to hear you’re designing a new production facility for E5. Could you share some further details on that? Thanks.
Hi Josh:
I am happy to see you posting. Looking forward to your next article.
Hello, Josh! Welcome back! My parents and I hope for your speedy and complete recovery!
Just a short “heads-up”:
Vince Giuliano and Steve Buss will be hosting a webinar Saturday, November 20, 2021 11:00 AM to 12:30 PM EST and discuss how we can reverse human aging (YOUGING)
https://www.anti-agingfirewalls.com/2021/10/20/online-meetup-younging-triggering-ancient-mechanisms-for-rejuvenation/
Recording now available on Youtube. Enjoy 🙂
I have found the presentation extremely interesting.
I am even more excited that they think highly of E5 for age reversal.
Wow! What is happening? My comments keep saying “waiting for approval”, then just disappear!
Josh – can you please email me and tell me if there is a problem please?
Thanks
Toby 🙂
Akshay,
Christmas shopping season is here! Are we going to be able to place orders for Blue Gel as Christmas presents this year?
Rick it would be a great Christmas gift as you are gifting younger skin! In November before Christmas.
To say that I’m excited would be a FAST understatement. Keeping my fingers and toes crossed!
Hi Akshay
Do you have any thoughts about the recent death of the treated rats (Dr. Goya’s study)?
Does this confirm that E5 extends healthspan (rats very young and healthy until a sudden death), but doesn’t extend lifespan (number of months extended was only around +5% compared to untreated rats)?
What are Dr. Katcher’s next steps to explore extending lifespan, or is he only focussed on healthspan at the moment (ie testing E5 in dogs, apes, humans then getting FDA approval for sale to humans)?
Would love to get your feedback!
Thanks Akshay
Cheers
Toby 🙂
The fact that E5 consists of plasma fractions does not mean it does the same thing as a weak young
blood plasma procedure, as Akshay told me, we have to wait to see what the lifespan study outcome will be. Hopefully it’s as strong as we all think. If we compare Goya’s treated and E5 injected rats, there is a much difference. I mean even the treated one in Goya’s experiments looks old, only difference I visually see is a fur color. But when I do compare E5 female rats, they look awesome, alive, their eyes are bright, beautiful shapes and generally a young appearance. Hopefully this will reflect on the lifespan itself.
Hi Leo
Isn’t the lifespan study by Dr Goya finished (because all the control and treated rats have died)?
Or do you mean we have to wait for biopsies etc to be done on the dead rats?
Thanks
Toby
I mean E5 rats. They still have 5 more months to reach their maximum lifespan. From that, we can start counting the record.
Good, as long as the treated rats don’t die it’s all good
Hi Akshay
Do you have any thoughts about the recent death of the treated rats (Dr. Goya’s study)?
Does this confirm that E5 extends healthspan (rats very young and healthy until a sudden death), but doesn’t extend lifespan (number of months extended was only around +5% compared to untreated rats)?
What are Dr. Katcher’s next steps to explore extending lifespan, or is he only focussed on healthspan at the moment (ie testing E5 in dogs, apes, humans then getting FDA approval for sale to humans)?
Would love to get your feedback!
Thanks Akshay
Cheers
Toby 🙂
Toby so there is a misunderstanding with regards to Professor Goya’s study and E5. Professor Goya’s study used only young plasma and not E5. So we should not compare our studies. E5 may give similar result or hopefully a better result as it is more powerful than just young plasma. There been other young plasma experiments but none of them have shown such comprehensive resetting of epigenome to a younger profile as E5. Both have one common thing though: A dose has a life and it’s benefits does wear off. In the case of E5 the benefits seem to last longer. Only thing missing was a lifespan study of E5 which is underway now. So we will find out soon.
Hi Everyone who is following E5 Lifespan study: I have an update: One control rat (not treated) died. Rest controls and all treated still alive.
Thank You Akshay. The most interesting process has already started. Good Luck, god bless us everyone.
My condolences to Mrs. Mouse – but it died for a good cause 😉
Rat died of natural causes which we all face sooner or later unless some intervention allows us to extend lifespan, if we so choose, in good health.
Thank you very much for the update Akshay, and thank you for clearing up the confusion between Dr Goya’s tests and your own ongoing rat trials! I will continue to watch for your future results with much hope and anticipation 🙂
Cheers
Toby
test test test
I have a long Christmas list. I’d love to be gifting the Blue Gel this year! (Fingers crossed.)
Hi everyone! After a wait of many months I am happy to announce the launch of pre-orders for blue gel now known as NEEL- blue in Sanskrit- on the happy occasion of Thanksgiving. The web page where you can pre-order is NEEL.bio
This is a launch for our supporters and aging research community members before we launch Nationwide in USA on Amazon in 1st quarter 2022. In the newsletter kindly circulated by Nicolas and Nina, Harold has given an interview about the powerful tripeptide ghk-cu which is the key ingredient of NEEL. As I had mentioned earlier it resets more than 1/3rd of our genes to a younger profile as discovered via gene mapping at the Broad Institute (Harvard and MIT). We have filed a patent for its transdermal delivery world wide. On the web page if you click on the ‘About’ link it will take you to a compilation of some of the interesting research papers on ghk-cu. We will get its full benefit systemically when the NEEL patch will be available in 2022. Till then I guess none if us will complain having much younger looking skin. If applied all over one may get some systemic benefits as shown in a paper in the newsletter. We will be launching deliveries soon and those who have pre-ordered will get priority. Wish you and your family joy and beauty!
I forgot to mention currently it’s available for pre-order in USA. We are working on the paperwork that would allow us to export to other countries. We hope to soon make it available for international orders as well. For the community launch we have kept only 1 size 100ml – we haven’t launched 30ml- as we thought that all of us would want to take full advantage of it rather than use it as a cosmetic.
That’s the good news I have been waiting for after all the damage COVID-19 restrictions have done to my likelihood.
I’m living in Canada and have used MyUS.com service to buy US products that don’t chip to Canada. Will this work with NEEL?
Stephan thats clever. As long as it’s showing a US shipping address it should go through.
I think the problem might be your local customs – maybe they won’t allow the gel into your country…?
YES that’s actually the biggest hurdle, especially for us here in Spain. Since January of this year they have really clamped down on anything coming from outside Europe, except for some reason packages coming from China. Britain is the easiest to import into and I use a reshipper that – at least thus far – has been able to transfer it down here into Spain without anything being rejected.
Great. To minimize my financial risk I will just order one bottle and share here how it goes.
Just be thoughtful with what you put as description for the reshipping 🙂
And thanks for the work Akshay
Thank you Raphael. Our human clinical trial is in Canada so for that country we already have regulatory filing done so there should not be any problem in customs.
I would suggest ‘beauty cream’ and there should not be any problems.
I am in Spain and regularly use a reshipping company in Houston that then forwards my packages to Europe (for a juicy fee). Since Spain has horrendous import restrictions and charges high import taxes I usually ship from Houston to Britain where I have another reshipper that in turn transfers in bulk to Spain. Costs me an arm and a leg each time but obviously for certain products we don’t want to do without it’s a heaven’s sent.
That sounds hilarious Michael. I sincerely hope NEEL will soon be available within the EU.
I would be interested in setting up distribution over here. But I’m sure Akshay will be able to find a more established distributor within the EU.
I live in Australia, your website won’t accept my address. Are the preordained only for North America ?
Mike
Michael we are working on paperwork required for Intl sales.
I live in Australia, your website won’t accept my address. Are the preorders only for North America ?
Mike
Thanks Ashkay. I have placed an order and I am enjoying reading the articles listed on the NEEL website.
Yes thanks Jim. And there are more. We were stunned when we came across how powerful this tripeptide is. But it has many challenges regarding stability and half life. We worked for 3 years to crack that. It’s come out so beautiful.
Many thanks Akshay! The European ones will have to wait till 2022, but I wish the greatest of successes!
Thank you Ines.
One extra question, when do you intend to launch the transdermal patch? that would be great for my parents in law (among many other people).
Ines last quarter of 2022.
Congratulations Akshay! Very exciting! I purchased two for now. Can’t wait to try it.
@Toby
We have to find out. Also, the terrible floods and landslides in BC will delay shipping. In addition, about 25% of Canadian postal workers might be placed on LWOP on Monday.
Congratulations, Akshay! Good job! Dad ordered four, 100 ml sizes, one for mom, one for himself, and one for my brother and me. We will start with those. When the 30 ml sizes hit Amazon, we will be giving some of those as gifts.
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My parents, currently 80 and 77, want to volunteer for E-5 trials, when those are available. How can they accomplish that? Thank you.
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Also: This is all VERY exciting! Thank you for all of your hard work!
Maybe I have missed that, is there a promotional code?
Hi, Stephan.
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There was no Promotional Code that I could find when we pre-ordered our four jars of 100 ml each. However, it has been mentioned here before that the 30 ml jars would be about $30, so pre-ordering the 100 ml obviously does save money, as compared to ordering the 30 ml jars (when they are available). We do need to keep in mind that this current offering is not a fast shipping situation; it is a PRE-order,
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I hope this helps to answer your question.
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Best Regards,
-Shay.
Just to give everyone an idea. When LifeLine Skin Care announced its line of non-embryonic skin care cream a little over a decade ago it started to retail for $297 – for a 35ml flask. They have since increased it to 50ml and it still retails for well over $100. That’s a decade later.
For Yuvan to offer a far superior product at $90 for a 100ml flask is extremely far IMO. And that’s at comparably small volumes plus Yuvan still operates at a loss and it will take many years to recoup the investment.
I meant ‘fair’ of course and not ‘far’. Sorry 😉
Thank you so much Shay and Michael. Wish you were working for Yuvan 🙂
Not to mention LifeLine skin, let’s take even a very well known Germaine De Cappuccini. Their Lifexpert 60+ cream’s price is 100€ for 50ml. People go crazy here for it and even they are claiming it’s a complex process of enzymatic engineering, capable of dynamising the key mechanisms of youthfulness. They say It works like a switch that turns on the genes turned off by certain epigenetic factors and generation of youthfulness proteins is normalised. It’s just a super strong marketing team, otherwise, it did nothing special for my 60- friends. Let’s take Caudalìe’s “Resveratrol lift” which has been patented jointly with David Sinclair, costs 100€ for just 60ml. Again experienced by plenty of people around me, total waste of money and full of toxic additional ingredients like parabens, triclosan, phthalates, sodium laureth sulfates and etc. NEEL is truly a god send, 1$ for 1ml! 3$ a day and not only your skin is getting younger and as falsely advertised from previous creams brands, your wrinkles are gone and facial contour is smoothed, but you are actually resetting 1/3 if your genes! It’s a miraculous stuff to me.
Thanks Leo 🙏
Hi Akshay,
GHK-cu regulates thousands of genes.
Where can I find a master list of all the genes?
Thanks in advance for the info.
Dr Katcher’s book is a pure GIFT ! Packed with great biology insight. Sometime writing style is difficult to follow, I disliked history digressions (necessitating much more thought), useless inclusions of religious considerations and sometime I felt a bit too much of arrogance to my taste … but who cares, if E5 works for us it is a HUGE step forward! Moreover, for sure, it might be well shifting the thinking about aging “theories”. Thank you Dr Katcher and Team…
Could you or Dr. Katcher elaborate on application to the soft palate? Skin treatment in the Yuvan interview mentioned twice a day for two weeks, but soft palate application was transcribed as twice a week.
Hi it is not something we officially recommend. It is a topical gel and for topical application. Harold has done as a personal experiment which proved useful to him and it would probably be twice a week – not day.
Does the product come with instructions, Akshay? Thus far I was under the impression the blue gel would have to be applied once per day minimum. Also for us early adopters you should include detailed instructions for the blood test. As I recall you wanted us to get that done before the first application. In fact it would make sense to post them here at the time shipping begins so anyone interested in tracking systemic changes can get things rolling as appointments may be difficult to get by given COVID and that it’s winter.
While we’re waiting for E5, it seems that GHK has many of its benefits:
https://www.hindawi.com/journals/bmri/2014/151479/
And it’s available in sublingual form
Is it available at this point? Or is it still only in the experimental phase?
Our transdermal patch when its comes out should provide the best possible systemic benefits covered in that paper of GHK. Till then if a manufacturer is offering product of very high purity in sublingual form you should take it. Personally I think very little if at all may get into bloodstream or cells as the tripeptide like most peptides is unstable. That’s why we are developing transdermal sustained release patch.
Michael the bottle comes with suggested use. It’s twice a day for first few weeks – after shower and before sleeping and then once a day ideally just before sleeping. If one is prepared to apply all over then getting your IL-6 tested before and after 2 months might show if it has brought down over all chronic inflammation levels in us.
Thanks Akshay – I remember IL-6 but you mentioned a second marker a few months back…
TNf-a
For those who, like me, can’t get an IL-6 or TNF-alpha test at their local clinic, a cheap CBC With Differential test can give you a neutrophil to lymphocyte ratio. Be careful about hsCRP – a mild cold will skew it.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892833/#!po=26.5957
Credit to Vince Guiliano for tipping me to the ratio.
@Wayne, when would be the optimal time to draw blood samples? There are many things that can skew it, like e.g. moderate exercise (up to 6 hrs post-exercise)
Doctors of oldsters like me like an annual lipids test with a 12-hour fast. In my case, they also want a fasting glucose. So, I always get blood drawn in the morning before breaking fast. It seems to me that what is important for everybody doing n=1 tests is that blood is drawn under the same conditions for comparison purposes.
It is the CHANGE in inflammatory indicators that you want to measure. The absolute value depends on a lot of genetic and lifestyle factors.
Thanks Wayne, I agree. It must under the same conditions each time, otherwise results will be useless. Btw. have you tried Vince’s 4-herb synergy to combat inflammaging?
Yes, I gave it a 3-month trial in early 2020. The results were slightly positive but a bit too costly for an 80-year-old man raising two kids. I found some liposomal products that are nrf2 activators for less money which I am now testing. In other words, I strongly agree with Vince on almost everything he opines, but his product is just a bit pricey for me. Also, various aging clocks already have me at 46 to 72 years of age, including two cheap DNA methylation clocks at 59. I can’t expect large improvements from that.
@Wayne what would be the meaning of a high neutrophil-to-lymphocyte ratio (>3) when the CRP is ultra-low (CRP ~= 0.1)?
Beats me! But I do know that low CRP should be measured with the hsCRP test (high sensitivity) and that might start to explain it.
@Wayne, here is a nice summary of neutrophil-to-lymphocyte ratio by one of the doctors who originally documented it:
http://www.elis.sk/index.php?page=shop.product_details&flypage=flypage.tpl&product_id=7271&category_id=171&option=com_virtuemart
If Vince has an article that discusses this ratio in more detail, I would love to get the URL to that article.
I understand it has been developed for a skin application, but I read it has been tested individualy in other ways, such as on the soft palate or for hemoroides. Do you have other examples to share?
Does it have an effet on the color of the hear for example?
Did someone test it on the eyes? (in order to reverse presbyopia)
Patricio I can’t comment on that as we have a regulatory clearance as a topical gel. I know someone who is buying 10 bottles for relative that is suffering from full body psoriasis – he is doing it at his own risk and doctors consultation. He will update me on the outcome. Unfortunately conventional prescription meds have not succeeded so far so it’s mercy case. We do intend to continue with our human clinical trials for different skin conditions. If the data us positive we will apply to FDA to allow us to mention the condition.
Hi! Could you tell us if 4th dose of E5 has already been administered to your rats? Any updates on their look?
Hi Azza 4th dose was administered. Latest update is that one more control rat died of natural causes on 1st December. So now we have 8 treated and 6 control rats remaining in the study. You could subscribe to this newsletter to get latest video and images. You could request Nicolas and Nina and they will email you: https://www.ntzplural.com/newsletter
I came across this mouse study
“Identifying and Validating Novel Biomarkers and Potential Therapeutic Agents for Abdominal Aortic Aneurysm ”
it said
“GHK might be potential therapeutic agents for AAA by reversing the altered DEGs”
Hi guys, curios to know if you listened to Sinclair’s latest interview about making a gene therapy into a pill and what are your thoughts?
“We’re working in my lab to take what is currently a gene therapy and turn it into a pill that might cost a few cents a day…give that to someone for a month and they go back 5 years, give it to them another couple of months and they go back 10 years…we know, at least in mice, that does reset the body…so hopefully that cycle can be repeated every 10 years many many times…yesterday we got data that any concerns about safety were not valid…we’re pushing forward to treat humans in the next couple of years (animals first).
Sounds exciting!
Thanks, I subscribed. I agree, pill form sounds pretty exciting but a bit utopian, is not it? Anyway, could it be compared to E5’a strength?
Azza, I think there are plenty of limitations to cellular reprogramming with OSK genes. Cellular damage is also upstream of signaling. That’s why even if his cellular rejuvenation therapy works it may still leave lots of problems left to fix. Problems that are not influenced by cellular reprogramming. Generally, Sinclair thinks aging is driven by dormant genes which are switched on in embryo and they are switched off when we are adult. He thinks epigenetic information loss is the main cause of aging, “reader of the CD”. Harold says aging is programmed, it’s not a disease but a progression of life stages and I do agree. Harold found and gathered all the factors which are presented only in blood plasma and which are driving and hacking the aging process itself. I do not know how we can compare their “strength”, but I totally belong to the Yuvan perspective and standpoint of aging process.
Thanks, I got your points but I want to understand one thing. In one interview, Professor Katcher says “aging is programmed and the nice thing is that it’s carried in the blood by certain factors so body can be reprogrammed”. So my question: is aging’s secret in the blood(plasma) so reprogramming with yamanaka factors are just “have to” for the cells or secret is in the yamanaka genes itself?
Azza aging’s secret is in the transcription that occurs in the non coding regions of our DNA and involved in regulation. It regulates all gene expression. Epigenetic marks are also regulated by this program (lifestyle factors too can influence but in a limited range). To even out this regulatory cascade blood is used as a carrier to carry these regulatory changes. Since blood or plasma needs to reach every cell in our body to keep it alive it becomes the best medium if one wishes to hack this regulatory cascade. Yamanaka factors influence the genes itself that’s why David Sinclair calls it gene therapy. Whereas our technology works through the plasma signaling factors. I personally feel the latter is much much more safer even in the long term – hope it’s taken as a bias- just based on biology.
Thank you Akshay, I enjoyed reading your answer.
Thank you Leo you are always kind and have a great sense if our biology. I missed adding that besides gene expression and epigenome the regulatory transcription also influences protein product and post production thereby having a vice like grip on our entire bodies biological destiny. Besides lifestyle factors microbiome too had an influence merely due to their sheer numbers – their genetic material outnumbers ours- but their influence too is range bound. Each and every cell collectively self regulate through its encoded programs in its DNA. And they talk to each other to ensure they are in sync. It’s fascinating once one gets the full picture. Also mind boggling because of its brilliant, complex engineering and fidelity.
I understand your answer, I appreciate it, I just can not understand, aging occurs because in the plasma these specific factors decrease with age and disappear, or because the Yamanaka factors are switching off? I mean the secret is in transcriptions but does it happen because of the special factors are disappearing?
Azza genes or DNA doesn’t change. What changes is its expression. Besides gene expression regulatory factors also influence protein production directly for example a miRNA can bind and degrade a freshly produced protein. These changes increase some factors in plasma decrease others and new ones too can emerge with age. Right from the time egg is fertilized change is constant. Regulation makes these intracellular and extracellular changes. . Yamanaka factors are also transcription factors which induce production of pluripotent stem cells which can become and replace any damaged cell. So when aging Regulatory changes up regulate unrepaired damage ipsc can repair it back. So yamanaka factors are competing in a way with the regulatory transcription that causes aging. Yamanaka transcription factors are dominant in embryonic stage. Which is why they are used only partially otherwise the cell can lose its identity. Different mechanisms arrive at the same goal: go back closer to homeostatic peak of post puberty where most damage was efficiently repaired. As Dr. Rosedale said if we could repair damage as fast as it occurs we could live forever. Hope this explains?
thank you very much, I have to apologize because I took your serious time, now I understand it better. As I got, transcription changes can change plasma constitution, so by administering E5, so setting plasma factors on younger person’s plasma ratio, you are resetting the transcription. That means we are changing just one thing which is a product of transcription change while yamanaka factors are direct way competing with the regulatory transcription. Gosh, I am messed up, sorry. I will say how I was thinking: I thought decreasing the plasma factors was the main reason why transcription was changing therefore adding E5 would be a natural way and Yamanaka factors would be a “have to” for the cells, artificial variant with the side effects. Also I thought plasma fractions had a greater results by changing everything associated with aging, not only a cell reprogramming like yamanaka, because David thinks osk reprogramming may not be enough to fully reverse the aging process and we could need senolytics and other therapies combinations. Again sorry, I am just trying to fix the expectations I am waiting from E5.
Azza you have understood it correctly. Yamanaka factors dominate at embryonic or growth stage therefore needs to be extremely precise regarding only partially being exposed. As well as they are growth stage one doesn’t want any unwanted growth causing cancer. So the engineering needs to be very precise. And the stability must remain for a long time to be considered safe. Whereas young plasma fractions are competing with the output of the regulatory transcription caused by aging which in a battleground which travels to every cell: the plasma. As the young plasma fractions are something that already exist but change in ratio with age – reversing their ratio is safer way to achieve reversal of age to youth.
That’s totally understandable, again thanks for spending your precious time on answering my questions.
It could. I currently see only two approaches that have a chance to tackle as complex a problem as aging:: young factors hacking the signaling system in the old via the bloodstream which reaches almost every cell AND cellular reprogramming like partial yamanaka factors or as Sinclair called it gene therapy which has the potential to reach a lot of cells. Only those interventions which create systemic reset can succeed against the transcriptional onslaught of aging. Inducing genetic changes via oral pill is something radical and he claims it’s safety in rats 8s proven. So that makes it quite exciting. Genetic changes in earlier studies led to genomic instability and cancers but if that has been solved its a HUGE breakthrough. But given 8ts past one would want to see long term studies to ensure it does not happen later. One wouldn’t want to become young only to die of cancer. So that’s a slight advantage that young blood factors has over gene therapy currently.
Thanks, that’s a good summary. In strength, I meant it’s “half life”. For example, as David said, we would need to do reprogramming again after maybe decades but as you said, we would need E5 once every few months. So I am trying to figure out if aging happens as switching off these osk genes, as Leo said or it’s secret is in the blood.
Azza, even David says that a partial reprogramming may not be a single and universal solution to solve the aging process itself, there are plenty of limitations he mentions. OSK reverses DNAme clock and resets methylation patterns so reprogramming can reverse the DNAme clock and restore the youthful functions in complex tissues but is epigenetic clock a measure of age or just a participant “actor” in aging? Also, he says transgeric progeroid mice overexpressing Yamanaka factors live longer but how longer? If his lab is able to make a mouse older artificially, why we still do not have a lifespan study? He can easily make a mouse old and let it die, this will show if his theory of aging and epigenetic noise is a real cause of aging or just one of the cofactor hallmarks. He did mention we may need senolytics and other kind of therapies in conjunction with reprogramming while E5 has shown a significant decrease of senescent cells in multiple tissues, including as hard and complex organ as brain. E5 rejuvenation was reflected on more than 30 biomarkers, why do not we see the same from the partial reprogramming experiments? Only question to me is if E5 can switch on and reactivate a dormant OSK genes in complex tissues. Another question is the “half life” thing. As Sinclair said, reprogramming lasts for about 5 months and it could be decades in humans, we do not know if E5 will be calculated translated the same way, despite the fact Harold is almost sure it will. For me, comparing those 2 things is like an analog of tooth reconstruction. Reprogramming is like a typical dental procedure, involving root canal therapy, crown reconstruction to have an artificially better, restored tooth while E5 is a new stem cell technology therapy which allows you to regrow your new set of teeth for the 3rd time)
To be honest, I do not know why Akshay is so exited, not to mention it’s utopian conception of making it as a pill to go back to your 20ies after a month or 2 course.
I don’t think there is any argument that what Harold and Akshay have done is remarkable and that this treatment has returned old rats to health. My only worry is that this is just forcing the body to use up its conservatively held reserve. It is possible that turning down inflammation and turning up mitotic factors (for example) could burn through reserves at a greater rate. Even Harold admits that whether or not the rats actually have significantly extended life depends on whether his idea of what aging is turns out to be correct. So even he doesn’t know for sure. We are all looking forward to the results of the current lifespan study and hope that Harold is right.
Forcing is exactly what I am saying about the Yamanaka factors, literally, you make cells to turn back to the youthful expression and the latest presentation from the Calico labs, where they are trying to reprogram cells without the Y factors is one more proof. I think E5 is the only nature intended solution, where you administer the special factors found only in young plasma and youthful gene expression is one of the “side effects” you get along with the grip strength, antioxidants status, redox etc and etc.
Hi Mark or Ashkay:
Has anyone heard from Josh, lately?
I have not been following all the comments, regularly. Maybe he has commented and missed it.
Hi Heather
He continues to publish on other topics here: https://mitteldorf.substack.com/
Very interesting to follow as always
Cheers
Hi Heather
He continues to publish on other topics here: https://mitteldorf.substack.com/
Very interesting to follow as always
Cheers
Hi Raphael:
Thank you so much for the information. It is much appreciated.
I am glad to hear that Josh is well enough to continue to write.
I will check out the link.
Hi, does anyone know if Dr. Katcher will do a presentation on E5 once the patents are filed? I mean, a Ted Talk or some interview with Lex Fridman would be great but something bigger might be more appropriate considering the importance of his discovery. By the way, has he found his lab technician? It must be frustrating to have the money to conduct the research but being slowed down by a lack of employees.
A research collaboration is in the works with a very highly regarded University which will provide the needed technicians and more. We will announce soon.
Wow, this is cool, your posts really hype me up about the future of aging research. Thanks for answering our questions.
Akshay, I would like to echo other commenters’ thanks and regards to you and your associates. Could I ask if there is a summary of timelines for the various projects you are working on (e5, neel release, patch release)
Thanks again.
Thanks Unutilisateur and Dean. E5 will depend on the FDA and whether we get fastrack designation for our IND application. We could be applying directly for Phase II by end of next year if our IRB Phase I succeeds. NEEL gel we should start deliveries soon. The product has come out beautiful – feels great on skin-you are going to love it. NEEL patch same time next year. We might have NEEL inhaler for COPD and other lung related problems. The product is in very early stage of development. If we succeed then it would also be a boon for all who smoke. COPD is the 2nd biggest cause of death in the world after heart disease. Till E5 is available NEELpatch could be one of the best anti aging interventions available. One could feel the benefits from the first week of use. .
Wow so much progress. You are doing God’s work and I feel truly blessed to have had the opportunity to have gotten involved in this project at such an early stage. My warmest regards to Josh for providing this forum and of course to you Akshay as well as Harold for all you do. Keep up the good work!
Thank you so much Michael! Such kind words of encouragement keep us going. Harold at 77 is working so hard that I have to step in and request him to breaks. Michael with you it’s not just words you too stuck your reputation out for us and boy will you be proud. Josh, Zisos and Jeffrey Lewis who was the first believer. We will always have you in our hearts.
Sometimes, I read without understanding what I read; I just returned to these comments and realized that if you expect the phase 1 trial for E5 to be completed by the end of next year, that must mean that Dr. Katcher had a breakthrough with E5 production constraints, or that the university partnership will allow him to bypass the problem entirely.
It is crazy to think that humanity existed for hundreds of thousands of years and essentially nothing happened until now, and we are the lucky few who were born a few years away from the end of aging as we know it, and then a few years away from regrowing any body parts (Michael Levin), and that on top of that we will also have self driving cars and AI taking over millions of jobs, cheap and effective BCIs (Kernel, Openwater) and much more…
Well we can’t stop our evolution. Past technology breakthroughs have done us a lot of good mostly. It allows us thos much more safer, healthier, more convenient, more productive and longer life. So I continue to remain optimistic about humans in the known Universe. We are an brilliant species. Our ability to manipulate matter seems to have the greatest potential amongst all known technologies for our future. It can allow us to build planets, build Suns, create new sources of energy. If we do get the ability to live a thousand years we may get to see some of these which seem unbelievable to us today.
I suspect using senomorphics at the same time as senolytics may be counterproductive. Does anyone have an answer?
Akshay,
Just got latest news letter, E5 animals look great.
Thanks for the update.
Thanks Gerald. Fingers crossed 🤞
I also got updates and pictures showing both groups, all I can say, there is even greater and massive difference than it was after the 3rd dose, that’s a good sign for Benjamin Button lovers)
Leo you do have pet related expertise so I sm glad your eyes can notice the difference between the two doses 🙂
Haha, you made my day, thanks😁 Exactly, as Steve can tell you the age of any species, so my eyes are accustomed enough to recognizing even the slightest difference, and this is due to my “home zoo” that I have been following since my early childhood.
As an ex-furrier (I was a fur trader for more than a decade), I too have a lot of experience with animal fur. I can confirm that the difference between control and treated animals is HUGE.
Thank you Zisos! Expert eyes can discern what we can not. This good news 🙂
@Akshay, have you any idea, if nitric oxide (NO) synthesis is restored to youthful or near youthful levels with E5?
Endogenous NO synthesis drops dramatically with age.
NO is involved in telomerase, mitochondrial biogenesis and the mobilization of stem cells to repair damage.
Some researchers argue that we should add the ‘NO theory of aging’ to all the well-known causes of aging, since lack of NO can be the cause of strokes, heart attach, vascular dementia etc.
Telomere attrition, mitochondrial dysfunction and stem cell exhaustion, as well as decreased levels of NO are all attributed to the cellular, The wear and tear theory of aging, including Sinclair’s loss of epigenetic information/epigenetic noise theory, which is basically a wear and tear OF epigenetics itself. Since some of us do believe in program existent, we think every exhaustive aspect should be changed.
Ole I agree NO is gaining more importance as we learn more of its role in so many of our systems. I recently came upon data from 25 cases of Chronic Kidney Disease which was reversed by Niacin. I will check with my colleagues regarding NO levels before and after. Thanks. As Leo said I would expect it’s levels to go up. But it’s a good idea to add it as another biomarker in our tests.
Thank you Akshay!
My father, aged 84 has been suffering 10 years now from CKD due to Wegener’s granulomatosis. CKD patients are extremely vulnerable.
Due to their kidney disease they easily toxify. Give them a large bowl of freshly prepared vegetables (which otherwise would be healthy to a normal person) and their blood levels of potassium and phosphorus reach lethal levels. Basically anything that gets excreeted through the kidneys can kill them in a day or two.
Currently he has 17% kidney function level left, and I dream that one day E5 may potentially restore some of the lost kidney function.
Keep up your fantastic efforts!
Hi Ole,
For your dad read up on Stephen McConnell and Dr. W. Todd Penberthy. In 25 cases they saw CKD reverse minimum 1 stage to multiple stage with this protocol:
Niacin 100mg – 500mg once to 3 times per day.
Baking soda 1.8gram p day (1/3 at lunch 2/3 at dinner).
Calcium Carbonate 400mg-1,000mg with meals.
T4/Levothyroxine 25-50uq
Methyl Folate 0.8mg – 2mg.
My wishes for his early recovery.
Thank you Akshay. I will dig furhter into the study. Your insight is much appreciated.
I cannot wait for the day that you and Harold finally receive the public recognition you deserve. Not for spurious fame or to satisfy anyone’s professional ego, rather countless lives could be saved by simply following a simple and well established regimen. Bless you both and keep up the good work.
Why do you say that? Why do you think they are not appreciated enough or need more attention? Instead of publishing a thousand of pointless and unnecessary papers, they work inaudibly and by their perfectionist and professional actions, they know exactly what is best for their success. An ideal example of this is David Sinclair, who has many blindly trusted followers, they repeat and do everything according to David, though most of them are wrong and irrational, such as taking statins, removing PUFAs and meat, etc.
I say that because it needed to be said. Not that I disagree with you about following false idols. You left out trans-resveratrol – another useless compound pushed by Sinclair.
Thank you Michael 🙏
I believe in Harolds “dream “. Something great is in the air. Tell him to take care. He seems such a nice bloke. What a great team you all are. Would be great to see Nursing Home residents run down those wards. God Bless.
Does any reset include mitochondrial DNA ?
Lost so many friends to COPD, How good that sounds.
Read the book and really enjoyed it.
Thank you Derek for your kind words! You certainly put a smile on Harold’s face. Mitochondria rejuvenation a favorite of our Medical Director. He gave us a molecule that can rejuvenate it powerfully. Are investigating its potential as a patch. Of course any product we come out with we would first test it in ourselves and conduct and IRB good quality human clinical trial to confirm its safety and efficacy. COPD is a bummer for sure we don’t realize that it’s the 2nd highest cause of death after heart disease. Rejuvenating and repairing lung tissue would literally help hundreds of millions suffering with COPD.
Thanks for replying.I take 900 mg of Co-Enzyme Q10 daily. So immensely interested. The news keeps getting better !
Calico (Google) is normally very secretive.
I was surprised to see this Youtube Video showing their work on Cell age Reversal similar to that of David Sinclair. I find their conclusions quite interesting.
Thank you Zisos I hadn’t seen that. Quite interesting but in sync with my earlier comment about the neoplastic risk in this intervention. What they see the teratomas is development of cancers. But this will evolve as scientific research progresses so it will be interesting to see where it leads to.
Hi, Akshay:
It is certainly in line with your prior comment regarding such cell age reversal, and the dangers it entails.
Nonetheless, I consider this video important for several reasons:
a) Calico’s involvement gives credence to the possibility of age reversal (The vast majority of people I talk to, including health professionals, just think of age reversal as another claim by charlatans). This will create more awareness, and attract more funding for “Age Reversal.” in general.
b) The fact that they are no longer as secretive, gives us an idea of where Calico is heading. And it is in the general direction of reversal, rather than “damage repair”.
c) And of course, it will be serious competition for Yuvan. I hope Yuvan will get there sooner 🙂
Zisos, that route to age reversal would probably take many years to be considered safe. Due to the formation of terratomas even if a solution is found many long term studies would be required to rule out any possibilities. Ours as you know has had no such risk due to its endogenous nature. Alkahest has already reached Phase II with fractions derived from young plasma. Regarding competition its sure to come but the market is so huge that even 10 companies won’t be enough.
Akshay, Alkahest has a single fraction GRF6019 for the treatment of neurodegenerative diseases like mild to moderate Alzheimer’s, indicating that proteins in the circulatory system directly affect motor and cognitive function, but it’s just one factor specifically responsible for the neurodegenerative dimension only, right? Therefore you are so far ahead, thanks to your indefatigable work and a bit of luck, as Harold said ⚡️
Thank you Leo. I wouldn’t take away from the great progress Alkahest has made towards having a young plasma fraction product approved as prescription medicine. It will help our application. We have seen system wide reversal of biological age but only in animals. Yet to reach human trials like Alkahest.
Akshay,
You are probably aware of these organizations, but if you are having problems setting up dog trials, you might want to contact The Dog Aging Project (https://dogagingproject.org/) or Loyal (https://loyalfordogs.com/). Both of these organizations appear to be well funded, motivated to find ways to extend the lifespan of dogs and might be open to a collaboration of some sort.
Now that you have had some time to receive a number of orders, would you consider the rollout of Neel a success?
You indicated in an earlier post that you expect results from an E5 trial by the end of 2022. I assume that you mean the phase 0. Do you have a start date for the trial set? How long do you expect the trial to run?
Thanks,
Rick
Hi Rick,
Those organizations are doing interesting work but may not be open or suitable for collaboration. The dog colony was unfortunately disbanded but we have come up with back ups: There are private dog owners who are willing to fly their dogs down to the study site which is being provided by someone considered US’s leading veterinarian doctor by Greg Fahy. Second back up is a study suggested by the doctor on cats whose primary cause of death is CKD. Something we wish to explore as a condition for E5 to improve or resolve. NEEL gel is yet privately launched only to our community and supporters to get them first access and for us to get feedback. We are very grateful for the great response- touched by so many pre-ordering. Deliveries should begin soon and I am looking forward to their happy reactions when they use the product. Main launch on Amazon should hopefully happen in March next year. E5 IRB application for human trial is under preparation – almost ready thanks to our talented Medical Director. It would be good if we can launch the Phase 0/Phase 1a, b and c by second half of next year. We will get results from 1st month but may see significant improvements around end of 2022. Fingers crossed.
Mark,
David Sinclair said his lab would be trying to duplicate the results of the following study in an interview.
Study was just published a few days ago:
Rejuvant®, a potential life-extending compound formulation with
alpha-ketoglutarate and vitamins, conferred an average 8 year reduction
in biological aging, after an average of 7 months of use,
in the TruAge DNA methylation test
Thank you. Do you happen to have a link to the publication?
albedo,
Sorry, My reply was blocked.
So, If you haven’t found it yet,
Just Google the study title above “Rejuvant … methylation test” and it should come up.
Hope this helps
Hi Gerald,
Is this addressed to me because of my past reports on using alpha ketoglutarate?
Yes, the results seem plausible with a couple of caveats:
1) reduction in epigenetic age is not necessarily reduction in biological age; my 6-7 years reduction in epigenetic age did not accompany any obvious physiological improvements (I’m 43)
2) the magnitude of the reduction in epigenetic age seems to be linked to age – I know people with a larger reduction from adding AKG to their regime but who are much older than me.
Also a couple of other points
1) adding Vit C and Vit A should add to AKGs upregulation of the TETs, but in my case it didn’t (My results were not better, but I’m still experimenting with this)
2) my results clearly show there is no need to using Rejuvant. I just used Kirkmans mix of calcium and magnesium salt (900mg/day for 6 months). I’ve recently tried Ca-AKG powder but nothing to report as yet. Arginine-AKG also seems to work, but you need to bear in mind you’re getting 2mols of arginine for every 1 of AKG, rather than 1:1 using the Ca-AKG.
Hope that helps.
Mark – I’ve also been using the Kirkman CaAKG @ 900mg per day and I’m 61. After about a year of supplementing CaAKG, I thought my eyebrows, which have been salt-and-pepper grey for decades, seemed darker. I compiled a set of photos going back 2-3 years and there was definitely an unmistakable darkening of both my eyebrows and beard. It didn’t reduce/reverse the amount of grey, but the non-grey hair was significantly darker – so there was much more contrast. I don’t have much grey hair on my head so no change there.
This result aligns with the mice studies on CaAKG, in that the mice’s fur darkened significantly. Also, I recently took TrueDiagnostic’s “TrueAge Complete” epigenetic clock test (850,000 methylation sites vs. the handful used in the Rejuvant test “TruAge” provided by TruMe Labs). TrueDiagnostics’ test gives you multiple results and mine were:
>> Epigenetic Age (intrinsic) – 52 – a 9 year delta
>> Epigenetic Age (extrinsic – immune system age) – 39 – a 22 year delta
>> Dunedin POAM Aging Rate – 0.91 (biological vs chronological age rate)
Unfortunately I don’t have a “before” test so no comparative analysis. I also take a large stack of supplements and fast/exercise regularly, so there are bound to be many confounding elements, but I found the light association between hair darkening, reduced epigenetic age, and CaAKG supplementation interesting.
Don, you wrote that after a year of consuming Kirkman CaAKG, your TrueDiagnostics “intrinsic age” was 9 years less than your chronological age and more interestingly, your “extrinsic – immune system” age was 22 years less than your chronological age. You mentioned you also took supplements. Would you be willing to disclose what supplements you take?
Hi James – Sorry for the late reply to your question. I had similar questions from some facebook groups, and this is what I shared:
===========================
Here are what I personally consider to be the things that MIGHT have impacted the test results (I admit this probably reflects my opinions more than strictly associated with hard research.) Now that we are getting more high-quality, data rich testing options, I’m hoping that in 3-5 years we won’t have guess what’s impacting our epigenetic age – we’ll have hard data to tell us.
EXERCISE:
>> long duration cardio (10 years, cycling 45-75 min., 4-5 times weekly)
>> resistance training (5 years, high-reps, medium load, 2-3 sets to exhaustion on last set, 2-3 times weekly)
>> HIIT (3 years, cycling sprints, ~ 1-2 times a week at the beginning of normal rides)
DIET:
>> focus on a low-glycemic diet, cycling in/out of ketosis a few times a month (10 years),
>> 90% paleo – especially NO GRAINS! NOTE:I also eat low-glycemic dairy, one cheat day a week (5 years)
>> 18:6 intermittent fasting (2 years), recently transitioned into OMAD 5-6 days a week (1 year)
>> 4-5 day quasi-fasts – ~800 calories a day, minimal protein, mostly fat (started six months ago, once every six weeks)
>> coffee (3 years, 12-24 oz per day)
MEDS/SUPPLEMENTS:
>> Metformin (8 years, 1g – 1.8g, daily)
>> Sirolimus [rapamycin] (1 year, 6mg, weekly)
>> Calcium Alpha-Ketoglutarate (1.5 years, 900mg, daily)
>> Trimethylglycine (TMG) (2 years, 1000mg, daily)
>> Glucosamine hydrochloride (8 years, 1.5g, daily
>> Vitamin D3 (5 years, 10,000iu, daily)
>> Biotin (5 years, 10,000mcg, daily)
==============================
Here is a list of other Supplements and Meds I take. Not sure if any of these would impact epigenetic age.
Ubiquinol (CoQ10), 200mg, daily
Chondroitin Sulfate Sodium, 1,200mg, daily
Resveratrol, 1000 mg, daily
NMN, 1000 mg, daily
Hyaluronic Acid, 300mg, daily
Citicoline, 1,000mg, daily
Saw Palmetto, 320mg, daily
Pumpkin seed oil, 320mg, daily
Palmitic Acid, 32 mg, daily
Oleic Acid, 58mg, daily
Linoleic Acid, 130mg, daily
Stearic Acid, 10mg, daily
Turmeric Extract, 500mg, daily
Melatonin, 10mg, daily
Fenugreek, 500mg, daily
Benfotiamine, 500mg, daily
Bilberry extract, 300mg, daily
Vitamin K1, 1,500mcg, daily
Vitamin K2, 1,100mcg, daily
Vitamin B12, 3,000mcg, daily
Fish oil – EPA, 2,500mg, daily
Fish oil – DHA, 1,000mg, daily
Black pepper extract, 10mg, daily
Aspirin, 81mg, daily
Additional meds:
Amlodipine besylate, 10mg, daily
Losartan Potassium, 100mg, daily
Atorvastatin, 5mg, 2-3 times weekly
Don, thanks much for taking the time to reveal the exercise methods, food choices, meds, and supplements that are likely to have contributed to your unusually youthful methylation age. You are a disciplined guy.
And more amazingly, youthful immune system age.
Hi Don:
Can you please provide a link to TrueDiagnostic’s site? I googled it but was unable to locate it.
http://trudiagnostic.com
Hi Zisos,
Sorry, I misspelled the name. Here is the link: https://trudiagnostic.com/truage/
For reasons I cannot plumb, TruDiagnostic normally will deliver a watered-down report that does not include, e.g., ‘Immunity age’. Be sure to request the report that they reserve for health care pros, if you want all the details. I don’t think it costs extra (my test was done as part of a supplier search, so I maybe they were just being nice to me). Hopefully, they have changed this policy. BTW, I really liked dealing with this company, and found them to be highly competent.
Hi Zisos thank you for recent advise – that is certainly a wiser approach. I would rather not reveal the scientists name.
Being an Australian (hint, hint) … I can guess who the Harvard researcher is (*very* well known in the anti-aging field) 😉
Pay no heed Akshay, I’ve seen this sort of behaviour relating to another well known radical engineer – Elon Musk. The guy doesn’t follow the “normal” acceptable approaches to business and engineering, and therefore the incumbents can’t control him and so instead they must attack him and try to discredit him. In the meantime, he just laughs at them, ignores them and continues to create ground-breaking solutions that benefit everyone on Earth.
You and Harold are the same. Just keep going. In the end, the facts will speak for themselves, and reluctantly, they’ll have to admit you were right!
Thanks Toby. The forum here is amazing!
Hi Mark,
I thought confirmation of your own results might be of interest.
Also, I was given to understand that AKG is involved in removal of old
methylization. I think that was from David Sinclair’s comments.
If so, TMG or MSM or some other methyl donor might be helpful.
Also perhaps this might be useful to add to support Akshay’s gel product as it corrects the epigenetics.
Mark,
Sorry, I missed your reference to TETs.
Thanks for the suggestion to use Vit A,C.
I have the AAKG but will switch to Ca-AKG when it comes in.
The animal studies show a lengthing of life span with a compression of the sick span pushed out to the very end.
In my case, I am hoping to see some of the aging effects reversed for now and pushed out a few years. At least that is my test to see if it works.
Thanks again for your original Post and getting this on my radar.
Yes AKG is a cofactor for the TETs so remove DNA methylation; it is not clear that it is demethylating the same locations that DNMTs (via SAMe) are methylating. No need to take methyl donors as far as I am aware.
Hello and happy new year to everyone.
Akshay, how are the rats doing? It’s been one month and a half since the second rat of the control group passed away, but, still, do the treated rats after the fourth dose show any sign of further rejuvenation (related to ovarian activity and/or beyond the already big success of keeping them alive, slender and far more active than the controls) ?
Hi Ines, No further rats have died but some do seem close to death. Harold has taken great interest in the difference that gender seems to be making with E5 response. There is definitely a lower response in female rats. Our PI has bought the kits and we plan to test various female hormones that change with menopause and age. Harold read papers where transplant of a young ovary led to reversal of aging related markers. Even removal of ovary seemed to result in longer lifespan. Anyway this has piqued his interest and he has some studies planned in the next few months.
Hi Akshay. Based on what markers do you know that it has much less response in females? But the difference between control and treated is as unambiguous and explicit as non in any other experiments rats and mice.
Leo there is significant response for sure but when compared to our earlier study in male rats it’s lower.
Hi Akshay, are you referring to the response of IL-6 and TNF-alpha to E5 treatment?
I was wondering why the drop in these levels you have reported for the on-going experiment was muted compared to those reported in 2020 (or took more iterations of treatment to achieve the same effect).
Is the current study females only?
Hi Mark, Current study is female only.
Hi Akshay! Glad to read some news. Regarding the difference between male and female response to the treatment, if it is significant, it would be interesting to present separated results when it is relevant.
Patricio yes we are adding them to our paper.
Hey Akshay – I have a question about presbyopia. I’m only 56 and it’s starting to be pretty pronounced. My wife is a few years younger and she’s actually having it worse.
Fortunately I’m near-sighted so I can always take my contacts out if I need to read a lot. But given that the blue stuff is about to be shipped the thought has occurred to me that we may ‘look’ younger let’s say a year or so from now, but internally certain day to day functions will remain compromised. Proper eyesight is a big one.
There are these new Vuity eyedrops that reduce the size of your pupil – I can’t really believe that this is a good idea on a long term basis. I wish there was a way to address the root cause, which is the hardened lens.
Hi Michael, I have some suggestions: first is two oxygenated macula carotenoids: Lutein and Zeaxanthin. Another is Astaxanthin. Dosage is very important in all 3 so please do read up on them to ascertain optimum dosage. Research from Buck Institute has come out with Glylo to address glycation end products. Upregulation of autophagy and mitophagy by upregulating Nrf2 will also be important. Niacin. And weekly rapamycin. You may be already taking some or many of the above then ensure that the ones you are taking have tested bioavailability and administer ideal dosage. I read many hours everyday so exercise does also help.
Honestly, No matter if we will need a future, female version of E5, it still remains the most amazing breakthrough ever, I do not see any kind of concurrency here, no matter how many billions are invested. Can they harness Y factors and pulse them for a limited time to rejuvenate a whole animal? No one knows yet. What’s so important about an embryonic cell isn’t its youth, but its identity. Yes, billions of dollars invested and the unity of leading science allows for quality research, but if it was so, we’d probably have seen a zillion papers with people trying to rejuvenate animals with the help of Y factors after so many years are gone, but we have not. I even do not believe in Sinclair’s claiming they did it without teratomas. The technology is 10 years old and also produces teratomas and mouse experiment was not blinded and the results were preannounced in his book. On a daily basis he says things known to be long ago falsified. I may seem too biased because when I posted about the NEEL in some groups, people attacked me, blaming I work for Yuvan, but that’s a fact, I am extremely pleased, happy and blessed to live today, knowing literally the smartest people in the world. It’s an honor!
I totally agree with you. If E5 keeps its promises with human trial, it is the greatest leap forward in aging science. And it lets us time for further improvement.
Thanks Akshay for your always quick and accurate answer.
I am pretty astonished as I came across this news just this morning. Despite they describe the whole thing in different terms, they talk about an elixir and a combination of signaling molecules and show the familiar images of senescent cells in young mice, old mice, and old treated mice…
https://www.newswise.com/articles/chula-medical-breakthrough-red-gem-molecules-to-reverse-aging
Ines, It never ceases to amaze me at how well informed this community is on aging research. This indeed a very interesting discovery about physiological DNA double strand breaks in hypermethylated heterochromatin that has a function to manage stress in the tightly bound DNA like gaps left in rail tracks. WOW! Nature’s engineering is so brilliant. But Ines I have doubts about their solution. It’s not any signaling molecules. They are using molecular scissors to recreate lost DNA double strand breaks but this strategy has many issues: Such induced breaks have not shown long term stability. So it can lead to disastrous consequences. Secondly the original DDSBs were in hypermethilated parts og the DNA but as we age they get hypomethilated so the DDSBs may not function the same without the substrate/co-factors. I wouldn’t go and try this treatment any time soon.
Akshay, and you do not stop amaze us by showing your mysteriously extensive knowledge, without any hesitation, you are truly one of a kind in this dimension, please take my totally objective and neutral compliment from my heart.
Thank you Leo you are always very kind. I hope we do not ever disappoint your expectations.
Thank you Akshay, the news are not a reviewed paper but in this web and many things sound ambiguous to me, I had interpreted that RED-GEMs were some molecules triggering JdJm3 and inhibiting Ezh2, so allowing an extra space among the histones and demethylation resulting in an expression of the genes unexpressed due to aging, In fact I didn’t understand the “scissors” concept In this context. Many thanks for your explanation.
And many thanks to you Ines for introducing me to the discovery about DDSBs made on purpose by Nature to manage the tightly bound cords of DNA.
I take it they haven’t published yet; I can’t find the paper anywhere? As an engineer/physicist I am partial to a nice, mechanistic theory of aging. But sadly, no details beyond what I can glean from that press release…
Akshay,
I saw where Steve Horvath has taken a position with Altos Labs. I was wondering how that will affect your collaboration with him? I assume that, through Dr. Horvath, Altos Labs is aware of Dr. Katcher’s and your work on E5. Do you think that there might be a future collaboration between you and Altos Labs.
Thanks,
Rick
Rick, Prof Steve Horvath has a non profit foundation that will continue to work with aging research companies with regards to their requirement of bioage clocks including us. Plus we are very fortunate to have him on our Scientific Advisory Board. I wouldn’t want to speculate any thought at all about working on any level with Altos Labs. I have had a very good, positive and supportive interaction in the past with one of the key founders of Altos Labs. Personally, I am glad that they raised such amount for aging research. This will benefit all aging research biotechs with valuations and funding. This is what we can call as a tentpole effect. I continue to be in bewildered awe of complexity of aging. So the more money is thrown at it the better.
Hi Akshay, I’m assuming Altos labs will attempt to rejuvenate adult cells by
1.) Applying Yamanaka factors to human cells while minimizing the risk of tumor growth and loss of cell identity.
2.) Figure out the mechanism of embryonic rejuvenation and how this can improve upon and/or replace the use of Yamanaka factors.
However, a company called Shift Bioscience is combining public and proprietary gene expression data from cell reprogramming studies to identify the contributions that different genes (non-pluripotent rejuvenating genes) make to the rejuvenation process. In addition, they use machine learning ‘enrichment’ to better differentiate rejuvenation pathways. Based on results, rank gene contributions. And ultimately they want to reset cells safely to a youthful state with mRNA or small molecules.
Harold was mentioned in the race for rejuvenation slide at 2:13 by shift bioscience co founder https://www.youtube.com/watch?v=TGcSwVjFdXc&t=1698s Neuromorphic computing, although it’s still in its infancy could accelerate ageing research
Ghalib, very accurate analysis of what Altos will do. Thank you for introducing Shift. Although a competitor I admire the team and their approach. Very interesting. Something good and useful is bound to come out of them. Using mRNA or small molecules to change gene expression one at a time may show some benefits but not sure it would create a comprehensive systemic reversal of biological age. Our system has too many important players that need to be changed/reset to get such reversal. For example I am writing a post on floppy Proteins/Intrinsic Disorder Proteins called ‘Floppy Proteins of Chaos. The shape-shifting magicians of Nature’. Our knowledge about Proteins is based on their folded structure and their functions but there is an equally big universe of shapeless unfolded Proteins that have some amazing functions and properties. Similarly we have been focusing on coding DNA from decades. This disregards a lot of other regulatory actions taking place coming out of the non coding part of the DNA..So they may succeed in let’s say activating a rejuvenative gene silenced/methylated by aging but even after that protein is coded it can be degraded by miRNA immediately after translation. Some data has shown 60% of translated Proteins are negatively regulated by miRNAs. Even before translation there is miRNA mediated silencing of mRNAs. So I wish them the best and hope they are able to solve these major hurdles to come out with a uniform response from every dose.
I never get tired of reading your blogs, posts and comments, literally, insanely addicted!)
You are very kind Leo. 🙏 Every researcher would be fortunate to get such an intelligent supporter like you.
Akshay, how can you summarize the results with added a control young? Have you also tested other markers like glutathione and some of the others you did in your first study?
Nanaka,
Young control was added based on some requests. There is a limited number of assays we can do during lifespan study.
Hi Akshay. Including young controls in the lifespan study is interesting. I have a few questions as a result of this inclusion:
1) What is the age of the “young controls”?
2) After repeated doses, TNFa and IL6 have stabilized at lower levels than the “old controls”, but at considerably higher levels than “young controls”. Does this indicate that e5 has limited reversal capability? Or do you think that either with higher doses or longer treatment time these values can reach the levels of “young controls”?
3) Grip strength of “treated” is substantially higher than “old controls”, but almost at the same level as “young controls”. However, their body weight is higher than “young controls”. Does this mean that in order to properly compare the grip strength, an adjustment should be made to take into account the weight?
Very interesting observations Zisos. We use 8 week rats as young control. These are female rats but in male rats in 2 studies we could see similar stabilization but more pronounced and closer to young control levels. Harold is quite piqued by this gender difference and has dived in to conduct various side studies to get more insight. One can do such adjustment but grip strength is a functional test and if it is considerably improved that is a great outcome on its own without any need to compare.
I am in awe that we can follow such groundbreaking study jusk asking one of the promoters and get information almost right away not only of the positive, but of the not so positive outcomes, like the partial response of females, and on how they intend to handle the issues concerning a not so strong response.
Can any of you imagine mailing Calico or Altos asking about theis studies?
Many thanks Akshay.
I landed on Josh’s blog by coincidence, and I am so happy it happened.
Very kind of you Ines! Let me break another news on our current Lifespan study through your reply: One more control rat has died yesterday. So now we have 8 treated and 5 control rats alive in the Lifespan study.
While not politically correct to say so, I declare that I will be opening the champagne bottle when the last control rat is gone (while the ‘treated’ remain alive & kicking) LOL !
Cheers to that Zisos but some treated may also die due some mutational cancers. As long as they overall outlive the control and in good health and youthful strength this would be groundbreaking results. Who wouldn’t want to live a long, healthy life with youthful vigour?
Thank you Akshay! Being familiar to veterinary practice I am aware rodents have a high rate of tumor when they reach late middle age, in rats this happens at two years old more or less. Rats in the trial are almost 3 years old, does any of the treated rats show any sign of carcinogenesis? And non treated? Cancer is rare in young and more and more frequent as we age, one out of three people will develop a cancer (if allowed to age, that didn’t happen in middle age/stone age). If rats that are naturally prone to cancer could skip that risk, wouldn’t the FDA consider E5 not only as a treatment for fraily, but a preventive treatment for cancer?
Ines, that’s a good point. Our Medical Director already suggested a rat cancer model study. We hope to do this during this year if time resources permit us. You are right cancer is the number cause of death in rats. The study rats would now be around 34 months which is very close to their average lifespan of 36 months.
Akshay, should not E5 have an ability to significantly reduce the cancer risk if a youthful environment and therefore, young body is presented?
Nanaka, overall yes and that’s probably we have the current 8:5 ratio but there are certain mutational cancers which may beat even a more robust immune system. So we should expect a few treated rats to also die. Hopefully they would outlive their avg lifespan and that of the controls. This outcome too can be further improved. For example they peak between 15 and 45 days after treatment and we are currently dosing them around every 90 days. What if we see doubling of the improvement by dosing every 45 days? We plan to do multiple such studies to probe the dynamics of E5.
Thank you. Could you please clarify what 8:5 ratio is? And is Harold going to modify a current E5, something like add some more factors? I read your comment that Harold is interested in the gender specific version.
Nanaka currently 8 out of 8 treated rats are alive and 5 out of 8 control rats remain alive. Yes Harold indeed is researching quite a bit on gender variances. He has side studies already planned for this.
Akshay I understand sourcing of the proprietary molecules is as important as the discovery/invention itself, but have you ever thought how a natural, plasma derived molecules would work? For example, if we take Professor Khavinson’s peptides, those extracted from young bovines, need some time to start working but it’s effects lasts for months and even after stopping ingesting, the effects are continually stable, since we are rejuvenating a special gland/organ by a signaling. If we take it’s synthetic analog with a fewer peptide chains, the working mechanism will be instant upon ingesting but the effects go away soon after stopping the cycle.
Leo all molecules have a half life. Once they let’s say bind to a ligand and convey their change to the cell they would degrade. If there was no further regulatory transcription that one change was enough to reset the epigenetic marks or the gene expression. But since there is so one would need to regularly replenish those fractions.
Thank you Akshay, as always. And the actual strategy, we are all super eagerly expecting to work is to hack the factors and proteins that cause progressive age related changes in the activation and repression of genes and replace them with factors and proteins from a young environment, that will change the gene expression signature back to what it was in youth and In turn, that would make us young again, right? Is it possible those elements to trigger a non coding DNA that gives birth to those molecules to start producing their own pro-youthful factors? Something like an opposite but interdependent reaction to happen.
Leo excellent understanding. To answer your question: our biology is incredibly complex for me to give a firm answer. I can only speculate: personally feel the non coding transcriptions are so highly conserved that they would continue. Which creates the need for continuous hacking.
Thank you so much for your words and your answer, so interesting.
Hi Akshay,
I’m a long time longevity enthusiast but a relative newcomer to yours’ and Harold’s work. My wife and I discovered your research through Harold’s interview with Modern Healthspan and are excited for both E5 and Neem gel. The progress you have made as well as the overall theory of aging are truly inspiring. My wife was wondering if you might clear something up regarding one of GHK-Cu’s established effects. It’s said that it “Increases hair growth and thickness and enlarges hair follicle size.” Should this be something for people to worry about when applying to places on their body which they do not want to grow hair from?
First of all would like to thank you and your wife for your kind words. I have good tidings for both of you: Ghk-cu’s mechanism of action for hair follicle rejuvenation is by blocking DHT on the scalp. DHT levels go up in males as we age – it’s conversion from testosterone goes up. Paradoxically DHT promotes hair in rest of the body but on the scalp it causes miniaturization of the hair follicle. Over the years it finally leads to loss of the hair follicle. Ghk-cu seems to reverse this loss by blocking DHT from damaging the hair follicle on the scalp thereby reversing to some extent male pattern baldness. So your wife does not have to worry about unwanted hair growth. She can happily and safely take it’s full benefits of skin rejuvenation.
Thanks so much for your speedy response Akshay. Those are indeed good tidings! I’ll pass on the good news to my wife!
Hi all. What is your thoughts on Conboy’s latest talk?
“It’s kind of interesting, right? It shows that young blood or young factors are not drivers of aging or rejuvenation. This may be a surprising conclusion, but it is the one that seems to be correct. That putative cause, young blood, doesn’t seem to be a cause for the effect, which is rejuvenation. Instead, we need to either remove or neutralize age-elevated plasma proteins.”
“Interestingly, in vitro experiments, if you mix young and old blood together, it shows that old blood dominates. Old blood is completely dominant in vitro, and it will inhibit all of the positive things that young blood can do.”
“ This notion is summarized by my favorite cartoon that I usually present and most of my talks that demonstrate that at three years of chronological age, a rat will be biologically very old and full of disease, but a squirrel, which has a similar size, even higher metabolism, and a very similar diet, will be biologically extremely young and healthy. They experience the same degree of damage, they live in the same environment, but their biological age is very different, which we hypothesize is because they have different repair efficiency”.
I do not think this is right but a few scientific arguments would be great.
Nanaka, Irina Conboy thinks pro-youthful factors are always circulating and we do not need to add more synthetically, that aging is actually caused by a variety of old proteins and everything is about the repair capacity. For me, it’s another typical opinion of “wear and tear” theory of aging.
‘Irina Conboy thinks pro-youthful factors are always circulating and we do not need to add more synthetically, that aging is actually caused by a variety of old proteins and everything is about the repair capacity’
If one were to somehow identify the old proteins and neutralize them or dial them down, effectively it is the same as increasing the concentration of the pro-youthful factors, which is what young plasma does. Since aging is progressive the effect of infusing young plasma is dialing down the concentration of the old proteins.
True.
But it depends how older biologically a one is, since the older we are the less pro-youthful factors are circulating, therefore, their capacity to rejuvenate organism by changing the gene expression signature back to what it was in youth and by having free space without the old stuff should not be enough to properly rejuvenate, right? I still think adding is far more important and prime then removing.
My opinion is that it is the other way round, i.e. the older we get, the greater is the increase in the pro aging factors, and greater is their influence on the pro-youthful factors circulating in the blood, and lesser the repair.
I agree with Dr. Conboy when she says that aging is not dependent on the pro-youthful factors, but on the old proteins and also that repair is dialed down progressively. This is where it gets interesting, because ‘progressive’ is the operative word, since she is also hinting that the aging process is progressive and dependent on the old proteins, that means the level of the old proteins increases as we age and therefore any dilution of those factors would be beneficial, since it would effectively reduce the influence of the old proteins.
Conboy vs. Katcher? Perhaps both are correct. Remember, transcription factors are proteins too and many can be inhibitors. So, theoretically, one could add a substance to old serum that reduces the creation of old factors. Then, remember that almost all proteins, both intracellular and extracellular are degraded and replaced over time.
Leo, Kunal and Wayne all are right. It’s like looking at the elephant from different sides and describing it. Harold only goes by evidence and there is evidence on both sides although more evidence is there currently for pro youthful factors influencing aging beneficially. There is no old protein and youthful protein in an aging body. There is no bad protein and good protein. All are important otherwise they would have been eliminated during evolution. Nature’s mechanism for tuning levels of all its systems and pathways is by agonist, antagonist and sensor proteins. For example Nrf2 is an important repair pathway. When higher oxidants or stress is ‘sensed’ it triggers expression of agonist proteins that activate Nrf2. But one can’t have continuous activation of any system as that would lead to harm after a certain threshold so then antagonist proteins are expressed to shut down Nrf2. When we are young this balance is homeostatic but as we age this balance goes askew. So less agonists are expressed due to increasing methylation or more antagonists are printed. That doesn’t mean they are old proteins or bad proteins as they are needed too. What diluting does or what pro youthful infusion does is reduce the imbalance to some extent. We have gone more deeper into the process through proprietary method and hence have seen more pronounced results. If the balance is restored to homeostasis as seen in youth the repair systems will again become nearly as efficient and thereby reverse the phenotype to how it was in youth.
I have no words, Akshay. You are a true mastermind! Harold is the luckiest man for having you. Thank you once again.
You are always too kind Leo
Hello everyone, a very interesting question. The Conboys were really brave to try heterochronic plasma exchange, that is a merit in itself, and a milestone.
My concerns about dr Conboy’s proposal are two, and they are both the results of plasma replacement when used in humans. There are two clear examples: the Grifols trial (AMBAR, Alzheimer Management by Albumin Replacement) that diluted plasma with albumine periodically, in order to improve/cure Alzheimer’s disease, and only managed to slow the progression of the disease, but didn’ t even stop it, and patients didin’t seem to improve other markers. The other one is the plasma apheresis, which results are not appalling. No one looks one day younger after that. It seems the patient feels great for a couple of months, and that is it. It doesn’t tick the clock backwards. And it intrigues me that no epigenetic clocks have been tested either in mice or humans concerning plasma dilution. It wasn’t difficult to do. And I presume they have the tissue samples of those mice.
Greg Fahy managed to click the clock backwards with some young factors, HGH DHEA are also peptides that are abundant when we are young and diminish when we grow old, and cheating body with metformin, as IGF is a proaging factor (in old age, young people have lots of it , specially if they sport, and they look great). All those 3 factors when given steadily, so changing the signaling to a younger one, not only tick the clock backwards, but rebuild tissues, like bone marrow and thymus, probably kidney, and lean mass, many of the functions of the body improve, so probably it build tissue in places that have not been checked, and people with white hair start to have grey hair instead.
Nothing like that was seen in the AMBAR trial. Not a shadow of it.
That is why I am eager to see the E5 trial in humans and bigger mammals, because it looks far more promising than plasma dilution. It seems that plasma dilution didn’t encorauge the body to produce the bricks needed to replace and repair tissues.
By the way, how are those?
Thanks again Akshay.
Have you seen the latest update on TRIIM-X trial? One likely case of prostate cancer in a treated man and two cases of prostate cancer caught in pre-treatment screening… Growth hormone is far too risky.
Hello Leo,
no I hadn’t seen that, can you provide link so I can check? As I understand from your statement:
The two pre treatment screening cases are not due to the HGH treatment, it means that they checked the guys before starting the trial and they were not suitable as they found that malignancies prior to treatment, so you can’t blame the HGH there.
A cancer is not something that appears immediately, but has a period of latency, it means that the factor that causes it has to be present for a long time. And the the malignancy bursts. Prostate cancer is more common in men aged 65 years and more, and lots in the trial may be well beyind that age, yes, HGH can be a trigger, but teenage people have lots of it, and I wonder if we checked Harold’s rats, how would they score in IGF1. That grip strength is meaningful of lean mass growth.
Thanks for your input Leo
Inès, that’s exactly why I underlined 2 pre-treatment cases. That does not mean TRIIM-X protocol caused this one case of prostate cancer. It might speed it up, caused it or just a coincidence. Here is the link: https://youtu.be/fWIU1SZuqvY
Dr. Conboy is saying that it is because of dilution of the old proteins, young plasma is effective, which leads to a change in the composition of plasma which had existed at an earlier age, which is kind of a reset, which is what Dr. Katcher is saying. So both are right in their own ways
Nanaka, I wrote a post back in 2016 and 2017 on how aging dials down repair efficiency. Both Harold and I have immense respect for the Conboys as they started the young plasma research with their iconic parabiosis study. But I do not agree with Irina’s conclusion about young factors are not drivers of aging. May we are small fry and our results from a quality study can be disregarded but reputed scientists like Vadim Gladyshev in his paper ‘Multi-omic rejuvenation and lifespan extension upon exposure to youthful circulation’ gives evidence contrary to her conclusion. That conclusion would negate Tony Wyss-Coray’s entire careers work. Villeda and he too gave this evidence ‘Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice’. In fact ‘young’ albumin is given credit for rejuvenation and increase in lifespan in this paper: ‘Young and Undamaged rMSA Improves the Longevity of Mice’ by Luo et al. In the Conboy studies I would like to see dose efficacy curve – basically how long does the benefit last, a before and after test on biological clocks and a lifespan study with albumin. Don’t get me wrong: every finding is valuable and so I respect their recent findings its just that I do not fully subscribe to her conclusion.
‘Don’t get me wrong: every finding is valuable and so I respect their recent findings its just that I do not fully subscribe to her conclusion.’
same here
What we have observed of aging is that it is progressive and if you infuse young plasma even if to dilute, it is the same as reversing aging.
I am glad we have come to similar conclusions.
It is exciting in itself that the Conboys are pushing ahead with human trials for (repeated) plasma dilution.
I agree with what others have said that the Conboys’ approach is not necessarily in opposition to your/Harold’s approach – only that it is clearly preferable to radically increase the concentration of the ‘youthening’ proteins directly, rather than to rely on a dilution of their inhibitors.
Of course the Conboys have no choice as they, like the rest of us, do not know what the ‘youthening’ proteins are!
Any estimate on when you and Harold will be sufficiently protected to reveal more of your proprietary method?
Probably middle of this year.
It should be revealed as a “proprietary blend” cocktail or something like that, should not it? Or are you going to make all its components clear?
Wait and see 🙂 We are already working on the next generation version which will bring even more powerful rejuvenation and dose standardization. I will allow myself to rejoice when E5 reverses the first age onset disease in a larger mammal as in pets followed by humans. Becoming truly and fully young and safely maintaining that youth is a glamorous expectation but what I am seeking is complete cure of major diseases onset by aging. Becoming young again is a welcome side effect of this treatment.
Cool info. I do not think your complete formula should be revealed, If I were you I would keep it as proprietary formula, that’s the reason I asked it because you wrote we will reveal it probably middle of this year.
There is always this dilemna between noble scientific endeavor and practical business considerations. If it were left to Harold he would have made it a freeware with many scientists replicating it but he respects the contribution of our investors and the importance of funding in driving a lab discovery through its long challenging journey to becoming a prescription medicine benefiting hundreds of millions. Our revelation is part of the patent process. But we would be far ahead on our next gen IP by the time this becomes public. What we continue to work on so is so exciting that one wakes up everyday impatiently waiting to take the next step.
I am afraid science doesn’t work like this. And besides, if E5 has to be authorized the FDA and other agencies (in order to help people, which is what Harold and Akshay want), the FDA and equivalents in Europe and the rest of the world, will want to know know what E5 is. If it has to become a medicine, the components have to be public sooner or later. Or they would never be authorized. If they are authorized it wil become easier for this product to arrive to people. I have always understood that the first goal both for Harold and Akshay is to help people.
In Spain Laura Soucek and Eve Marie Beauleieu have patented Omomyc, a small mollecule which inhibits myc gene expression in solid tumors, leading them to dissapear (myc is always expressed in cancer), they are finnishing the first trial in humans with good results, and I hope that if it works, this two girls get rich with omomyc, they would have benefited human kind and they deserve it much more than people who did their fortune with real State, for instance.
Would any medical agency approve a medecine whose chemistry is unknown? I am afraid not. Did they patented it in order to protect their future and their benefits, of course.
Of course patents offer a benefit to the developer and it is fair, and this lasts decades, great! Harold and Akshay have poured effort and money, good for them if they can have benefit! But sooner or later it will be needed to know what E5 is.
On the other hand once it is known many other people can work on it. When Pennicilline was discovered it was a hit, but it is not the only antibiotic we have, God thanks! Many more were developed. Howard Florey and Chain were the first, but many other continued the research and now we have a bunch of resources concerning antibiotics (which unfortunately we are wasting due to misuse, but this is another story)
I am really curious about E5.
I wish the best to Harold and Akshay and I hope they can issue the patent asap. And I feel very lucky for having Akshay answering questions of people he doesn’t even know.
Thanks again Akshay.
Bio pharmaceutical company Alkahest has its own chronokines called AKST4290, GRF6019 & GRF6021, selected plasma proteins, undisclosed novel factors and they are actually their phase II trials already. Do we know what they are? No! But phase and phase II stages are about to end soon. So I can not agree that it’s essential to reveal it in detail. What, Sinclair must make hundreds of millions by falsely promoting his Sirtuin and other theories, even making a patented NMN and Harold should reveal his formula completely? No, that’s not fair.
Nanaka that’s very kind of you. You made Harold smile today for sure. But Alkahest has filed patents which become public after a period of time which do have the details of their chronokines. But on the flipside they get protected by patent law.
I do completely agree with Nanaka, David Sinclair is now connected to Metro International Biotech, that has assembled a team of so called industry leading scientists to drive its lead compound, MIB-626, through clinical development and fuel the Company’s robust R&D engine, to build a library of next-generation analogs with tissue-selective NAD+ increasing properties. The latest video by Dr. Stanfield is a good example how Sinclair is in this field to make billions of dollars. I do not even believe his lab used Y factors successfully without teratomas and that they rejuvenated a whole animal. I do not know how a one can trust him after knowing he’s cut out fish oil, meat and is taking C60 EVOO??!! A molecule which is directly linked to cancer development and toulene intoxication right to the mitochondrial level, caged in a carbon molecule structure? And he is still believed and known as a leading scientist, people are even having Sinclair on their profile pictures on Facebook… It is dangerous to even think about how people can turn someone into a cult and blindly follow them. So if anyone is to be appreciated, just go to Harold and Akshay. You need to protect your intellectual property, which is inspired by your unsparingly hard work, dedication, and luck given to Harold in his dreams, converted to real life. Altruism and modesty is good, but balance is important, you must be told how outstanding you are, literally every day!
Thank you Leo 🙏 fortunately I do have past experience of conducting business at larger scale so will follow all the steps to protect our IP as any other competent biotech would do.
Thank you Ines. What you say is true. Also thank you for bringing to my notice the work of Laura Soucek and Eve Marie Beauleieu. My warmest felicitations to them for their incredible work. There are many heroes in science but I reserve my highest admiration for the heroines of science.
Thanks to you Akshay, as always. I really liked to read in another post that Harold would had happily let the recipe free to anyone so others could have worked on it. Tell him he reminded me of Howard Florey and Ernst Chain. Florey and Chain never wanted to patent penicilline, despite is was possible and would have made them rich, as that antibiotic (we give antibiotics for granted now) was a revolution, just to save lives. Harold is great.
Hopefully you both can make profit of E5.
Do you think others can make the experiment better with the same “recipe? I do not! Others will make money only. I am glad Akshay is well experienced and knows exactly how to successfully secure and manage the business. It was essential for Harold to had met Akshay, great synergy.
Well, in science replication of any experiment that claims any result and third part validation are the basis. And Harold’s work is based on other scientists’ works (Conboy’s, Tony-Wyss Coray), who published their results. When during the commercialization of E5, or after the patent is completed if Harold wants to share it with the world, the compounds of E5 are revealed, the most common is that other scientist start working on it. And other companies which want to work providing E5 in a health care context will have to pay royalties to Akshay, Harold, and other investors, which is fine. I agree they deserve not only our gratitude, but reward.
I dont’ understand your comment
“Do you think others can make the experiment better with the same “recipe? I do not! Others will make money only”
In first place it is not a matter of doing it “better” is a matter of replication and of evolution, I commented before comparing Harold to Howard Florey, he developed Penicilline, great life saver in the 40s and 50s, but other great scientists have developed other antibioltics based on Florey’s job, and we are using they now, much more than penicillin.
Even Harold is working on improving E5 right now, as it is not that effective in females.
And concerning “others would make money only “, well, not the rest of the word is evil, and there are other honest scientists, MD, and people in general.
About the Alkahest clorokines you mentioned in a former post, Alkahest is currently engulfed in Grifols, the Spanish company that bought it in 2020, Grifols operates in whole EU and beyond, and provides with blood derivates many hospitals and Health centers. Well, they can keep the formulation while they proceed with trials, but if those cloroquines work and they are to be in the market, EU won’t allow that unless the formula is known and analized. Not in Europe.
Kind regards
I live in Europe and I understand you want it as soon as possible, I also understand you are very optimistic, but the world is not working with your attitude. We all knew Sinclair and other scientist were dedicated to us but the reality is different. You forget about the big pharma and FDA. I like the manner Akshay works because any effective age reversal therapy will have difficulties and denies.
Sinclair can continue his provocative and pseudo optimistic statements to make a gene therapy pill to make everyone live for hundreds of years but that’s bad for the business due to simply denying and stopping it happen. So secret is one of the main tools and I am glad this wonderful group has a special strategy!
I don’t expect this to be widespread in the next 10 years, (unfortunately for elderly), we still have to see results in humans (I wish the best there) and I am not optimist as I come from a MD environment and I am aware of the hurdles any new treatment has to overcome to reach the market. I am currently working/writing on publication concerning female biology and I am thrilled and extremely curious about E5 and other signaling mechanisms. I think I have answered politely, we can leave it here.
Ok, but I do not see why it’s important to underlining “politely”. It’s just reality, again I am glad this guys are specialized in business and have an experience how to handle it in our money cult environment. Good luck.
Thank you Nanaka and Ines 🙏
One treated rat died. So now it’s 7 out of 8 treated and 5 out of 8 of control
Too pity ((
Are you going to send the samples to Steve now, Akshay?
We have preserved the organs for further study
Still interesting. Let’s see which are the differences between treated and non treated deceased rats. Hopefully you will release a paper detailing death causes in each rat.
Are you going to proceed with a male rat survival test study this?
Thank you for speedy information and for the honesty Akshay.
If these treated rats won’t outlive as dramatically longer as their result of epigenetic age reversal was then all other interventions measured by todays available clocks will be just a waste of time and money I think so. So your experiment will be pretty crucial.
There is a reset of the epigenome to a significantly youthful signature, which should lead rats to a longer life expectancy, of course, if this dramatic results will be maintained. Our biology is so complex and what E5 does, is hacking the factors and proteins that cause progressive age related changes in the activation and repression of genes. I am super optimistic, in fact, I do not see any other intervention today which will extend lifespan as dramatically and maintain youthfulness by regularly hacking the aging process carried by blood plasma. Dying of 1 treated animal does not say anything and does not mean E5 is not able to fully and truly reverse the aging process, even young animals/humans are dying every day due to some natural and artificial effects. Now it’s super interesting 1 died rat to be fully researched, this will give us everything. Before that, I hope we will get some new photos/videos to know how they are looking and how they act.
Thank you Leo, Ines and Nanaka. That’s why we have minimum number of animals in a study as there can be a stray due to random mutation or inherited condition. Remember these are rats if the treated outlive even by a few months on avg that translates to a decade in human years. If they cross their maximum lifespan by a few months it would mean they lived to 135 or 140 years in human age. The treated do seem livelier, have less wrinkles and thinning of fur vs control and they also are much stronger. So healthspan too is improving. When we look at both these benefits of longer lifespan and healthspan and consider that we have had 100% safety record in all studies so far this becomes even more valuable. This is part of research and development it’s just that we are sharing all openly. So we too are learning with every study and continue to improve the potency of E5.
thank you too. But what I said above, if a general ~52% reduction of epigenetic age won’t at least double their lifespan then all the clocks should become just useless. Though I get your positiveness about healthy and strong lifespan, You seem to be pessimistic. May I ask you why? Have you doubts in the theory of blood carried signals causing aging ?
I do not think what Akshay thinks about your comments and pessimism, but as I am aware of, both I and Akshay are on the same position on that, though I think you could be right for the clock concerns. I am extremely optimistic and looking forward to know a new, lifespan study results of E5.
As for the theories, from the latest interview, David Sinclair seems to still strictly promoting his Sirtuin pathway theory of aging. I have highlighted some of the new information revealed in todays podcast. To me, Sinclair is very confused. He thinks aging is programmed and includes 3 pathways:mTOR, AMPK and Sirtuins, also saying NAD production is declining as we age but does not state why! Here is his citation:
“You won’t read a lot of this in textbooks because this is new science, you won’t even read the word x differentiation, that comes out of our work. New idea of aging is there is not just random stuff going wrong, this actually a program that begins at birth what happens during birth and and prior that is the cells gain an identity. We start as a stem that’s fertilized and it gets these cells different identities, brain cells, skin cells, liver cells, everything that makes our body up. The many thousands of different types, 10.000 types actually are given their cell type specificity by turning on different genes out of the same genome. The Epigenome is not as easy to describe as the genome. The genome is just a chemical with four letters, for chemicals that is the instructions but then there is a computer that reads that software called the epigenome or we also use the analogy, the reader of the compact disk that all device we used to fit like 20 songs on. Now we can say instead of 20 songs, there is 20,000 genes and but the reader is the epigenome and over time, by that analogy aging is due to scrap due to scratches on the CD and cannot read the right songs at the right time in a brain cell over time starts to play the music of a liver cell or a skin cell and we get the diseases of the aging including Alzheimer’s.
There are Seven Sirtuin genes in every cell in our body. The brain makes a lot Sirt6 and Sirt1. Overtime the levels of both go down with aging as well as the fuel that those enzymes need called NAD. We focus on Sirt1 mostly because that’s what seems to be the most important for controlling brain aging
let’s talk about the role of Sirtuin‘s when it comes to aging in the brain.
remember this clock is ticking away because the loops in the bundles of DNA are getting messed up the bundles become loops and the loops are becoming bundles. We have linked Sirtuins to that process. What happens when a cell is overstressed, over broken or overdamaged. Sirtuins have two jobs:They have to create those bundles of DNA and make sure the cell has its identity so the genes are read like a proper but when chromosomes break or you crush a cell there is a panic attack and the Sirtuins rush away to help with that stress and repair the broken DNA and find a way back to where they came from and reestablish that structure of the Epigenome.
They do a pretty good job, 99.9% of all of those structures go back to how and where they were but that .1% never goes back and overtime accumulates and these are the scratches the cause aging.”
Exactly Leo I am not dismayed by this death. In studies we calculate the overall average. The current ratio is highly encouraging and if we see the average as well maximum lifespan milestones being crossed we would enter historical territory. Fingers crossed.
Nanaka, each study gives a unique result. There are variables between the study that showed the 54% reversal in age one of which is gender which had been flagged much earlier by us. We are looking at conducting a replication study with male rats but even that can have variance in clock results hopefully by not more than 10% to 20% on either side: meaning it can be lower or higher than last time. There is a big step of dose standardization as part of the development of E5. Only when this is complete will that variance go below 5%. I do believe that E5 platform has the potential to significantly reverse systemic biological age in all mammals regardless of gender but there are many bridges to cross such major therapeutics do not mature overnight as you know. At the same time Harold and I have never hesitated to say that translational from rat to larger mammals including humans is crucial – since the tools we are using are highly conserved we are excited about the prospects but can’t count the chickens until they are hatched. All I can tell you is that there will still be many more highs and lows to come on the path towards making a very powerful prescription medicine that we hope will help hundreds of millions and if possible I would like to take this community of supporters on this journey with us.
I had suggested a hypothesis that aging is the result of a growth gene network transitioning in to a aging gene network at the milestone of puberty and antagonistic pleiotropy is the evidence of such a network.
Infusing young plasma dilutes this aging network and this results in a temporary positive outcome.
An aging gene network will always dominate the growth gene network because it has evolved to sequentially come after the growth network and implement the aging program
What is actually happening is that the growth genes are all there in the old blood, but they are now part of different network and the relationship between them has changed, and the network itself has a different objective, that is to implement the aging program
Kunal that’s one way of putting it but I agree.
Cancer is also similar to aging in the sense that in cancer many genes which are thought to be anti cancer in a normal environment have been found to be assisting cancerous growth.
I was wondering how a bone marrow transplant (stem cells finding their way to the bone marrow) could affect aging in a reasonably healthy elderly person, without leukemia? I found this entry interesting (although these people seem to subscribe to the “aging is caused by damage” school of thought, which Doctor Katcher’s book has convinced me is erroneous thinking):
https://www.fightaging.org/archives/2016/01/temporary-reversal-of-hair-graying-observed-in-stem-cell-transplant-recipients/
Let us suppose for a moment that the benefit due to young plasma is not due to dilution, instead due to the reset of the epigenetic clock. In this case the gene network which existed when we are young changes its behavior due to the event of puberty and some components of the gene network get boosted (as in the case of testosterone), some get inhibited, but the network along with its components essentially remains the same. this network then gradually advances the epigenetic age. In this case the infusion of young plasma would rebalance the the components of the network and the rejuvenation would be systemwide and age would be truly reset to younger profile with a single infusion of plasma. But that does not happen in the numerous experiments till now, and the benefit due to plasma is temporary.
In second case wherein the benefit of young plasma is due to dilution, it can then be hypothesized that some types of cells are refractory to the effect of young plasma and the effect is temporary requiring repeated infusions.
In the paper ‘Epigenetic age is a cell-intrinsic property in transplanted human hematopoietic cells’ aging cell, a two year old child is infused with hematopoietic cells from an aged donor and the infused cells continue to reflect the age of the donor. In a normal two year old the epigenetic age of the hematopoietic cells would be having a steep curve. This shows that the hematopoietic cells are irreversibly transformed at puberty., which is where the curve changes.
There are hundreds of types of cells in the human body, a simple experiment of testing of all these cells in pre pubertal plasma will uncover which types are refractory to young plasma. One can then hypothesize that these refractory cells are the source of the pro aging factors and identify those factors by analyzing the secretome.
I think all these misunderstandings and confusions-Add or Remove can simply be refuted by Tony Wyss-Coray’s latest presentation. I am getting excited when I understand plasma proteins are easily reaching to the brain, especially to the hypothalamus and literally every cell. The word SYSTEMIC is so crucial here. His claiming that plasma proteins are changing in 3 waves during aging is so cool as well.
can you point me to his presentation, thanks
Young plasma should ideally rejuvenate all tissues and cells in one single infusion, since it changes the systemic profile of all the factors present in the blood to a younger state, the fact that the effect is temporary and it requires multiple infusions points to a barrier.
There is evidence that blood cells are refractory to young plasma, there might more types of cells that are refractory to young plasma.
https://youtu.be/D1Qqbz3wb7M
There might be nothing as such to remove, maybe only to be dialed down. Puberty might even not change the balance of the factors in the blood, but by just activating a program in certain types of cells and propagating that program through plasma and to make that program robust enough insulating those certain types of cells to feedback from the plasma.
OR
The aging program is activated system wide at puberty, but as an added insurance certain types of cells are irreversibly transformed to be refractory to feedback from plasma. In this case young plasma reverses age in majority types of cells, but in certain types, which are refractory the program just continues.
We need to discover the region of non coding DNA that gives birth to elements that trigger the various changes leading to the aging phenotype. I do not know it will ever happen, maybe the probability is 1/2 but until that only real biological rejuvenation is to hack the factors carried by blood plasma regularly. Let’s the what happens. Harold is optimistic and thinks it will translate as a rat-human conversion and will take years to see some effects in humans but the treatment frequency will be longer. Akshay is optimistic in a different manner, thinking those factors will have a half life so we would also need to hack it more often, for example once every few months.
If we consider parabiosis effects, after detachment, young circulatory system’s strengthens and opportunities was kept for additional 2 months, but there should be a massive difference between the regular plasma and E5 possibilities. We still need to wait and see.
I like Leo’s reply to Kunal. Besides our studies Tony Wyss Coray from Stanford/Alkahest has shown multiple evidence in his various studies of young blood plasma fractions causing systemwide rejuvenation. Also as Leo mentioned there is an active transcription program running which young plasma components are fighting against. They do rejuvenate successfully we already have evidences but they too have a half life and therefore the changes too will have a life. We will soon find out how long does the effect last. Alkahest/Grifols have human clinical trials in Phase II with young plasma fractions for neurodegenerative diseases. We too hope to have data from larger mammals and humans which will give us dose efficacy curve and ideal time duration of dosing to sustainably maintain the rejuvenation.
Thank you Akshay for your answer. Very much appreciated. I have big hopes we will attain and win.
Another human / rodent Stanford study from 2021, “An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging” had pertinent findings, including:
“Canonical markers of acute infection such as IL-6 and tumor necrosis factor-α were not major contributors to iAge, indicating that, except for IL-1β, infection-driven inflammatory markers of the acute inflammatory response do not contribute to age-related chronic inflammation.”
Their main findings concerned CXCL9, a T-cell chemoattractant induced by IFN-γ, such as:
“We find that CXCL9 is mainly produced by aged endothelium and predicts subclinical levels of cardiovascular aging in nominally healthy individuals.”
Great discussion here. We have all probably been thinking about and referring to the epigenetic (methylation) clock as a monolithic state. What do you think of Levine’s latest preprint that shows evidence of different modules in the clock, not all of which respond to reprogramming? I will link to her Twitter thread, as she makes some important observations. https://twitter.com/DrMorganLevine/status/1493934783356973059
Great paper
It shows that partial reprogramming is going to be tricky. I feel that there is a lot of similarity in the partial Reprogramming approach and the young plasma approach. Both approaches are similar, in the sense they assume that a single intervention will lead to a reset of the systemic age. In fact young plasma itself is a reprogramming medium and a far more robust one.
There is also one more point which needs to considered, that is the epigenetic clock in many tissues and cell types will be the consequence of aging and in some tissues and cell types it will be the causal factor of aging i.e. some cell types maybe driving the program of aging.
Kunal almost all cell types participate in the complex program of aging. Cells like senescent cells do cause acceleration of the deterioration so to that extent they may be ‘drivers’ of aging but the causal factors are higher up. If the repair efficiencies are restored then autophagy would clear out the excess senescent cells. Although it looks daunting at present a system wide reversal of biological age is possible.
Consider this scenario
At age 20, after puberty phase is over and aging has commenced, and the plasma is very young.
A cell from the liver(which has been shown to rejuvenated by young plasma) attempting to change the state of the plasma, because of a program activated within itself. Since this cell itself is responsive to young plasma, which is trying to make the cell young, a feedback loop is formed, where it is virtually impossible for this cell type to contribute to aging.
Consider a different cell type from the immune system, a program activated in this cell type can influence the state of the plasma, because this cell type is refractory to young plasma and therefore it can implement the aging program.
Without certain cell types being refractory to young plasma. it is impossible for the aging program to exist.
Kunal I understand what you are saying and it makes sense but the aging program is multi factorial and global. So almost every cell participates in this program over time. Change is constant from the time any cell is born. Early cycle changes are developmental and post puberty changes involve dialing down slowly our resilience capacity. Blood plasma is used to even out the changes across the body so that one finger is not older than the other or one leg is not older than one hand.
Thanks for all your comments, Akshay. “Blood plasma is used to even out the changes across the body so that one finger is not older than the other”
This is a great point that isn’t highlighted enough in arguments against “damage” theory proponents. When hair starts to turn grey, it’s usually symmetric on both sides of the body. In fact the following study showed that hairs centimeters apart cycle between grey and dark synchronously, implicating blood factors. https://elifesciences.org/articles/67437
Akshay could 19% (less than other tissues) rejuvenation of hypothalamus be explained by the fact that the brain is aging far slower? Maybe as aged the tissue the more rejuvenation (like the liver by about 80%)? Any idea?
Nanaka yes as the Barnes maze memory test results showed remarkable improvement so the rejuvenation does occur. Epigenetically the brain is quite different organ then all others. So it has its own unique methylation trajectory.
hello Akshay. I read above comments of yours and Leo on the limited range bound role of microbiome and lifestyle factors on aging process. Does it mean we can not do anything to slow down this transcription made changes and composition of signals by for example supplementation and lifestyle? Could you recommend anything for that?
Thanks.
Hi Nanaka, even though lifestyle factors give a limited range of benefits we must make good use of them to slow down rate of aging. Nature has installed cheat codes to incentivize productivity and reproduction for the survival of the species. So Nature wants to extend the life of a member of the species that is hunting/gathering more or us actively reproducing. In the modern world we do not hunt but exercise would be equated to that and we will get a booster dose of repair and renewal as a reward. Until we have available a tool to significantly bring back repair efficiencies we should include beneficial lifestyle activities. Microbiome is an interesting co-passenger in our life journey. There an estimated 38 trillion of them in us. Ten times more viruses too are there. One task we know of the latter is that they produce phases to keep bacteria in check. Bacteria developed intelligent gene editing machinery to protect itself from these phases which we now co-opted as CRISPR. We have underestimated the major role they play in our health. For example 95% of serotonin a very important neurotransmitter is produced via the gut brain axis! There are probably 2 to 3 times more exogenous RNA (not secreted by our cells) circulating in plasma then from our own cells. So we must research to find out all methods to improve our beneficial microbiome and viriome.
Nanaka I meant ‘phages’ as in bacteriophages and not ‘phases’ in my reply – autocorrect made that error 🙂
Thanks a lot for your explanations, I appreciate. So taking an Nad precursors and AKG and etc are pretty useful as I understand, Right? Even though its ability to extend mice lifespan for 10-15%.
Nanaka supplements can help but majority of them do not reach cells or are absorbed by cells. Dr. Alan Green prescribes rapamycin and that seems to show some beneficial response. From other supplements any animal or especially human double blind placebo trial confirming cellular uptake would be the one to consider.
Hi Akshay) Any of your new comments is a true reward to my passion of Nature intended, thank you. Too interesting. By the way, Georgia is the only post Soviet country still using a phage therapy. It’s extraordinarily effective and for those knowing its power, will never use the most horrible antibiotics.
I have successfully reversed super dangerous condition in an intact female dogs-pyometra with the help of phages and it was the only intervention which stopped the irregular and heavy bleeding on the second day.
Leo using phage therapy on pet bacterial infection successfully would make you a leading veterinarian. Congratulations. You should investigate launching a company to develop phage therapeutics for the veterinarian market.
Thank you, your words mean so much to me! 😉
@Akshay
I have over a decade of first-hand experience of a hunter/gatherer lifestyle while living off the grid and land in the 90ties and early 2000s in Canada’s Yukon Territory (over 80% of it is pristine wilderness, and Moose still outnumber humans by far).
I can assure you that physical exercise in this context is way more different than going to a gym. Just imagine, cutting 15 cords of firewood with hand tools each year to survive the harsh 6 months of winter with temperatures below -50 degrees Celsius. Or hunting, field dressing and butchering a Moose.
While I had to give up this lifestyle for family reasons, now in my late 60ties, I’m close to going back for good.
I practice resistance exercise five times a week, hike on average 250 km a month and do daily intermittent 18:6 fasting. Once a year, I have a medical checkup and blood test. My doctor still says: “You are a very healthy man, keep doing whatever you are doing.”
There are so many things I would like to share, but most of you might not bother.
My question for you: NAD+ and Glutathione levels decrease with age, but is it due to aging? Or can it be that it is due to constant abuse of our body with food that has not much in common with what our pre-historic ancestors were consuming and low level of physical activities?
Elders of hunter/gather tribes, which still exist, might have the answer.
‘ Blood plasma is used to even out the changes across the body’
I completely agree, without that there is no synchronized aging. The cell types which are responding to young plasma also contribute to aging with their signaling. But to implement the aging program, which is progressive in nature, cell types refractory to the anti aging factors in the plasma are essential.
Nick our intervention too shows variance in reversal of epigenetic changes caused by aging. We have found tissue specific responses. But this Prof Horvath has already shown in his many papers. Even in ours. He has developed an accurate pan tissue clock though. The variable response has to do with various factors including coverage, surface proteins with specific targets, miRNA transcription, etc.
One obvious difference between the brain and the rest of the body is that brain cells don’t like to burn fats. Hence starvation causing the rest of the body to burn fats, whilst gluconeogenesis ramps up for the brain. This would imply a lower ROS level in the mitochondria of the brain compared to the rest of the body. From this we would expect less cycles of DNA damage and repair followed by remethylation via DNMTs (and then demethylation ‘clean up’ via TETs) in the brain compared to the body. This is a possibly explanation for why the brain ages slower, at least according to these methylation clocks.
I will give an explanation for why the aging program always gets started: there are two clocks, telomere and methylation. If your (stem cells’) telomeres never shorten, you get selection over time (via random methylation of promoters) for stem cells that don’t differentiate. These Selfish, immortal stem cells come to dominant their stem cell niche and leave the rest of the body to rot. But if you maintain proper methylation patterns, then stem cells continue to function and supply the body, but exhaust their telomeres. Either way you are cooked.
Interesting.
Mark, in your opinion, what strategies might work to force stem cells to differentiate normally, once they become aberrant?
Akshay, do you (or any of those following you) have a lifespan curve for your current study? It would be useful to see how old each rat is as it dies. Thanks.
That’s what I want, why can’t we have their epi age for now? We have to wait to die?
Yes I was going to request Josh to make that for us.
Just a silly thought. But if tests were started on dogs. What about ex racing greyhounds that may have measured speeds from earlier racing. This could prove a definitive on seeing if speed is restored. Forgive me if too silly for words.
Lol, speeds? It’s not superhuman thing, it won’t give you wings to fly. And grip strength is the least thing needed to be proved, it’s extraordinarily higher in treated rats already than control.
Derek it’s not silly idea at all. I love race horses and have a very similar plan to test on retired race horses to see if they can compete again. As a priority it is low as our focus for the next few years will be trials that are needed for regulatory approval but sometime in future when sufficient funding is there I would like to conduct this trial.
I fully agree with Akshay, legs and ageing brain are deeply connected, here you can check, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789972/#:~:text=Leg%20power%20predicts%20both%20cognitive,goal%20of%20healthy%20cognitive%20ageing.
I was trying to dive in Morgan Levine papers on aging clock and partial reversal while my mind keep going back to the Ucraine war we have so close in Europe, apparently driven by the will of one single dictator, most of Russians I’ve talked to are wildly against it. My question today is philosophical: If E5 (or any other recipe) are to suceed and extend significantly lifespan, sooner or later and unfortunately the richest first, will have acces to this source of life.
Can you imagine a more distopic future than some elite in certain countries (the ones which are not against the war right now) being able to enlarge time in power by not getting old?
That’s a super counterproductive question. As from a neighbor country to Russia and Ukraine, already felt the same hell in 2008 by Putin’s Russia, I can make you sure their psychology is different. For example, they will die in a war for mother Russia, mother homeland, no matter how many billions their net worth are. Elon Musk is another example. In December, he mentioned in his interview:
I’m not actually a huge proponent of longevity. I mean I do think that having a good life for longer is better. You’d want to address the things that happen to you when you’re older, like dementia and so forth. Those are pretty important, but I’m not sure it’s actually – that I want to do that, get into the genetics thing, but I do think it’s going to fundamentally change humanity, along with AI.
Sorkin: You don’t want to live forever so that you can actually get to Mars?
Musk: No, I definitely don’t want to live forever.
Sorkin: How many years do you want to live?
Musk: I don’t know, a hundred good ones.
Sorkin: A hundred good ones or a hundred more good ones? You’re 44?
Musk: I mean I think a hundred good ones in total is probably fine. Maybe a bit longer.
I find most of the “immortalist”, hundreds of years living people in some anti-aging groups, presenting a low or moderate income families, not definitely in a billionaire elites. Though I know Putin has been taking Khavinson’s peptides but not sure that’s true.
Well, the philosophical question is still there. Because Putin is obsessed with youth and strength and therefore shows stripped every summer, trains a couple of hours everyday, uses botox and plastic surgery and on the top of it, he has no intention to leave power. If he could use a longevity medecine, he would.
And having a bunch of russians in my surroundings, I am not that sure that once they’ve known the EU and its modus vivendi, they want to die for motherland. They’re proud of it, but a big lot detest the corruption, the politics and the repression. And therefore they have moved. Sad but true.
Alright, let me ask you this: Given your concerns, where do you draw the line then? At what level of ‘evil’ do we refuse treatment for a person? And how exactly would that be enforced? 😉
Look, the bottomline is that every medical or technological advancement in human history has and always will be available to everyone, the saints, us normies, and evil bastards alike. Plus also consider this – IF Putin gets to live to 150 years, then most likely many of his fervent opponents will also be able to add many years to their lives. So in the end it all evens out and history will take its course, perhaps in the way you have hoped or maybe to the contrary.
Which brings me to the very core of the issue, which boils down to eternal human strive and struggle. Enhancing the length and quality of human life does not exempt us from either, meaning we still have to fight our battles and live up to our own aspirations. Otherwise it’s just more years that are being wasted. In that case we may be better off to make space for a new generation of people who live their lives with true passion and purpose.
As the saying goes (and quoting this may be almost heretic in this forum): It’s not the years in your life, it’s the life in your years 😉
You’re absolutely right, Michael, everything that science produces in order to improve life should be available to the whole human kind. And none of us can decide who is worth and who not. In fact it is just totalitary regimes who stick to such kind of thinking, and no one can decide who can live or not. I think I am so overwhelmed by the conflict that I couldn’t help thinking that once longevity resources are available, in some countries like Russia, just a tiny elite will reach them. Their situation is so desperate right now (and much before the conflict it was too), that it is hard to understand for me how a culture that has produced such amount of good science (Irina Conboy is russian!), tremedous art and literature, and great intellectual achievements, simply cannot get rid of tyrants and is engulfed in perpetual poverty. While that corrupt elite can enjoy and reach anything.
I was simplifying a lot and being naïf, Michael, and I share your point.
This one goes for Akshay and our beloved rats:
Nature has just released a very interesting paper according to which FSH blockage improves cognition in Alzheimer model mice.
https://www.nature.com/articles/s41586-022-04463-0
Great, because high FSH produces fat accumulation, loss of bone, and it can be considered a proaging factor. The rats in the trial sure they have skyrocket FSH, and it was not lowered by E5 (estradiol and inhibin counteract FSH ). FSH is very low in infants, and in women (and men) increases with age, since they reach puberty. In women having a tremendous pick more that 10 times its presence after the reporductive period.
Do you think FSH has been contraproducent for E5?
I have been coming across your comments and sorry but you seem to be over stressed and just taken by overthinking. Researching and science is good but too much of it especially if your not doing
any study and just in field can even have bad impact on health span and lifespan too, simply by spending too much hours looking at blue light and EMM exposure.
Ines we don’t know yet what changes E5 made to female rat hormone levels. Harold has been studying this quite a lot over the last 2 months and will soon conduct various tests to find out more. The kits have already arrived. FSH is one of the hormones which changes significantly after menopause. One consideration to keep in mind is that the female rats were 24 months when the study began. Menopause for them is much earlier around the 12th month. We are launching a study with equal number of male and female rats that are 18 month old the same age of our last male study. So I would think in the next few months we should learn a lot more about gender variances and whether we do need two versions of E5 based on gender.
As quick and kind as always, Akshay, many thanks for your answer and for your balanced gender equity experiment. For ages females/women have been excluded as subjects of test. Every scientist that changes this makes me(us) happy.
A stunning paper has been published in Nature by Dr. Izpisua Belmonte and Genentech:
https://www.nature.com/articles/s43587-022-00183-2
This result has multiple implications for Altos (and other aging science biotechs) due to involvement of a major biotech/pharma player Genentech/Roche, for safety of long term partial reprogramming and timeline by which we can now expect reversal of biological age as an available treatment. What is also interesting is the finding that duration of treatment determined the extent of beneficial effects. They did not find cancers in the mice treated for 7 months and 10 months which is remarkable finding for safety.
Thanks Akshay. Dr Izpisua Belmonte besides of a great scientist is a great person, and one who had to overcome many hurdles (poverty in childhood, being rised by a mother with three kids and extremely scarce resources) to become the brilliant researcher he is. The fact that mice did not show tumors when they are so prone to them in old age anyway is amazing. I will take time to read this. Kind regards.
Ines I already was a great admirer of his work but now after learning about his early struggles it highlights his achievements even more. Thanks for sharing that.
It’s a huge step if the treatment seems to not causing some nasty teratomas, even if used the 4th, c-Myc factor, since Sinclair believes OSK are safe, M is the cancer causing one.
Despite the fact people are astonished, I still remain skeptical of a different kind of reasons. Firstly, the treatment restores a youthful epigenetic signature to aging cells and extends the life span of a premature aging mouse model, but the effects of longer-term partial reprogramming in physiologically aging wild-type mice are yet unknown. Then, despite the fact I stand with Harold’s thoughts about the shortening of telomeres as a cause of aging, people still believe and consider it as one of the hallmarks of “cellular aging”. Even if so, while full reprogramming extends telomeres, no such effect was observed in the case of partial reprogramming. Second, only 25% of the cells were successfully reprogrammed to the maturation stage. 35% failed to reach it, while for the rest, the results were inconclusive. This might signal a limit for partial reprogramming. Even if considering the latest, MPTR technology, which lowers cellular age about three times more than previous partial reprogramming techniques, still plenty of downsides can be found here. So not only the engineering needs to be very precise but the stability must remain for a long time to be considered safe. I think the word SYSTEMIC is so pivotal and determining here. One does not want his liver to be 80% younger but the brain, intestines or other parts of the body to remain as an older. Of course, if we are talking about the claiming for extending the lifespan dramatically and/or keeping
the youthful phenotype by regularly battling with the constant and ongoing program inserted into us. Otherwise, Y factors can be refined appropriately to at least treat the blindness or other types of diseases needing some electrical signals to be restored.
Very insightful analysis Leo.
I think people over 100 will act less childishly than Putin – doing what he can get away with regardless of impact on others
Akshay,
Congratulations on the partnership with Johns Hopkins. Can you share what aspects of E5 they are specifically interested in: ageing in general, or specific disease indications? Who’s lab will you be working in? Did they recreate Dr. Katcher’s test results before making the partnership decision?
Thanks,
Rick
Rick thank you. We are bound by confidentiality.
Wow, that’s a serious vote of confidence for E5 if Johns Hopkins will be partnering with you guys, congratulations!
Akshay, any idea when the official website go up for Neel gel?
Any idea when the Gel will ship??
David we hope to ship in 1st week of April. For every bottle ordered we will be sending a complimentary 30ml bottle during our main launch on Amazon as a small thank you for your patience 🙏
In future too we will not be forgetting our early supporters. We have made a list of all those who pre-ordered and they will get another nice surprise during Christmas.
Hi Dan USPTO rejected our trademark application for NEEL. On the advice of our trademark attorney we are appealing. But I hope we can launch the main website in 2 to 3 months.
That’s too bad they rejected it, Akshay. Does that mean there’s already another product with the same name?
They rejected because of a brand call Neil. But how both are pronounced are slightly different as NEEL has a longer hold like NEEEL whereas Neil would be shorter. Also wide difference in meaning. Ours is a Sanskrit word for blue that is powerful. Plus the other one is not widely used. So let’s see.
Just make it fancy and exotic by adding the French “Le” : “Le NEEL”. As everyone knows all the really good skin care comes from France (j/k). Seriously though, if “Neil” and “O’Neill” can co-exist as separate unique trademarks then there ought to be no problem with “Le NEEL”.
Plus this would amuse me as my last name is composed of those two sounds, though in reversed order, like the famous hockey player “Cam Neely”.
Akshay,
Will there be a formal press release from Johns Hopkins about this partnership?
Are your plans for dog/cat and human clinical trials still on, or have these plans been superseded by the Johns Hopkins partnership?
Thanks,
Rick
Rick as a biotech our path towards prescription therapeutics becoming available can not be undertaken without all of those trials. JHU will accelerate our progress on that path. Over the next few years we will be conducting so many trials.
Akshay,
Very interesting non answer. My concern is how much of your effort will be locked up behind the JH nondisclosure agreement. If all of your effort is behind this wall, the result is that you will be going dark, with your current followers not knowing what you are working on much less any progress.
There are many advantages to a partnership with JH, including funding, labs, manpower and expertise. However, there are potential disadvantages. JH comes with big institution bureaucracy and an industry standard approach to new drug development. If all of your effort is tied to JH, that could relegate E5 to a 20 year development cycle. I was hoping that you still had some development programs outside of the JH agreement that could provide a faster track.
I do not want to interfere instead of Akshay, but has not he said their collaboration is bound by confidentiality? If not him, who is more transparent today? Altos? Sinclair lab? It’s just too pity not to see, underline and appreciate all the effort he is investing in it along with the other board members.
Rick I see your concern but let me assure you nothing changes our momentum to try to achieve human trials next year – which in biotech terms would be considered fast. JHU team is only going to help us accelerate towards achieving our goals- opposite of your concern. I want you to trust me on this. We are working with them only on specific projects needed in E5 development that we can’t do on our own without the labs and skills.
Akshay,
Thank you, that is very encouraging news. I look forward to new updates and supporting you in the future.
:”My concern is how much of your effort will be locked up behind the JH nondisclosure agreement. If all of your effort is behind this wall, the result is that you will be going dark, with your current followers not knowing what you are working on much less any progress.”
Two weeks since the Johns Hopkins announcement, and no further comments. Is Mr Davis’ worry about your effort “going dark” a real concern?
SEE AT BOTTOM REGARDING “NEEL” UPDATE
Yuvan updates posted by:
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Updates about Yuvan Research
Yuvan and Johns Hopkins University establish a partnership
“We are happy to announce a research collaboration agreement with Johns Hopkins University, one of the most reputed Universities in the world of medicine”, stated Akshay Sanghavi, CEO of Yuvan. He added that “at JHU we hope to progress E5 from a crude biologic to a potent therapeutic with standardized doses. We have already mapped out our first year’s research work with their brilliant team and amazing lab equipment.”
New E5 study
To further understand the effects of E5, Yuvan is starting a new study that will be conducted in rats of both sexes and 18 months of age — the starting age of the male rats in the study published in May 2020 in bioRxiv. In this new study, it will be possible to clarify whether there are differences between the effectiveness of E5 in females and males.
Lifespan study
Regarding the lifespan study, the first death of a treated rat has occurred, so to date 3 untreated rats and 1 treated rat have died. Initially, there were 8 rats in each group.
!!!!!!!!!!!!!!!!
NEEL gel
According to Sanghavi, “We are scheduled to go into production on the 14th of March due to raw material supply issues, so after batch testing and bottling, the orders should be shipped by the first week of April. We truly appreciate our customers’ patience and will gift them a complimentary 30 ml bottle of NEEL gel for each bottle they purchased in return for their kindness and support.”
!!!!!!!!!!!!!!!!!
The information in this newsletter was provided by Yuvan Research.
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Akshay, how is the E5 production progressing?
Robert so far the production has been for rats. From the various rat trials we are discovering various nuances of E5. Based on the learnings we continue to do research to improve it. Currently it is a crude biologic. The work we plan to do this year with assistance from skilled experts and equipment will move it towards becoming a potent therapeutic with standardized dose.
Akshay, would you be able to provide any update on the trial. The lifespan curve on the most recent liveforever.club blog post appears to reflect the death of a treated rat. Is that accurate?
I find it fascinating that the rats in the Goya young plasma (not fraction) trial had all died by 36 months, both control and treated, younger than the current Katcher trial rats. I believe both strains were the same, and both used females.
Does maximal age differ between colonies of the same strain that dramatically, or is something else going on?
Hi Akshay,
I have another Neel related question…I’m wondering if there’s any risk of copper toxicity with the gel or the patch?
Dan GHKcu has been extensively studied for over four decades and its safety and biological effects has been confirmed in cell, tissue and animal studies. Even at levels hundreds of times greater than present in the body it wasn’t found to be toxic. What permeates across skin is quite low. Unless one took injections of very high doses repeatedly it should not result in any toxicity. Ideally it should not be applied with any other skin cream like retinol.
Hi everyone. So the rat should be 39 months for now longer than their lifespan. Are all untreated still alive?
Nanaka 7 out of 8 treated are alive
So control group is no longer alive?
A few of the controls are still alive.
Thank you Akshay, as always. It will be interesting to compare the median lifespan. Despite of the bond you have the JHU, will the study sponsored by Didier Cournelle be published anyway? I understand you cannot share information like you’ve been doing till now (I am amazed to be able to have a glimpse of this research through you, Akshay), but it would be great to have a summary of the current thing in summer, the results may be really significant then. How are the treated rats doing cognitively? Compared to the untreated, I mean. AD is much more feminine than masculine, I am afreid.
All the best
Thank you Ines. The Didier study will be published. We noticed they are doing much better on grip strength. We checked hormones and unfortunately did not find any trend. Memory test wasn’t done recently. Can be requested.
Hi Akshay, what does this mean? So some hormone producing organs are not rejuvenated or other things have to be done? May I ask you what are your plans? Thanks.
Thank you Akshay for the information and for highlighting the hormonal issue, which is of my interest. It is interesting because I have the feeling the ovary is key in the different response among male and female. But I think at same time it is not a complicated hurdle to overcome. Women in early menopause have hard times unless they use HRT, and in fact their epigenetic clock clicks faster and all issues related to old age come sooner. But awakening ovaries might be not as complicated as once thought. I think menopause is to ovaries and postreproductive period what an epifisis closing is to a bone concerning the FSH and the HGH respectively. We don’t grow our bones once we’ve reached reproductive period, no mather how much HGH we use.
With the difference that we don’t know how to reopen an epifisis, but regenerating/restoring ovarian function has been done quite easily with substaces as different as prp, bone marrow stem cells, and embyonic extracelular vesicles, and to me the most promisin IPSC withput long term teratomas, by KM Elias. The response of all those is better the younger the organism is, but there E5 might play a role, as i improves the organismic environment. It has an enormous market, as menopause is like taxes, it will reach every woman after a time. And it improves no one life.
It would be super interesting to follow the next studies with both sex rats, but I guess we cannot ask for further details.
Anyhow my gratitude for your attention and your kindness Akshay.
Hi Nanaka, Ines has given a very good reply. Harold has constructed a study involving ovarian transplant along with E5 and he will conduct this experiment this year. He is also flying to our Mumbai lab to further investigate and improve E5 for females. We won’t accept partial results for females. We will persevere till we resolve the issue. If that requires a separate version/protocol then so be it.
Thanks Akshay this is so important. Do treated rats still look alive and younger like we all seen on the video after 4th dose? It was a big difference between T and C. I think it is the most important if they still remain young phenotype.
Nanaka I can see them looking older and the inflammatory cytokine gap seems to be narrowing but somehow their grip strength continues to remain quite superior to control rats. There are caveats to this study though – we started very late – and our female E5 is not optimized – so we can expect to do much better in subsequent studies.
Another lifespan study on NAD+ by Mayo Clinic out on 5th April shows an increase only in male mice and not females. There needs to be much more gender related research.
Akshay, I guess you are taking about the inhibition of the enzyme CD38, right? That’s interesting, but there are also molecules and studies where females are benefiting significantly and the results are highly sex-specific, for example, Alpha Ketoglutarate, seemed to be more effective in females than in males. Generally, women live longer than men, consistent with lower biological ages as assessed by molecular biomarkers, but there is a paradox. Women are frailer and have worse health at the end of life. While men still perform better on physical function examinations, women outlive men. The survival benefit in women is also seen across nonhuman mammals, where some species present a greater median difference in lifespan than humans, although aging rates are similar across sexes.
There is no doubt about the importance of sex chromosomes in the biology of aging, and the effects may be more pronounced due to increased genomic instability as we age. this theory fits well with the programmed aging theory that everything is set in the genes. For the sex differences in aging, likely, X and Y chromosomal effects do not explain the full range of the biological differences, and other sex-specific genetic factors may contribute to the programmed theory of aging. For example, mitochondrial inheritance takes place through the maternal line and women have a survival advantage already in utero, although the latter could be driven by hormonal factors as well, which we describe next.
Sex specific interventions are too interesting, but as Akshay said, something combating aging as a class, systematically, real rejuvenation should be the same in both sexes and conserved across most of the mammalian species. I have big hopes Harold will solve this soon. Also it’s interesting to see if
It is due to the programmed menopause and therefore, hormone depriving or other mechanisms are Involved. Since we have seen some kind of hypothalamus rejuvenation( roughly 19%) in the previous Elixir study, and since the hypothalamus regulates hormonal release from the gonads through the pituitary in response to different stimuli, it still should have had some effect on hormones in female rats. Too complicated… ))
Thank ypu Akshay I strongly agree with you. Gender research should be compulsory in any trial.
Leo, hypothalamus-hypophisis-gonads Axis for estradiol and progesterone production, depends in healthy female individuals mainly on the gonads, so the ovaries. If you transplant an ovary (it has been done in identical twin sisters one of them menopausal b, cancer tratment) or improve ovarian environment so the once menopausal ovary regains function to a extent (done with several tecniques even in human models) the hypothalamus wont superstimulate the hypophisis and the second one won’t secrete the tons of fsh and lh that it does once menopause/ovarian failure has arrived. If the ovarian tissue responds adecuately, so developing antral follicles that will produce Estradiol formerly (this estradiol will reduce the fsh production) and PRG later, after ovulation, the hipothalamus does not have to work that hard. So it is not a matter of hypothalamus rejuvenation (even so, a 19% of rejuvenation seems not a despicable one to me)
So after puberty it is mainly the functioning ovary that prevents the fsh/lh from being up to the moon, and hypothalamus and hypophysis of producing the ovulation hormones. During menopause and after, the body tries to ovulate, all tthtime, but the ovarian tissue is not responding, and this has consequences as high fsh has really undesirable effects.
I thing aging has severals locks/dams in especific tissues. Adrenal gland could be another one, Our DHEA diminishes steadily during aging. Would be interesting to check that hormone in both males and females after E5. TSH tends to rise as well as thyroid finction declines and t4/t3 production are suboptimal.
And so on.
If grip strenght is conserved and improved, as Akshay told, can be a signal of an improved HGH secretion (we need that to build lean mass not to lose grip strength).
I don’t think there has to be an universal solution for both males and females or just an unique intervention. After all mother nature wants us to die in the last term, so our offspring has more place, And therefore has provided several mechanisms in a programmed aging. Why not set some locks in some organs?
In males hypothalamus improved 19% epigenetically I am impressed. In females ovaries improved 0%. I am intrigued as Dr Izpisua belmonte pointed out, menopause depends on two gene’s epigenetic expressions than regulate oxidative stress in ovary.
In mammals males tend to be able to reproduce through all life unless they are touching decrepitude, as for them it is cost effective. They just release some sperm in the adequate place and they have the chance to conceive. So if they are old and receive a shot of signaling/E5, thay may feel great again and improve their testosterone, the chance is worth it.
For females it is not that simple, they need to be fit to carry the offspring AND to nurture and take care of it. Which is really expensive in biological terms. Requires of certain phisical and physiological conditions. In social mammals females are very valuable (as Carl Safina explanes not only good science, but beatiful writting) , and they are valuable because they carry experience, knowledge, and are the ones to transmit culture (Safina is an etologist). Much more than males. So it would be worth to have them alive for the group, concentrated in the group, and not in own offspring. After all mother nature cares for the species. So it invented extended post reproductive period for just some mammals.Yes, this gender condition that arises reproductive hurdles in women and in some whales, does not affect ANY OTHER primate. Just us. So no biologial imperative, exception. Althought a heavy one, Other female species as longlived as us are much fitter than us five year prior their death.
In the rest of mammals the postreproductive period is much shorter. So I am looking forward the experiment Harold has programmed.
I do not know what the E5 is, I simply believe in Harold and Akshay, I am sure they will solve it soon. I can not agree with you regarding the universal mechanism conserved across almost all species and in both sexes is not important.
I do not think we are simply a mechanism assembled in parts and we need to address ovarian aging, brain aging, muscle aging separately. We need to do it as a class, we need an antibiotic class
to aging and until we have opportunity to discovering the region of non coding DNA that gives birth to elements that trigger the various changes that lead to the aging phenotype, I consider hacking the factors and proteins that cause progressive age related changes in the activation and repression of genes and replace them with factors and proteins either from a young environment or removing sole negative ones stopping us repairing, the only solution. This will change the gene expression signature back to what it was in youth and hopefully, lead us to rejuvenation. I am sure Harold is able to have a gender specific version based on the same principle. As Akshay said, E5 is still a crude biology, needing some perfectionism, which will happen by this team, I am 100% sure.
I also can not agree that menopause should be considered as one of the most important phenomenas. For example, dogs do menstruate till the last day of their lives. I myself bred 12-year-old female Labrador for the first time and go a perfect litter. In addition to that, spaying dogs after their development, let’s say 1.5-2 years, does not affect their lifespan nor healthspan. I think human biology is one of the difficult and strange ones.
Mammals developed an elegant mathematical program in which life span is maintained at a relatively short, but just long enough to try out new traits and also reproduce. An essential part of the program includes pruning or removal of old animals which don’t have the new traits. This also makes room for the new generation to have space to thrive without competing with older bigger more robust members. You can see proof that this works in computer programs and also in the fact that after the extinction of the dinosaurs, 66 mya, mammals had extraordinary success in taking over the land.
The consequence of the program which led to such great success of terrestrial mammals is humans have a programmed life span of about 38 years. We can manage to outlive our programmed lifespan of 38 years. but not without decades of increasing senescence. However, programmed aging requires genetic programs to drive aging. Anti-aging medicine is about the identification of druggable targets and then treatment to reduce the action of these programs driving aging.
Earth is a very challenging planet for living things. 98% of species that ever lived have become extinct. There have been 5 mass extinctions since 440 million years ago. The Ordovician extinction 440 mya wiped out 85% of species. Late Devonian extinction 360 mya, 75% species extinct. Permian Triassic extinction 253 mya, called the great dying, extinction of 96% marine life and 70% terrestrial life. Triassic-Jurassic extinction 200 mya, 80 % of species extinct. The K-Pg extinction, 66 mya, known as the day the dinosaurs died, extinction of 75% of species. There have been times when Earth very hot and times when ice covered most of the planet Times when food sources were wiped out and periods of intense volcanoes. Predators and prey can evolve and there is the threat of disease.
In view of these mass extinctions, it is peculiar that aging theory is all about how animals should focus on longer lifespan as opposed to how animals should try to avoid extinction. The best way to meet the challenges is to evolve new traits to adapt. Understanding the best way to evolve new traits involves mathematical reasoning.
Animals almost always continue to reproduce until they die. There are just three exceptions that we know of: humans, short-finned pilot whales, and killer whales. In all three species, females lose the ability to have children, but continue living for decades after. That’s menopause. Female killer whales go through in their 30s or 40s. Why? Why sacrifice so many future chances to pass on your genes to the next generation?
One of the most compelling explanations is called the grandmother hypothesis. Proposed in 1966, it suggests that older females forgo the option to bear more children so they can support their existing ones. By helping their children and grandchildren to survive and thrive, they still ensure that their genes cascade down the generations.
Thanks Leo, In short, I agree with some of your points and not with others.
I don’t know whether I have not been clear about menopause, it is a phenomenon happening only in human, narwal, beluga, orca and pilot whales and postreproductive period in other mammals is much shorterf, some times it takes a year, and it is a consequence of decrepitude, but you and me are basically saying the same there.
Human bodies are not programmed to live till 38 age in the wild. We’ve found stone age people aged well beyond 60. And they reached that age because they were fit. You just have to look at Africa in XVII to XIX centuries. Or Yanomami tribes they were living in stone age. And despite so there where 70 plus year old individuals. A good bunch of them. No doctors nor hospitals then. Lots of physical activity.
I have not said there is not an age programming. The body works at an organismic level. There is a program. Epigenetics show a bit of that as its progresssion shows a pattern. What I have said is that there may be some locks. That nature imposed some locks to make sure we don’t go back despite the programming, or just for evolutionary reasons.
If you don’t believe that, try to open the epiphisis in the femur or somewhere else. Try to grow in heigh at 50.years old. Growing is part of the aging program. Epiphisis closing is a lock.
When you say “I also can not agree that menopause should be considered as one of the most important phenomenas.”, it is obvious that you are a man. For women, believe me, this is important. It is a cliff. It is the on set of beginning of heart failure, dislipemia, diabetes, osteoporosis, AD, and many other hallmarks of ageing.
The grandma theory fits some whales, but not some others, and does not fit human completely, as giving birth can start at 15 or before. And endure well into the 40s, even in primitive societies with (a very loved auntie of mine reached menopause at 59. Many kids in that family there). But concerning whales I think that Safina is the author to check.
Your contributions are always interesting Leo. Many thanks.
But I am really happy that Harold has prepared experiments that concern ovarian transplantation for old rats.
Obviously the first bioarxiv paper released showed spectacular results concerning citokines and epigenetic markers. And those were not achieved in female rats trial. Harold just has pointed what may be a lock for females.
And both Akshay and Harold are heroes because they are going to perform both sex/gender trials. Such a thing is an exception in the developing of any pharmacological product. Male models are used mainly.
And this alone deserves my admiration and the gratitude of half of planet population. The half that science has very often ignored.
Thanks again Leo, it was an interesting exchange, kind regards.
Thanks Inès, please, do not think I said menopause is not important from a human being standpoint. I just say, I consider aging as the conserved, nature “inserted” program and it should be treated with the same mechanism in both sexes, though a gender specific version should be fascinating and once again, applauses and acclaims for their passionately inspired works. As for the DNA methylation of 38 years of early humans-
New Report: “New study shows an animal’s lifespan is written in the DNA. For humans, it is 38 years”. (12/12/19) [Paper a year old; but I just saw it and it has huge significance; ASG 1/23/22]
When looked at complete genome of large number other other vertebrates, the DNA methylation lifetime predictor says maximum human lifespan should be 38 years.
“A genomic predictor of lifespan in vertebrates, Mayne, Scientific Reports. 2019
They looked at epigenetic changes in DNA methylation(DNAm). “DNAm of cytosine-phosphate-guanosine (CpG) sites. DNAm of CpG sites, involves a covalent modification of cytosine to form 5-methylcytosine. This has potential to regulate gene expression, including genes critical for longevity, without altering the underlying sequence.”
Summary: “Aging is associated with epigenetic changes involving DNA methylation. Furthermore, an analysis of mammals showed that the density of CpG sites in gene promoters, which are targets for DNA methylation, is correlated with lifespan. Using 252 whole genomes and databases of animal lifespan and promotor sequences, we show a pattern across vertebrates. We also derive a predictive clock based on CpG density…The lifespan clock accurately predicts LIFESPAN in VERTEBRATES.”
Results: Early humans, Neanderthals, Denisovans 38 years.
Rougheye fish 205
Bowhead whale 211.
Chimp 40 years.
Humans: 38 years.
According to our DNA, the maximum lifespan of humans should be 38 years.
It is very chilling to read that based upon DNA epigenetic clock, humans would be expected to have a maximum lifespan of 38 years.
As some programmed theory believer scientists suggest and I do agree, that humans have modified the program and turned dying into senescence. I think the DNA study explains why humans have a very long period of senescence.
After age 38, We are living on borrowed time.
In view of these mass extinctions, it is peculiar that aging theory is all about how animals should focus on longer lifespan as opposed to how animals should try to avoid extinction. The best way to meet the challenges is to evolve new traits to adapt. Understanding the best way to evolve new traits involves mathematical reasoning.
A mouse has a gestation period of 19-21 days. A female mouse gets pregnant about 5 to 10 times each year and can give birth to a litter of 3-14 pups.
If you think of evolution in terms of what happens with 50,000 individuals in 10,000 generations as regards best ability to evolve traits and you have very good mathematical intuition, you start to see the value of a short lifespan versus a long lifespan.
One reason to remove older individuals is they have already bred and introduced their genes into the evolving gene pool. The old individuals are removed to make room for the new generation which may have favorable mutations.
Note that none of this is being done for the benefit of an individual mouse who is programmed to have a short life. It is being done for “the greater good”.
An estimate is that there are 20 Billion mice in the world.
A totally different plan is used for many fish is negligible senescence. Chronologically old fish are frequently more valuable because they have grown big enough to avoid predators. For a Rough eye Rockfish, a good plan is just keep growing, become more fertile the older you get, and lay a million eggs a year when over 200 years old.
An estimate is there are 3500 Billion fish in ocean. In the ocean, the best plan is negligible senescence; but for terrestrial animals, senescence is generally best. The best evidence is that negligible senescent fish dominant the water and senescent mammals and senescent birds dominate land.
Killer whale and short-finned pilot whale females undergo reproductive senescence on a trajectory independent of somatic aging and cease reproducing at just over halfway through their maximum lifespan of 90 and 65 years. Menopause is somehow a mechanism to control the population of the species who have resolved their maximum lifespan limit and went into senescence. It’s
obvious in humans and some whale experts think orcas and short-finned pilot whales do all these to focus their attention on the survival of their families, grandchildren rather than on birthing more offspring.
Nature is amazing, intelligent, rough. Doesn’t stop astonishing me every single day.
What an interesting exchange between Ines and Leo! Really enjoying reading it 🙂
Wow Leo. This is probably one of your best posts on this forum. You could write a compelling book. I know I would buy it. Agree with everything you mentioned. Scientists underestimate the power of regulatory transcriptional program. It would take significant force to wrest its control over our biology. The incredible complexity at nano scale adds to this challenge. But it’s possible. We have seen it in trees. It’s a matter of time.
Omg, thank you so much, Akshay, you most definitely made my evening, I appreciate and super
happy right now. All the things I know today is just a result of reading some good literature and forums/blogs, where most of the information, I would say 95% comes from you. You and Harold, both are definitely the leading, nature intended scientists, who figured out the secret of centuries. I am sure you will be the first who will discover the mechanism of Ginko Biloba and we will be able to edit or block those non-coding regions for maintaining our youth without the constant hacking. But before that happens, we should be very grateful what you have already discovered. Would one care and hesitate about the constant infusions/dilutions if could maintain youthfulness? I do not think so.
So thank you so much for all these.
Thank you Leo 🙏
Hi Akshay,
Another Neel question for you….After doing a bit of research on GHK-cu, it seems it’s actually used in quite a few skin and hair products which are currently available. What’s the difference between the formulation Neel utilizes and all the others already on the market?
Leo I concur with all that you said. Very well put. Harold has noticed major role ovary and hormones seem to play in female aging.
What amazes me a lot is actually the latest presentation from Irina and Mike Conboys on their effect of neutral blood exchange. https://youtu.be/dixJOssJ0NQ
There are claiming young blood does nothing especially on the brain and only a slight benefit can be achieved caused by some factors in young blood like oxytocin while removing 50% of the plasma and replacing with Saline/5% albumin is the real rejuvenation. Irina said this is the real rejuvenation, not 20% better but the tissues are not distinguishable from young animals. Also it’s obvious what E5 did but conboys work deserve some attention. Irina says we need both negative proteins and positive proteins because they both do their job but as we age negative critical proteins elevate 3-5 fold and then they start working counterproductively inhibiting tissue repair instead of activating and once they are removed then gene expression changes of so called young proteins which are diminished in our blood and they are diminished because they were suppressed at the level of gene expression by those age elevated proteins. After that young proteins are elevated and you do not need to add them ectopically because it’s production does not stop during the aging. They still have questions like why these proteins elevate, how the process evolved, what’s evolution significance and etc. You will simply become confused about the knowing what’s reality. Do you have any idea?
I do not have an exact answer, but if it’s right, as I read, several patients have had Horvath-type DNAm bio-age tests before and after treatment offered by Conboys-Kiprov method collaboration and the apparent epigenetic reset from the treatment is about 3-4 years. Kiprov does not think the epigenetic reprogramming is “permanent”.
The effects of the plasma dilution sessions are cumulative, and Kiprov recommends that they be done monthly for about 6 months, with semi-yearly or yearly treatments after that.
The observations of recipients are that there are immediate benefits from a plasma dilution session, but they are observed to diminish in a few weeks. This motivates the repeated sessions. As Irina Conboy says, 80 kilograms of old body won’t become instantaneously younger but if it becomes gradually younger or does not
become older at the same rate throughout, this will be a very good outcome from their technology. To be honest, for those entirely believing in a programmed theory of aging, this should be sounding a bit utopian and extremely easy for such a complex, inserted by nature mechanism. So will this be a true reprogramming? She says we are consisting of organs, glands, liver, kidney, heart, immune system and theoretically, if all these are rejuvenated, then lifespan should increase too. I do not know, maybe Akshay will have some better explanation. They also had an experiment where the old blood caused more aging and harm in a younger mouse than the young blood rejuvenated the old. It’s interesting why they do not collaborate with Steve and check mice clocks. But Irina does not consider epigenetic clocks as a gold standard of measuring biological aging, she thinks epigenetic changes are happening daily, weekly and depend on a multiple lifestyle physical and psychological factors and that all the other parameters like younger healthier tissues, good metabolism, organelles, Proteostasis, exosomes, gene expression, epigentics, homeostatic attributes should change as well, which, based on their claims and experiments, they did and achieved. It must be mentioned that E5 changed all the aging associated
biomarkers, reduced inflammatory cytokines, raised glutathione, SOD, catalase, reduced senescence, liver enzymes, triglycerides and etc.
Nanaka I share your respect for the Conboys. E5 wouldn’t exist were it not for their parabiosis experiment. I also happen to personally like them and just had lunch with both of them the other day. Any treatment that can make us young and healthy is welcome. So I wish them success. Before I form an opinion on their strategy I would like to see more data. So far I have not seen how long the beneficial effect lasts. I have not seen if it reverses any of the biological age clocks. I have not seen comprehensive biomarkers and assays. If all of this comes out and is positive I will not hesitate to acknowledge their work. I personally feel that the transcriptional onslaught that regulates aging would require hacking with youthful factors to achieve significant reversal of biological age. Time and more trials and studies will tell.
The treated rat that died, what did it die of?
But was that because the treatment could not raise NAD+ to the same levels in females as it did in males, or was it because their NAD+ levels were not as low to start with in females? The same question goes for inflammatory cytokines treated by E5. Males seem to age faster and suffer earlier from most (not all) age related (caused) diseases, so it makes sense a treatment would benefit them more strongly.
And if you are going to worry that much about sex differences in responses to treatment you maybe need to establish that these are consistent between species, a somewhat larger differential.
Mark, in the latest update presentation, they had young control included. While the results are still good, not as dramatic as shown in male rats.
Why should co-administration with retinol be avoided, Akshay?
Mark It will reduce the benefits of ghkcu
With Neel there won’t be a need for retinol anyway (I hope)
@Akshay, when do you expect it will possible for customers within the EU to order Neel?
Really? Loren Pickart has talked about the two (or other agents to increase skin turnover) being synergistic. What leads you to think retinol products reducing the effect of GHK-Cu? Thanks
Thank you for you answer Akshay. Is the shipping date for the pre orders still April 1st?
Yes Dan 1st week of April. Production was successful. You will soon receive it 🙂
Hi Ashkay,
I have been trying to watch the current trial closely?
Perhaps I missed something? The last I remember
there were still 5 surviving “controls”? Your prior
comment said a “few” were still alive? Does that
mean that now there are only 2 or 3 of the “controls”
still surviving? Sorry if I missed something. I am
anxiously trying to follow events with every new post!
Thank you!
The program we call aging is actually the onset of the reproductive span of the species at the turn of puberty. For the population of a particular species to be controlled effectively, the control of this reproductive span/aging has to be stable, isolated from the various threats and vagaries faced by the species in its quest for survival such as infectious diseases, injuries etc. If this program were to be controlled in a decentralized manner across various tissues and cell types, this program would no longer be stable and thereby the ecosystem.
Therefore the aging/reproductive span program can only be implemented by cell types which are privileged in their isolation from these external threats.
Therefore, if natural selection has to succeed, then the aging /reproductive span program has to stable. Lot of papers have shown autophagy to be involved in aging and various interventions such as fasting, exercise lead to improvements in autophagy. but autophagy is also activated during viral infections and immune response and it can drastically change during infection.
To carry this thought further, nature cannot complicate the aging/reproductive span program too much, because it will impede in the objective of natural selection. If nature had tried to complicate the aging program, by creating interdependencies between various cell types, the the program would no longer be stable. nature itself depends on the stability of the aging/reproductive span program.
Hi Akshay,
Another Neel question for you….After doing a bit of research on GHK-cu, it seems it’s actually used in quite a few skin and hair products which are currently available. What’s the difference between the formulation Neel utilizes and all the others already on the market?
Also, it looks like a transdermal patch already exists which utilizes GHK-cu (LifeWave X39).
Will the Neel patch work in a similar method?
Dan, we have already had a discussion about the LifeWave X39 patch above. It does not actually release any kind of molecule from the patch. It’s meant to elevate copper peptide by so called phytotherapy. We agreed that more research is needed to prove its effectiveness and only a biased one directly from the company is not enough. Also in some longevity communities, many people said it’s a scam and fake.
Hi Leo,
I must have missed the previous discussion re: LifeWave X39 patch, but thanks for clearing up how it works. I’ve seen the opinions that it’s a scam, but also a few who say it’s working for them. Should be interesting to see how it all plays out when the Neel patch is released which actually delivers the peptides.
Still curious to know the differences between Neel gel and the creams/ hair products currently on the market. Is it the concentration of peptides? Or quality?
Dan, here is a part of the interview with Harold:
“ Its basic ingredient is GHK, which is glycyl-L-histidine-L-lysine. It’s normally present in young people at about 200 nanograms per mL of blood, and in old people, it drops to less than half, about 80 nanograms. It seems to be involved in general with wound healing. It was discovered by Loren Pickart back in the sixties, and he and eventually his daughter started working on this and publishing on reputable papers with good results. In fact, this substance, GHK, is widely used, and you can buy it en masse. You can buy it on the internet in powder form. And if you really want, you can buy it in an injectable form, but there aren’t that many people who were willing to do that. GHK is used in all the high-end cosmetics, in famous brands. They say it rejuvenates your skin. And oddly enough, unlike most cosmetics, which just hide blemishes or decrease pore size, or things of that nature, it actually does rejuvenate skin. It does encourage the basal cells that form your skin to start multiplying faster. It increases your collagen and your skin thickness after application. So that’s great. But that’s hardly what we’re aiming for — because it already exists and you can buy your own GHK on the market and make your own cosmetics if you want to.
But what Pickart, and the Broad Institute of Boston, associated with Harvard and the MIT, showed? That GHK has more than a limited effect on skin cells. In fact, it seems to reset more than 4000 genes back to a youthful gene expression. It affects them by increasing or decreasing their levels by more than 50% and in some cases, many folds. And one of the things that it’s been effective on, besides skin, is the intestinal lining. Also, lung fibrosis, COPD and cancer, because it seems to affect the cancer cells in at least two ways. It stops what they call the EMT, the epithelial-mesenchymal transition. That’s a cause of cancer and lung fibrosis. And it seems to stop that, and it seems to cause cancer cells to commit suicide, a process known as apoptosis.
The problem, however, is that its half-life in the blood is half an hour, which means you inject it and it’s gone. So, you really can’t hold hope to achieve something like youthful levels, unless you’re injecting yourself ten times a day, and most people object to that.
The big problem in terms of commercialization is that it’s an available product — you can’t patent it. It’s a natural tripeptide that’s naturally present in the body. Therefore, it’s generally regarded as safe because it’s always there. I mean, if it can’t be patented, no drug company wants to invest money in a drug that can’t be patented, except perhaps for us, because we’re interested in people, and if something has a potential to help people, then let us be the vanguard and let the drug companies follow us. We actually went a little bit further thanks to Akshay, Kavita and Agnivesh, her husband. We have a patent, and the patent is for our formula which improves permeation to all the dermal layers and transdermal delivery. This solves the problem of the short half-life, and our upcoming product NEEL patch will be able to maintain optimum levels of GHK in us 24/7 to get the maximum benefit.
We’ve proven this in vitro, with artificial skin, and then seeing how far it penetrates. But more than that, I tried it for almost a year. And the first effect that really impressed me is that I had actinic purpura on my arm. So, I applied it to my arms, and the standard recipe is twice a day for two weeks. And sure enough, my actinic purpura disappeared. And they didn’t come back again. Every once in a while, I’d have one little spot somewhere else on my arm, but tiny and insignificant.
But more than that, I felt better, I felt energy. What before had been a slog, where every step was like pushing myself further, became a walk, and sometimes even pleasant. And finally, when I came home, being in Utah, rather than Mumbai — I have a sort of home there too, and good friends — the walk from my carport to the back of my house, through my yard, which had previously been like a trudge, became a walk, just a stroll, just nothing of any significance. And you guys don’t know because you’re not old. When you see those old people walking one slow step at a time, it’s because it’s very painful for them.”
Interesting, where is this interview published please?
Here is the full version:
“ Nicolas Chernavsky: Hi Harold. So, finally, the former “blue gel”, now called NEEL gel, will be launched.
Harold Katcher: Yes. NEEL is simply the Sanskrit word for “blue”.
NC: Interesting. We would like to know about the science behind the product, since there are millions of products available in the cosmetic field, and we suppose this gel isn’t just another one, and you are the best person to explain about it.
HK: Its basic ingredient is GHK, which is glycyl-L-histidine-L-lysine. It’s normally present in young people at about 200 nanograms per mL of blood, and in old people, it drops to less than half, about 80 nanograms. It seems to be involved in general with wound healing. It was discovered by Loren Pickart back in the sixties, and he and eventually his daughter started working on this and publishing on reputable papers with good results. In fact, this substance, GHK, is widely used, and you can buy it en masse. You can buy it on the internet in powder form. And if you really want, you can buy it in an injectable form, but there aren’t that many people who were willing to do that. GHK is used in all the high-end cosmetics, in famous brands. They say it rejuvenates your skin. And oddly enough, unlike most cosmetics, which just hide blemishes or decrease pore size, or things of that nature, it actually does rejuvenate skin. It does encourage the basal cells that form your skin to start multiplying faster. It increases your collagen and your skin thickness after application. So that’s great. But that’s hardly what we’re aiming for — because it already exists and you can buy your own GHK on the market and make your own cosmetics if you want to.
But what Pickart, and the Broad Institute of Boston, associated with Harvard and the MIT, showed? That GHK has more than a limited effect on skin cells. In fact, it seems to reset more than 4000 genes back to a youthful gene expression. It affects them by increasing or decreasing their levels by more than 50% and in some cases, many folds. And one of the things that it’s been effective on, besides skin, is the intestinal lining. Also, lung fibrosis, COPD and cancer, because it seems to affect the cancer cells in at least two ways. It stops what they call the EMT, the epithelial-mesenchymal transition. That’s a cause of cancer and lung fibrosis. And it seems to stop that, and it seems to cause cancer cells to commit suicide, a process known as apoptosis.
The problem, however, is that its half-life in the blood is half an hour, which means you inject it and it’s gone. So, you really can’t hold hope to achieve something like youthful levels, unless you’re injecting yourself ten times a day, and most people object to that.
The big problem in terms of commercialization is that it’s an available product — you can’t patent it. It’s a natural tripeptide that’s naturally present in the body. Therefore, it’s generally regarded as safe because it’s always there. I mean, if it can’t be patented, no drug company wants to invest money in a drug that can’t be patented, except perhaps for us, because we’re interested in people, and if something has a potential to help people, then let us be the vanguard and let the drug companies follow us. We actually went a little bit further thanks to Akshay, Kavita and Agnivesh, her husband. We have a patent, and the patent is for our formula which improves permeation to all the dermal layers and transdermal delivery. This solves the problem of the short half-life, and our upcoming product NEEL patch will be able to maintain optimum levels of GHK in us 24/7 to get the maximum benefit.
We’ve proven this in vitro, with artificial skin, and then seeing how far it penetrates. But more than that, I tried it for almost a year. And the first effect that really impressed me is that I had actinic purpura on my arm. So, I applied it to my arms, and the standard recipe is twice a day for two weeks. And sure enough, my actinic purpura disappeared. And they didn’t come back again. Every once in a while, I’d have one little spot somewhere else on my arm, but tiny and insignificant.
But more than that, I felt better, I felt energy. What before had been a slog, where every step was like pushing myself further, became a walk, and sometimes even pleasant. And finally, when I came home, being in Utah, rather than Mumbai — I have a sort of home there too, and good friends — the walk from my carport to the back of my house, through my yard, which had previously been like a trudge, became a walk, just a stroll, just nothing of any significance. And you guys don’t know because you’re not old. When you see those old people walking one slow step at a time, it’s because it’s very painful for them.
Nina Torres Zanvettor: Harold, regarding this peptide, there is GHK, and GHK complexed with copper…
HK: Ours is complexed with cupric ion.
NTZ: OK, so in your product, copper is also present.
HK: The name NEEL gel means “blue gel” in Sanskrit, and it’s not blue because it’s colored blue. It’s blue because it contains cupric ions, the same thing that makes copper sulfate blue.
NC: Was it tested on humans? Besides you, of course.
HK: Yes, we are all set to test it in an IRB human clinical trial with 25 volunteers. The IRB committee has already granted full approval and it should start by December or January. In fact, it’s Akshay’s baby, but we both agreed on this three years ago. We sat in a hotel on the waterfront, on the beach, the Juhu beach in Mumbai, and we discussed what products we thought were worth developing. And I was, and Akshay agreed, a great advocate of GHK. And GHK has already given me blessed relief, quite honestly. And I’m just hoping to give it to other people. It’s not really expensive. So to be able to walk like a human being instead of like a reanimated zombie, it’s a big thing.
NTZ: You said you made in vitro tests with artificial skin. Was it in those tests that you evaluated that using this excipient the GHK went through all the layers of the skin?
HK: Yes, but let me add a little bit to that. After a while, I stopped applying the GHK to my skin. And instead, I put a little bit on my fingertip, about two drops worth, and I put it on my soft palate — that’s the space just behind a bony ridge on the top of your mouth. And the soft palate directly leads to the pituitary gland and the hypothalamus above it. And I thought: perhaps if I brought this to my hypothalamus… And it worked, and for almost an entire year that I used this gel, I applied it twice a week to the roof of my mouth. And the fact that it prevented the actinic purpura, and still gave me all the energy, meant that it was working systemically.
NTZ: While you were using the gel every day, did you do any blood tests to see if the blood level of GHK increased?
HK: We tried to do it. We just didn’t have the technical facility. Theoretically, we could find the increase of the copper level in the blood because it’s a copper-carrying peptide, but that wouldn’t necessarily prove the increase in the amount of the peptide itself in the blood.
NC: You said that the product can’t be patented, but that the product is used by the cosmetic industry in the products…
HK: GHK can’t be patented, but its method of application can be patented, and the excipients used to speed its entrance into the body can and were patented. The patent we have filed is for transdermal delivery, as that would solve the short half-life problem and create sustained levels of GHK-Cu in us.
NC: If GHK is so good in all aspects as you described, the reason the industry — the pharmaceutical industry, the cosmetic industry — didn’t develop a way to deliver it through the skin seems to be that they didn’t invest enough.
HK: The cosmetic industry had no reason to do it. The fact of the matter is you can show that GHK will penetrate through the stratum corneum, the thick layer of the skin that prevents things from entering in, but slowly. It’s good enough for skin, however, because you only have to go through a fraction of a millimeter to get to the base layer of the skin cells at the bottom of the epidermis.
NC: So the beneficial effects of the NEEL gel are not just for the skin…
HK: Right!
NC: …because if it were just for this skin…
HK: There are one million products out there for that.
NC: Yes, exactly. This is important.
NTZ: So it’s like a systemic action, but that you apply it through the skin to get this systemic effect.
HK: The skin or, as I mentioned, I applied it to the roof of my mouth. And you can apply it to any mucous membrane, to uptake it into the systemic circulation. And this is generally regarded as safe. It’s already a constituent of humans, and there’s never been shown to be any harmful level of it.
NTZ: You said the half-life in the blood is like half an hour. Do you think this happens because there is some kind of homeostasis to keep the concentration at a specific level?
HK: Sure.
NTZ: OK, so probably there is a system that the body has to maintain a certain concentration of GHK.
HK: Yeah, I’m sure. And I’m sure it’s age-dependent.
NC: So the aim of NEEL gel is not only the skin but a systemic effect to reverse a bit a set of health problems?
HK: We don’t know how much effect it has and we’re looking for volunteers now. We’re going anywhere from cancer to COPD, which is otherwise untreatable, to intestinal irritable bowel syndrome too, because it helps regenerate intestinal lining, to various problems dealing with bone, to incurable diseases like idiopathic fibrosis of the lung, or kidney, for that matter, because it seems to prevent fibrosis. So honestly, we’re talking about what the ancients called a panacea, which seems crazy. But it seems to have that effect, at least to a limited degree, but it’s a known limit so that you really feel the effect. And you feel the lack of it as well.
NTZ: The peptide GHK, as you said, is generally regarded as safe, but the excipients that you created, did you also test to confirm their safety?
HK: Yes, they are safe too, of course.
NC: Harold, there is a thing that worries me a bit, because you are working with E5 as well. E5 is a product that can potentially reverse aging in humans, in a way that would be a great revolution. And I fear that if Yuvan launches a product that, let’s say…
HK: A product that makes money and we will forget about E5? No. E5 is our goal. NEEL gel is a boon to the elderly, but it won’t reverse their age. It may make them healthier. It may make them more fit. It may make them more capable, but it won’t make them young again. It may reduce their wrinkles, yes, and increase their endurance, etc. But they won’t be young men again or young women again.
NC: OK, because I fear that if people see that Yuvan launched a product that is, let’s say, similar to many other products in the market…
HK: If it were similar, we wouldn’t have marketed it. The fact that we have, so that it enters your body and does deep healing, not just the superficial healing, that you don’t have to inject it, which nobody wants to do, makes it a product that goes from a bizarre case of self-hacking to a legitimate product that will help people.
NC: Will there be further testing in humans during the same time that the product is on the market?
HK: Of course!
NC: Will it be continuously trialed?
HK: It will be continuously trialed until we see just how much it can do. And we are thinking about developing specific applications and specific methods of application as well.
NTZ: Do you know if it’s a gel for the whole body, or just the hands or the face?
HK: It’s a gel that can be used anywhere on the body.
NTZ: Nowadays, the scientific community doesn’t know exactly the mode of action of this peptide, right? They know that it’s good, that has a lot of beneficial effects, but exactly what it does is not clear.
HK: We know it changes gene transcription profiles. I mean, that much we know. Exactly how it does that, we don’t know.
NC: When you say that GHK influences so many genes and brings so many benefits, I was wondering if people will think it has something to do with E5, you know?
HK: No, I want to make it very clear that it has nothing whatsoever to do with E5. I mean, as far as I know, E5 may cause its increased production, that’s certainly a possibility, but E5 permanently changes the age phenotype and the epigenotype of cells. This, I don’t know if it does. Actually, this is an interesting question I’d like to answer myself with Steve Horvath’s help. But having used it for a year, I found it very beneficial, but I still don’t look like I’m 21.
NTZ: Can you tell us a bit about how the research with this peptide started? Were you in India working with E5 already, or had you started working with this before? How did this happen? Whose idea was it?
HK: Akshay Sanghavi has been looking for quite a long time — actually, since his mother’s death — for the causes of diabetes, aging and the diseases of aging. And he read my papers. And he thought I had something. He wasn’t a trained scientist, but it’s his passion, and he’s very knowledgeable, and he was right. So, Akshay looked through all the possible chemicals that might have an effect on aging. And we went through the list and we decided which ones were the most likely candidates. And we picked the NEEL gel as one of those, we picked something else which probably would have worked too, but it’s a long story.
NTZ: So you started working on this before E5 then.
HK: No. It was intermittently, while we were working on E5. Originally we didn’t start to work on E5, we started with what I called Heterochronic Plasma Exchange. It is what I published in 2013. It’s the exchange of plasma from young animals to old animals, from young humans to old humans, etc. I have a more than reasonable expectation that it would work at least somewhat. E5 is in fact a much better solution, or potentially a much better solution. I’d like to see it tried, actually. But once we realized that the rats would not take this plasma exchange, then I had to come up with something else. So in the meantime, we were working on a lot of different things. We were working on an Ayurvedic plant-based mixture, which did seem to have good effects. Not quite as dramatic, and it took a very long time and huge amounts, but it did seem to show the reversal of aging. And then E5 came, which to me was a total surprise. It was based on guesses, assumption upon assumption upon assumption, and apparently they all proved to be correct. So lucky!
NTZ: Regarding the gel, there is copper in the composition, and I know this is a common thing that people might be worried about, like “there are metals…”
HK: There’s not enough copper to be harmful. We checked it out. You would have to have tons of the stuff to get enough copper to be harmful.
NC: So I think that’s it, right? Thank you very much, Harold.
HK: Thank you.”
Thank you Leo for sharing this really good interview of Harold here!
“It was discovered by Loren Pickart back in the sixties, and he and eventually his daughter started working on this and publishing on reputable papers with good results.”
Loren Pickart – OMG that brings me back. It must have been like 15 years ago that my wife and I were using some of his topical copper cream that was being sold online. It was bluish in color and was supposed to accelerate wound healing and also provide some level of rejuvenation. Honestly I never had the impression that it was doing any of those things and we eventually switched over to Lifeline Skin Care when it was being promoted by John Mauldin’s newsletter.
I’d like to think that LL Skin Care actually made a difference over the past decade – until I contracted a nasty thyroid disease (now cured) people always pinned me for being in my mid 30s. The thyroid condition unfortunately added at least 10 years to my face in the span of only two years, so now I am very much looking my age. Hopefully the NEEL gel will be able to shave off a few years in the near future 😉
Yes ghk-cu discovery is Loren’s great gift to us all. He is a really nicer person and scientist. His products are still available. We did a comparison in our lab and we had 3 times more better permeation but from all the products available in the market with ghk-cu as one of its many ingredients his is the best. He has written a very good paper on the results of the Broad Institute gene mapping study of ghk-cu. The results are stunning. Which anti aging product available in the market actually can reset 1/3rd of our genes to a younger expression? I can’t think of any. Of course we won’t get those full benefits by applying it only to our face. We should apply to some more skin area especially around the shoulders, chest and abdomen.
Hi Dan peptides in general are highly vulnerable to degradation due to various factors. They need to be stable during production, as part of a lotion, cream or gel and then upon application and in vivo. Also mixing it with chockfull of other ingredients dilutes its effectiveness. Finally permeation to all the dermal layers is a significant challenge for lotions, creams or gels. Our gel was developed by biotechnology lab over 3 years to overcome each of the challenges to ensure maximum efficacy in all the dermal layers making it more like a therapeutic product rather than a cosmetic one.
I’m not a scientist but can add a few thoughts to Askah’s comment regarding the difficulty of using peptides. In the past I have often used BPC-157 for accelerated healing of injuries, e.g. tendons, muscles, bruises, general inflammation, etc. The stuff works as advertised but comes in powder form and needs to be reconstituted with bacteriostatic water. Here’s a YT vid that shows how it’s done:
https://www.youtube.com/watch?v=BLj7UGMjO3g&ab_channel=BJGruber
When reconstituting any peptides one has to be super careful as you shouldn’t even shake the stuff or risk breaking up those peptide chains and thus degrade the product. And after use it goes back in the fridge so to prevent development of microorganisms.
Anyway, long story short. Peptides are very powerful and new compounds are being discovered all the time. However they are a PITA to handle and in most cases they need to be injected, which isn’t everyone’s cup of tea.
I agree that with Michael that peptides and hormones need carefull handling as even injecting bac water can break them up and need carefull handling afterwards ,
I’ve just started injecting GHK-c 12th of a gram in 1/4 pint of bac water having read that much smaller amounts are needed
I’m ( injecting 15ml each injection as a starter ) compared to mixing a third of a gram mixed with a cream for the face used once a day , I’ll try 3 injections of this for a few days then up the amount and take note of any differences I notice ,
John you are a brave longevity warrior. Depending on your age you should notice some biomarkers moving to better territory so try to blood panel before and after a month.
Continuing on the stability issue most of us buy regular cosmetics which shows just 1% to 3% of its contents permeate. Most of the benefits we see are from hydration temporarily pumping up the skin. Ditto for most supplements and bioavailability.
Thank you Akshay , over the years since reading the Baati rat study I’ve tried quite a few peptides generally after researching them as to amounts and efficacy plus safety , many injectable but after a reasonable trial if I don’t notice much difference stop using them , I use insulin syringes and an Autoject which makes it easier than a bare needle , and as GHK and many of the others I’ve tried are present in the human body I’m not as worried with safety issues other than not injecting to much the only others I take that don’t show any effect are senolytics which I take and keep my fingers crossed they are doing there job , I’ll let others on this post know what difference I see especially any that seem to have a lasting effect , I’m 77 now and with the research that Harold and you have published on this blog have encouraged others to research reverse ageing so the futures looking bright and the hope I can make 200 yrs orf more is getting nearer , once again thank you and Harold
@Akshay, when do you expect Neel will become available to customers inside the EU?
Peptides aren’t that fragile. They are already broken up pieces of protein. GHK just looks like bits of collagen, hence why it upregulates collagen production. I guess this direct effect works because collagen is a very simple, repetitive structure. Most other peptides are not specific, in my opinion, because their equivalent protein is more complex. But because they look like broken up bits of protein, peptides cause ribosomal genes to get turned on, to upregulate protein production in general. This probably why you get such wide spread gene expression reset from GHK – you are turning up protein production from RNA. Whether or not gene expression (transcription) is really restored I don’t know, it depends if they are measuring RNA production from the gene or protein translation from the ribosome. I suspect it is the latter. Anyway, I hope that has demystified peptides for people. What I shared is not known generally, I discovered it through my own research.
Thank you Aksahy, Leo, Michael and Mark for the thourough explaination of peptides. The interview with Harold is an absolute goldmine of info. If the product is anything like what Harold describes then we’re in for a real treat.
Akshay, any indication on the “flavour” of Neel gel? I’m curious after reading Harold had applied it to the roof of his mouth…
Dan, it tastes like a citrus cocktail but I must add that it’s NOT meant for oral use. Harold is a bold scientist and likes to try different things but there is no data available for such use on the roof of the mouth so best avoided till it is. I too enjoy reading Harold’s interviews. He is honest and witty and knowledgeable. When he first discovered the benefits of blue gel, as we called Neel before, he was like a kid discovering a hidden bottle of candy. But I request everyone to have patience. Be regular and give it a couple of weeks to see the benefits.
Akshay, do you have any idea, when Neel gel will be ready for customers inside the EU?
Ole I don’t know why my colleagues have not been able to answer to me this regards to shipping from US. How can it be so difficult? I will keep trying. Hopefully soon. Regarding shipping locally may be in 6 months time.
Many thanks Akshay. Much appreciated.
Hi everyone, I have an update which all of you might like: Harold is at our Mumbai Lab and yesterday our lab technician was conducting grip strength on all the female rats in our lifespan study, so Harold volunteered to conduct the grip strength himself: He was so happy to find that the treated rats were 3.4 times stronger than the controls!
That’s so cool, thank you so much for such a wonderful update. You should be feeling fortunate and advantageous. 🙏🏼
Yes indeed: very very happy 😃
You forgot to post the picture, Akshay:
https://cdn-o.fishpond.com/0026/161/160/14825273/original.jpeg
😉
Alrhough aging is no laughing matter,, you always bring a smile on my face Michael.:-)
Akshay: After we receive our pre-ordered Neel. Do you have any idea when we’ll be able to buy more on Amazon? Thanks.
did the delivery of the blue gel in regards to the pre-orders start?
Great News indeed.. Also on Neel. Thanks to Leo for HK interview really enjoyed.
Hello, Akshay! Thank you again for all that you and Harold are doing! It gives us all great hopes for the future! Any recent news about the Neel Blue Gel Pre-Orders? Also, can we expect to see Neel for sale on Amazon soon? Thank you!
Hi Shay, The preorders are already shipping! You should receive yours soon. The multiple bottle orders are going out first. But by next week all will be shipped. You will receive an email with tracking details so you will be able to track your orders.
Thank you, Akshay, for your timely answer! As busy as we know you are, I am sure I speak for everyone here when I say how grateful we all are for your many interactions with us!
Shay, Josh Mitteldorf has been very supportive and so has this community so I will always have a special fondness for everyone here.
Was mine shipped as well? I didn’t get a tracking number, that’s why I’m asking… (and I need tracking for my reshipper in Europe). Thanks in advance! 🙂
Michael I will check and reply but will get to know tomorrow as today is Sunday. Is your address a US one? Your reshipper must be in US right?
Hi Akshay, As i have previously stated, I live in Australia; how do I go about getting the NEEL etc
Michael some overseas buyers have been using US based reshippers. They will charge a fee for that service. Someone here could suggest a reshipper which they have used before.
Have a look at MyUS.com
I have a U.S. reshipper as well but they only work with FedEx. UPS, DHL, all of which get intercepted in Spain. I only use that one for important letters. Trust me – I have been doing this for a decade now, shipping to my reshipper in Spain is the only way it’ll slip through.
Michael noted on the fair warning on Spanish customs. Your shipment will go to the reshipper’s address you have given so UK address. I will double check on that. I don’t know if UK reshipper has given US address. As our warehouse logistic currently may not have paperwork required for customs clearance for UK. I will find out and email you later today.
Got my UPS tracking number this morning……the blue gel is on the way
Congratulations David wish you lots of benefit from Neel gel.
Akshay – the notification I just received claims otherwise, Looks like you guys did send it to my U.S. address which effectively renders it useless to me as it cannot be forwarded to me here in Spain for reasons I explained previously. A bit distressing to be honest….
Don’t lose heart so easily Michael. I told you our warehouse is not equipped to do International shipments. But send me an email with where you want it sent and I will make alternate arrangements and send by tomorrow.
Ok confirmed we have your U.K. address and that too is being shipped
Hey Akshay – no my reshipper is in the UK as their customs are a lot easier to slip through than the Spanish customs gestapo. If you shipped the package directly to Spain it would be almost guaranteed to be intercepted and may be stuck in a customs warehouse for weeks on end (in the blazing Spanish heat). It may even get stolen.
I’ve been shipping items into Spain for a decade now and this by far is the easiest way to do it. May take longer but the last thing you want to have to EVER deal with is the red tape involved in Spanish custom procedures. I am not even kidding – Aduanas makes the IRS look like amateurs.
Once they snatch your package they literally have you download a PDF from a website, fill it out manually, and then email it back. Usually they want the purchase receipt and some other documentation, e.g. your passport or national identity card.
THEN a few days later you get a some kind of reference number along with an import fee which oft en amounts to 40% or more of the original product price. The way to pay it is to manually go to a bank and pay it there, after which you email the payment confirmation back to the Spanish customs. Easy – right? 😉 LOL
My reshipper through Britain takes two weeks longer but it’s hassle free.
Got my tracking number and cross my fingers everything goes well with the reshipping service.
Akshay, are you interested in documentation of skin before and after certain time intervals?
Micheal.You’ll be able to row to Britain for your 2nd shipment.
Hi, Akshay! I ordered 4 jars of Neel, in a preorder, paid on 11/25/2021, order # 235. I have no tracking number as yet and don’t seem to be able to get a post on the public board. Do you have, or can you find, any information about my order? My wife, Daughter and I look forward to trying it! Thanks! -Dave.
@Akshay: We received our tracking number today! Our 4 units of Neel are on the way! Wooohooo! My parents will take before and after pictures, especially of age spots (They are 81 and 78.) I need to bug you with two more questions. #1. My parents have dentures and use a denture adhesive with Zinc in it. I have read that Zinc does not play well with Copper. Should they change over to a non-Zinc adhesive? #2. They also take some of the usual Supplements. Are there any other common Anti-aging Supplements that might interfere with the Copper Peptide? Sorry for all of the questions! Thank you!
Shay, the dentures are in the mouth and they should not bring Neel anywhere inside the mouth. Also Neel gel has been developed to permeate all the layers of the skin but very little would enter blood circulation so no worries there as well regarding supplements. It’s already present in us only goes down with age. As a gel we won’t be any where close to youthful levels of ghk-cu. So most of its benefits will be available to the skin but if they apply all over since skin is the largest organ they may see overall drop in chronic inflammation levels. This may lead to additional indirect benefits as chronic inflammation is a precursor to most diseases of aging. Just use as per instructions given on the box and they should enjoy the benefits without any worries.
I received my 6 bottles of NEEL today.
How would you recommend I store the other 5 bottles?? Refrigerator??? Room temperature??? In a dark place???
Thanks
David, for upto 2 to 3 months your bottles can be kept in a cupboard that does not get direct sunlight – cool, dark place. If you have space in your refrigerator then you could keep them there as an extra precaution.
Is there any problem with applying Neel to the scalp?
I have a summer haircut, and my hair is about 2 cm long. Haven’t noticed any differences from skin application over the past three days.
I don’t foresee any problem. It would be like applying an hair gel. But try out a little and see how you feel first. On the skin PRice you will need to apply diligently atleast for couple of weeks to see it’s full benefits. It works on the deeper layers of the skin, healing and repairing which takes time and timing is also dictated by skin cell turnover rate.
Akshay: Thank you very much for clearing that up for us! I passed all of that on to my parents. Your informed answers were much appreciated!
How can we sign up for phase II/III trials?
Hi, how is Dr. Katcher doing? If he is traveling, he must be alright, but given his age I can’t help but think about how sad it would be if he didn’t get the chance to try E5 on himself; is it possible that if he became seriously ill, he would give it a try? Is it something that has been accounted for (is it even possible?) or does he feel confident in his ability to stay healthy?
It is something with which I grapple everyday. Fortunately he comes from a great biological inheritance: he is tough as nails and his mind is still sharp as a razor. I personally keep constant look out and have successfully remediated some occasional health issues with well researched supplements. When it requires care beyond supplements we have consulted with very talented doctors who do help. Everyone in our team dotes on Harold especially his man Friday Jay who is always with him and is also his room mate. If all goes well he should be able to get E5 as early as next year. Fingers crossed.
Hello everyone. by the way is anything new from the lab in addition to the latest grip strength test? Is the ratio still 7:5? Did they receive next dose?
Nanaka the grip strength is the last update. Harold is still in Mumbai lab for couple of weeks.
What’s this comment about? That’s a shame! Harold reads these comments here. He is not even 80 yet and looks great at his age, not to mention his sharp mind and the passion in his invention-discovery. And he has Akshay, I do not know anyone better able to create an appropriate protocol with the right supplements.
>What’s this comment about? That’s a shame!
The situation is what it is; but I do agree that it is a shame that old people have higher risks of getting sick (and dying). That’s why we’re here, right? What’s not shameful, however, is asking questions about the health of the possible discoverer of the most important treatment in the history of medicine.
>Harold reads these comments here.
And he will have learned nothing by reading my comment, he already knows what the risks of being old are. As for the rest: I didn’t suggest that he didn’t have access to the best treatments available or that he wasn’t well taken care of; I was inquiring about his health because I know that the best treatments available sometimes aren’t sufficient and because I (we all?) think that what Dr. Katcher has created could be the solution if current medicine fails.
I fail to see how my comment is controversial, but I am sorry if it offended you. As I do not wish to create an argument or a conflict, I will avoid this topic in future comments.
Leo I think UnUtilisatuer meant well. I did not perceive it as a negative comment. I worry about what he said everyday. He is 77 which makes him vulnerable to some extent. Anyway let us all pray that he will remain in good health till E5 infusion. Just to make us feel better let me cite one example: Harold had taken Covid booster when he and his roommate both tested positive for the virus. The roommate who is half his age did have symptoms for 3 to 4 days including fever for 1 day and body ache etc. Harold did not have a single symptom except a little tired on the first day. His father was healthy in his nineties except for loss of hearing. So hopefully these worries will be behind us by next year. Aging is scary to me. I have seen too many cases of daily suffering- what we consider as normal tasks become torture. I am glad there is a sudden upsurge in research to cure aging or atleast alleviate its intensity. Hopefully our Yuvan family too will contribute in these efforts for a better world with less suffering.
Understandable, though, the form and narrative were crude and unhewn, unlike your comment, Akshay. It is a fact, though, that old age is a huge risk factor, but no one is insured from the sudden death on a daily basis due to the naturally and artificially driven brutal planet. Besides that, I do not think you need to be told to do something, if we consider your proactive and ahead of the time nature. Anyways, I am glad Harold is fine and as motivated and full of drive as a teenager. I am sure he will turn the crude version of E5 into a super refined, effective and perfected intervention very soon🤞🏻
Understandable, though, the form and narrative were crude and unhewn, unlike your comment, Akshay. It is a fact, though, that old age is a huge risk factor, but no one is insured from the sudden death on a daily basis due to the naturally and artificially driven brutal planet. Besides that, I do not think you need to be told to do something, if we consider your proactive and ahead of the time nature. Anyways, I am glad Harold is fine and as motivated and full of drive as a teenager. I am sure he will turn the crude version of E5 into a super refined, effective and perfected intervention very soon🤞🏻
Hi Leo:
Just a little anecdote in support of Askay’s defense of Unutiltears comment.
When I was in college, I took a job at achain pancake house. The chain trained me to ask if a person was a senior citizen.
Why???? Because they offered a 25 percent discount to seniors.
First day on the job, I ask an older man, if he was a senior citizen?
Well, he jumped out of his chair, red faced and screaming that his age should not matter. He was a big guy and he scared me half to death
The manager rushed over and calmly explained that I asked in order to provide the discount. Phew!
Needless to say I never asked anyone that question again, no matter what the manager said.
It’s easy to misinterpret benign intent.
Hi Heather, thank you, I completely understand what you are saying, but being offended by asking if you are a senior citizen seems different to me than saying Harold needs to have his intervention as soon as possible because of the risk of death in later years of life. At least because he is truly a powerful biologist, I am sure he knows what to do/take etc. But your case is a good example, thank you.
Is there any plan to test NEEL inside the ear, I mean to rejuvenate eardrum and friends around for those unfrequent hearing loss cases related with external ear function?. Thanks.
E5 and chronic disease.
Hi everybody, these are amazing discoveries (-:
I was wondering about the limitations of E5 and the death of one of the rats in the treatment group.
Maybe, if E5 reverses age to the young-adult stage, then any chronic disease that already progress at such an age, will not be cured.
For example, atherosclerosis can begin in adolescence. So a person who remains at the age of 20 for many years due to E5, might eventually suffer a heart attack anyway.
Please let me know what you think about it.
Best Regards
Menahem
Our four bottles arrived today. My parents (Ages 81 and 78 are going to take before, at regular intervals, and after four months of use (or so) pictures of certain areas of skin. This should be very interesting. The Neel is well packaged and the delivery system is awesome!
Thank you so much Shay for your positive feedback 🙏 I am wishing that your parents truly derive great benefit from Neel. I am already getting some incredible feedback: someone had an abrasion wound from a bike fall that wasn’t healing. He reported Neel has finally healed it. We keep aside a few dollars from every sale for burn victims who can not afford the many many graft surgeries they need. I shared because all of you are the true contributors to this relief reaching them we are just the conduit.
My reshipped has classified NEEL as dangerous goods. Waiting since Thursday for clearance.
Akshay: Excellent! I love it! <3
Trying to help someone with OA Hand. Thinking reduce inflammation. Then try to rebuild cartilage with supplements. MSM, chondroitin and glucosamine. Made my knees feel better 10 years ago. I am only a layman with deep interest in medicine.
The joint nodes/cysts are present. Of course they will decide whether to follow any ideas. Would appreciate any feedback. Hope post is appropriate to thread content.
They Take Vitamin D3 {forgot)
AKG helps:
https://www.ijbs.com/v09p0521.htm
Thanks Tom for info & link. Appreciated.
Good morning everybody.
A friend of mine, sent me this from New Scientist.
IT WAS as if someone had turned back time. Once-faltering paws gripped objects with renewed strength. Hearts and livers regained their youthful vitality. Fuzzy memories sharpened. And according to Steve Horvath’s experiments, the biological age of his rats had been cut in half. “I was stunned,” he says.
Horvath, an anti-ageing researcher at the University of Los Angeles, California, saw these startling effects in 2020 after injecting old rats with blood extract from younger rodents. And he isn’t alone. A growing number of labs are reporting findings that indicate we might have been thinking about ageing the wrong way.
It is obviously Harold’s experiment.
It seems interesting, the experiment has transcendend and there is a growing interest on its theoretical basis of aging.
I hadn’t seen any big media publishing anything about Harold’s procedure, this is the first time. While Vittorio Sebastian, Izpisua, and others are everywhere.
Here the whole link
https://www.newscientist.com/article/mg25433843-000-growing-younger-radical-insights-into-ageing-could-help-us-reverse-it/
Thank you Ines! You are all so well updated! I had not seen that.
Hello. I see 6 treated and 4 control rats are alive. Maybe too early to tell but Does this mean E5 may not be extending lifespan dramatically since
2 treated rats still dies? Even though grip strength is different, do they look and acting different? 🧐🙄
Let’s see median lifespan and let’s see future studies both in males and females. Perhaps females are suffering the effects of high FSH and E and PRG deprivation.. Those are deletereous. Males can skip that till a much older age.
Let’s see the epigenetic clocks of all animals.
Ines the joint gender study coming up will give us a lot of insights.
Thanks Akshay. Hopefully you can share some details of it in the future, despite I am aware that while you are linked to JHU you won’t be able to share it freely, like you did right now.
All the best.
Inès he has already answered this question about JHU above. “ I see your concern but let me assure you nothing changes our momentum to try to achieve human trials next year – which in biotech terms would be considered fast. JHU team is only going to help us accelerate towards achieving our goals- opposite of your concern. I want you to trust me on this. We are working with them only on specific projects needed in development that we can’t do on our own without the labs and skills.”
Inès he has already answered this question about JHU above. “JHU team is only going to help us accelerate towards achieving our goal
opposite of your concern. I want you to trust me on this. We are working with them only on specific projects needed in development that we can’t do on our own without the labs and skills.”
Thank you Nanaka. Ines we will update here and the newsletter on the mixed gender study.
Teaser: Some sensational videos and photographs are coming your way of Harold’s visit to our Mumbai lab: you are going to love this 🙂
Great video! Could be my perception, but the controls were holding on, whereas the treatment group wanted to climb.
Yes, great video. If not least because of the window into the scientific process in action. Regarding e5, here take my money now! Seriously though, are there plans to use it topically?
I ordered Neel and had it sent via myus resending service to the UK. An extra 30usd or so, but should be well worth it to be an early adopter. Thanks to all involved.
Thank you PRice. Thank you Dean for your business. Hope you are very pleased with Neel. Harold is a maverick and loves to try things so never thought of E5 topically 🙂 I know it would do wonders on skin but it may be much more expensive then Neel.
Hi Ines, could you too please contact me via email? I would ask you something if possible. Here is my email address: [email protected]
Azza, people show their skepticism about the blood based rejuvenation therapies because none of previous studies was able to show a radical life extension, only Rodolfo Goya made the rat live for 44 months, but people simply do not understand, that the injecting a full spectrum plasma with all its complements, pro-youthful and pro-aging factors is not the best way to rejuvenate, though, I am impressed with the results from one of the latest parabiosis study, called Multi-omic rejuvenation and lifespan extension upon exposure to youthful circulation, where a 3 months period of parabiosis had a great, systemic rejuvenation effect and this effect was sustained even after two months of detachment (reduction in age by 16-32%) Application of four clocks to liver data showed comparable immediate (5-26%) and sustained (10-26%) epigenetic age reduction as observed in blood. The treated rats lived longer and healthier, even after a tissue damaging surgery due to the parabiosis experiment. This is impressive and we do not know how long they would have lived if we would not have detached, but as Harold says and as Irina Conboy said, despite the fact there are thousands of proteins in plasma, only a “handful” of them is responsible for aging program being carried in the whole body itself, so Harold should have much greater results and the most impressive part to me is that all the parameters raise after a while from injection but they start to go down to the youth level again and again, as long as the new dose start to flow into their veins. Only thing I can not answer is about the gender responsive nature, I have no idea about it yet.
That’s a good citation on that recent parabiotic study Leo. I am confident we will crack gender variance if any. It’s a matter of time and effort.
Azza we can not draw that conclusion yet even though that can be a possibility. It is too early to draw such a definitive conclusion. Let me give you one example: the current dosing cycle is 90 days but they achieve peak benefits at 45 days so what happens after the peak? The age related damage again begins to creep up. So now in the new trial of mixed genders we are trying a 45 day dosing cycle to maintain E5 benefits throughout. Will this change the outcome? We don’t know but that’s the R&D process to develop a therapeutic. We are also parallely working to improve the potency of E5. This too hopefully will change outcomes. Having said that they have crossed their average lifespan already of 36 months and every month in addition is a lot in rat lifespan. But so have 4 controls. They also appear better and measured to be much stronger then the controls so despite the lower response in females we can still see some significant benefits of E5. Now we are excited to find our results of the next trial which is about to start.
Thank you, I like your confidence, very much ✊🏼
I appreciate updates but I can not understand one thing. Let’s say in the original study we have 50% reversal of aging and we maintain this result and as a result we get permanently younger and consequently, life expectancy is also dramatically increased. In a new study with an average of 15-20% reversal in order, we should still get a dramatic prolongation of life, but age freezes not by 50% back on a young phenotype, but by 20%, which means you will still keep alive but in order, 15-20% back phenotype. Is this even a valid reasoning? Or 50% rejuvenation means 50% longer life and 20% rejuvenation means 20% more life? I do not know how to ask it to be more understandable sorry.
A related question might be, what chronological age average do we use if everyone is rejuvinating? Is it a bit like the flynn effect of moving iq averages?
That one beats me 🙂
You can’t draw any solid conclusions about future lifespan from reductions in aging clocks, I’m afraid, or even from real biomarkers, as it is easily possible to improve these in the short term but lose out in the long term – this would be akin to an athlete on performance enhancing drugs. Of course they are going to look and feel great short term, but they won’t in 20 years. That is why we need lifespan studies. E5 will either extend life or it won’t. Let’s find out.
With E5, you are hacking biology itself, not a particular symptom, pathway or metabolism. You can lower your epigenetic age simply by taking absorbable form of calcium AKG, raise your glutathione level with acetylated glutathione, lower triglycerides, raise SOD, NAD levels and etc, but you will still die because of the transcriptional onslaught regulated by aging. Therefore, I do not think it’s a good idea to compare E5 with anything.
Leo I must congratulate your grasp about E5 and it’s mode of action. Yes E5 is one of the interventions l which has a systemic impact. Aging is so complex that it is the least we can do to cheat it. Lots to find out.
I agree with you Mark. Let’s find out if it does manage to only make you look and feel great but die at current maximums or if we take repeated doses to maintain youth does it have the potential to prolong our lifespan beyond maximum for some of us.
Leo I’m not comparing E5 to anything, just pointing out reversing aging clocks aren’t proof of age reversal, you need a life span study too. We can’t make any theory about E5 ‘hacking the aging process’ as we don’t know what it is or anything about its mechanism of action. You are just telling yourself stories.
As Akshay says, we will soon find out what E5 can do, and whether improvements will be healthspan only or not.
Mark, it is not “myself story” or simply my opinion. Until we discover the region of non coding DNA that gives birth to elements that trigger the various changes that lead to the aging phenotypes, regular factor hacking will be essential. You should read all the great literature on parabiosis and generally, plasma fraction studies. Besides Yuvan studies, Tony Wyss-Coray from Stanford, Alkahest has shown multiple evidence in his various studies of young blood plasma fractions causing systemwide rejuvenation. Vadim Gladyshev in his paper ‘Multi-omic rejuvenation and lifespan extension upon exposure to youthful circulation“, Young and Undamaged rMSA Improves the Longevity of Mice’ by Luo, Conboys and etc.
I have read those studies, Leo. And guess what? None are lifespan studies…
Mark, how do you think, why none of them was done for lifespan? Do not you think suturing for life is nothing but cruelty? We can not do anything to measure a true biological aging.
For Yuvan, this was address by measuring both-epigenetic age and almost all of the biomarkers known to be decreasing/increasing with age. That’s a synergy we can find out with how the intervention is working, until a true lifespan extension is achieved.
Leo
I think that Mark is saying that life extension is very complex and may not be as simple as reversing a clock. The newest study demonstrated in mice that just cutting back on calories and eating during only the active part of the day gave a 35% increase in lifespan. That’s an incredible result just by adhering to a circadian rhythm.
This is all complicated stuff and needs to be reproduced over and over like in the ITP trials. Only rapamycin has met that criteria so far.
Paul I totally agree aging and biology are incredibly complex and we still have to discover so much. But on some rare occasions we are shocked by some results leaving us tingling with expectations: for me recently it was Harold’s impulsive application of a little E5 on his hand. The results were quite heartening. I spoke to him yesterday- it was 6th day after application- he saw the improvements on 3rd day onwards from a single tiny layer of application so I asked him is that improvement sustaining – his answer it’s looking like it’s beginning to wear off. But he also told me he does indeed have lyophilized E5 with him so he is going to try it on his left hand where we now have a before picture and also his face! I am now quite keen to see what happens. This is Harold for you 🙂 always pushing the boundaries, trying something new.
You’re both very bright Akshay, and you know that I’ve always believed that, but I’m a pure life extension guy. I need to see very significant and impressive results that can be duplicated many times over. The goal is to live to a healthy 150 and beyond- hopefully whole feeling like a 40 year old.
Thank you Paul. All our efforts are towards that. Longer lifespan will not have much appeal unless we can enjoy it in a youthful, healthy state. But my cheers to humans: we are on course to achieve that.
Azza, Leo have a good reply. Let’s say you get 50% younger after a dose of E5, unfortunately that’s not a permanent change. As the benefits of the dose will begin to fade with time. How much at what rate will it happen in humans we don’t know. So one dose may not translate to longer lifespan. But if you take doses regularly at intervals that allow you to maintain your benefits now that is rich with a lot of possibilities including longer lifespan. As I say at our peak there is very little that can kill us. There are some more unknowns at present. For example let’s say you reversed biological age by 20% and when you dose again does it again take you back another 20% or does it maintain you at 20% younger. My guess is it may be the latter.
Please inform Harold we’re now gonna require him to take a bath in the stuff 🙂
Wouldn’t be amazing to get baby skin all over at 78! 🙂
What Harold’s just claimed in his email is already amazing Akshay 🙂 But “extraordinary claims require extraordinary evidence” – any chance of pix?
Akshay, do you have an estimation when the new E5 study starts? And when you say it will be a more refined version and gender specific version, do you mean that you are adding some other plasma factors or how are you modifying the protocols? Only by administering once every 45 days?
Azza it should start by early next week. E5 is constantly being improved so it’s that plus the shorter dosing cycle to not let damage creep back in.
Do you have a site to sign up to possibly be in included in the study? Or has that already been done?
Thanks for your reply, exciting news. So it won’t be administered as different versions for male and female?
Not yet. Based on the outcome of this study we will decide.
Thanks Akshay very much. Someone wrote and I too watched to Dr.Kiprov interview and based to conboys research, where they say dilution causes a real rejuvenation, treated mice are non distinguishable from the young, 3 layer tissues, brain, liver and muscle, Kiprov says plasma dilution in humans does not have any effect on skin improving, hair pigmentation and generally, physical appearance. Even Dobri himself looks good for his age, clear mind, but he does not look younger and younger. Does this mean blood based rejuvenations can not be a real rejuvenations and could we consider E5 in this category too? Dilution restores the balance between so called positive and negative proteins, as does E5.
Azza while I can answer that only when we have conducted a human trial of E5, the mechanisms and strategy used are quite different. Aging is caused by time based changes in gene expression, epigenome and proteome by regulatory transcription factors. The changes seems to be evened out by cell secretome in the blood/plasma. Dilution is a crude way to try to mitigate the harmful change messengers. E5 is a more active and precise way to blunt the effects of the transcriptional onslaught resetting the gene expression, epigenome and transcriptome to a more youthful signature. It is a massive battle and will a defensive move or an attack with GPS and laser guided missiles succeed comprehensively is anyone’s guess right now but will soon be answered by evidence by next year.
Based on Irina Conboy’s presentation, they are developing a new exchange fluids for rejuvenation plasma exchange, not simply saline/albumin, but to keep the effect of dilution longer. I do not know, but, if they are saying young factors are not responsible for aging and that aging is driven by old factors, why a special fluids are still necessary? They have also been doing the same/modified presentations, did several experiments, why we still do not have any lifespan study done on mice? Only evidence is their claim of doing a “true rejuvenation”. In addition to that, we should have seen, at least, Dr. Dobri Kiprov looking far younger, but, we do not. As Kiprov says, aging is so complex and it’s ridiculous to think as silver bullet or even plasma dilution as a potential lifespan breaker. Since E5 is not simply a discovery but invention too, I have hopes only
on it. Oh yes, and do not forget Harold’s hand evidence here.
Why do we see Y factors and a few researchers working on it? Because these types of studies and possible products serve to recruit more and more audiences and flow of money over and over again.
You may not even be understanding and realizing that It’s always better to have this kind of research done in the shadows than to talk about it in all the news, given the fact that the giant pharmacy and the ambush world are ready to destroy, blame the cancer and simply suppress the really effective medicine, so I am only happy for that, ongoing slowly, quality, real science, realism and etc.
Thank you Nanaka that’s the reason we keep a lower profile. Science and results should do the talking.
Since GHK decreases with age, I suppose Neel usage should increase as well. Any guess as to how many bottles of Neel per month at age 70 would be appropriate?
Tom topical use would permeate only little amount of ghk-cu systemically. NEEL is structured for deep penetration so you can expect all dermal layers to benefit. Additionally if you use it all over then since skin is the largest organ you would feel noticeable benefits but not equal to bringing ghk-cu levels back up to youthful levels.
Are you saying that NEEL application only to face and neck wouldn’t be recommended?
Akshay,
Are you saying that applying NEEL only to the face and neck isn’t doing much?
I totally agree with you, Nanaka and I’m glad Akshay too. I know Akshay’s skills not only in biology, but also in business and marketing, not to mention the synergistic superb tandem between him and Harold. I am 100% sure they know what they are doing.
Thank you Leo! Now we have to live up to your faith.
I love the little escaper, it’s brain is most definitely working differently. Treated rats are very concentrated, thinking we have to adjust to the situation during the grip strength test while the control rats are like-why we are here, what’s going on. They are messed and given up. The difference is obvious, not to mention what it did topically on Harold’s hand.
My wife has complaints! lol
I ordered it as a present for my wife, but…
She can’t stand the smell. Says it shouldn’t have any fragrance, and it smells like a mans cologne. When she puts it on her face, the smell drives her crazy.
She also says women can only put NEEL on twice a day, and not the recommended three times a day. Because they get up, clean up and put on make-up. The make-up doesn’t come off until time for bed. According to her, “no woman is going to put on the lotion during the day and mess up their makeup.”
So, she gave it back to me to use. She isn’t a real believe in NEEL anyway, I’ve been the one following it. So, I’ve started using in a test patch for the past 3 days to make sure I don’t have any adverse reactions. I’ll start tomorrow with it on my face. I think if I start looking better, she’ll start using it, too. But right now she has too many creams and lotions that claim can help her skin, she doesn’t need a new one she doesn’t know or believe in.
So, nothing on you guys, I’m going to keep using it. However, I did think you might appreciate a woman’s viewpoint for future reference. Maybe a no fragrance version or mens and womens versions, or keep doing what you’re doing.
Akshay,
I was wondering if Harold has notice any inflammation, pain, grip changes or other aging symptom changes in the hand with the E5?
By the way thank him for the picture of the visual improvements, just amazing.
Gerald I am going to share a treat with you. Harold’s internal e-mail verbatim he sent on 2nd May:
Hi all,
I applied a little bit of an old freeze-dried prep – there’s no trick here Jay (how could there be), my right-hand looks 30 years younger,even my veins are narrower and less prominent, (I wonder if they’ve let go of their calcification) they also seem less visible because the skin appears thicker. Obviously, the experiment needs to be tried on many people, but I’m certain their reaction will be the same as mine. The interesting thing is, as you noted Jay that the E5 used was essentially just the precipitate, (so therefore crude), but if only for external use, it would not have to meet the same criteria for use as something used internally. I’m looking at my hands right now and am amazed, a real miracle. I suppose it will fade (as my blood contains pro-aging factors) – but surprisingly, we now have real evidence that E5 works on people. Yesterday Kavita said it doesn’t look like both hands could belong to the same person). I only applied a small bit to the upper surface of my right hand, nothing more. It was actually historic.
Best to all,
Harold
Sounds like a topical E5 product could be available much sooner than an IV version. It would also seem possible that E5 packaged like NEEL could have systemic effects. I’m ready to preorder now!
Wayne you know what?! It probably could be sold in a container at your corner store or on Amazon: why? Because Harold used the lyophilized version which remains stable in powder form at room temperature!
My only worry is cost. I always think of myself as a potential customer first rather than producer of the product. And so I like to go easy on pricing. That may be difficult with E5. That kind of cost is ok if you take it as IV and your entire body is benefiting tremendously. But will begin to look very expensive if it’s only for younger skin. Unless insurance can cover it. They won’t cover it unless it can be prescribed. So there is a catch after all. Let’s see if someone in the Yuvan family can come up with some way to resolve this big issue.
An obvious (possibly too obvious, and not fully thought through, but a starting point?) came to my mind almost immediately: Further tests could reveal that a lower concentration of topical E-5, could be just as effective, or nearly so? If it can be combined with Neel, or something else, and still show a good deal of visible skin improvement, that could then be a way to reduce the cost. (It could even possibly be sold in different concentrations, at different pricing.)
Shay, all good suggestions. With such a dramatic effect we will now have to investigate all of what you thought and more to see if a product can be made at reasonable cost. We need to also conduct a human clinical trial with 25 volunteers of different age and different skin damage to confirm the various benefits. Fortunately safety is not even a consideration – it is that safe. Another good thing is that FDA approval may not be needed as it may qualify as GRAS. But it will add a whole layer of work for me – if it helps people like that it will be worth it though.
Shay, which country do you live? It’s widely available procedure in every country to have your own or someone young plasma Facial and all body treatment. It does not cost much and plasma cocktail has a great results.
Fascinating. This comment section reads like a novel. Dr. Katcher’s next book could be a bunch of these posts and his emails stitched together and I would buy it.
But that’s not what I wanted to talk about. I noticed that someone posted the photo of Dr. Katcher’s hand on Reddit, and some people complained that they couldn’t be sure that the result is real because there is no before/after picture. Now that we have a clear photo of his hands, could it be possible for him to use some spare E5 (if there is any) on his left hand?
Harold has already flown out of Mumbai so he won’t have access to E5 powder for some time. Will see if customs will allow us to ship it to him. But I agree it’s something we will want to do.
Akshay,
Thanks for sharing the memo. I’m with Harold in wondering how long
the effect will last. Please keep us posted.
To help us understand the scope of the cost problem of E5.
How much would the amount Harold used in his test have cost?
Gerald we are getting a lot of requests including for him to do before and after and to apply full body. Well Harold is always up for such experiments. Will post on the Newsletter the results. That single application could cost $30. But if manufactured in bulk it would come down to some extent.
Akshay you can be assured that people won’t be totally satisfied until you have HD videos of you personally dipping Harold into a vat of E5 twice daily and recording the results from all angles and lighting conditions 🙂
LOL. I am considering something even better an IRB human clinical trial with reputed dermatology CRO.
Akshay,
One of the things I am wondering is if some of the improvements to
Harold’s hand could be a reset to a zero damage state.
Something to find out.
You/we are on the edge of something big boys and girls ! Ive been watching closely, from all the way down here in Australia …. … My Love goes to you two for your heart felt work…Harold K. and you; Akshay … you will change everything after this… your names will go down in history… It’ll be a new world after this is all said and done with you guys crowned the saviours of Mankind as we know it …. just to put it lightly ….. Now thinking on the affordability note; obviously is essential so surely next idea is to find and cut deals with the people whom produce these “ingredients “; they’re will be a massive cut to be hand out of all this and if a ramp of production could be insured for lower costs at the consumers end there will be an even bigger pie to be had at the end of the rainbow … Yuvan will be bigger than BIG ….. 😉
Thank you so much Ryan for your kind words of encouragement! Made my day! 🙏
RE: “azza
on May 5, 2022 at 6:46 am said:
Shay, which country do you live? It’s widely available procedure in every country to have your own or someone young plasma Facial and all body treatment. It does not cost much and plasma cocktail has a great results.”
Hello, Azza! United States. Thank you. I will look into that for my Parents. They are 81 and 78 years young.
Hellow Akshay, I suggest taking a look at the US patent Application #20210161925 “Methods and Compositions for Epigenetic Age and Mitochondrial Disfunction” Feb 16, 2021. It’s about rejuvenation by proliferation of VSELs (very small embryonic stem cells). I saw in a different paper that male and female VSELs are different in a way that could affect the resulting rejuvenation, which would fit with the E5 results.
Correction: “Methods and Compositions for REDUCING Epigenetic Age …”
Robert, interesting patent and thinking behind it. But without clinical evidence one has to wonder if oral supplements, even if given cleverly, would elicit a system wide effect. Thank you for sharing though – very interesting thinking though.
What I wanted to call attention to is the possibility that VSELs can play a part in rejuvenation, and male and female VSELs are genetically different (Google VSELs). Since E5 affects males and females differently I thought this might be relevant.
Robert sorry I missed this message earlier. I did Google VSELs thanks to your suggestion and came across paper by Dr. Ratajczak. Quite interesting. There is a Dr. Berenice Benayoun at USC. Her lab focuses on epigenetic changes caused by aging with a focus on differences in gender. Her various papers too confirm that there can be significant differences and not sufficient research is done in female gender.
It seems like a life span test that differed markedly from the implications of the epigenetic age tests would cast doubt on the value of those. Did you have any epigenetic measurements of the female rats which showed a markedly different reduction than for the male rats?
Ed epigenetic test results are a snapshot of that particular point when samples are taken. That doesn’t mean it’s a permanent change. So having great epigenetic test results can still lead to deaths within average lifespan. Our results on bioRxiv show that there is a dose curve. So in E5 intervention one would need to ensure that once we reach peak reversal we must titrate the dosing cycle to maintain that youthful epigenetic and gene expression signature. The studies and trials that you are witnessing are to find out such dynamics of E5 so that the treatment efficiency continues to improve and is maintained. So one should not get exhilarated at one good result and disappointed at a lower than expected result. As each result is teaching us another aspect of the treatment. This is normal research and development. What is encouraging is that there is a system wide reversal to a youthful phenotype occurring safely. As we continue to improve the treatment dynamics we may get to a stage where we are able to successfully hold on to the reversed state. That’s when one would really like to see a lifespan study result. We are launching another mixed gender study with smaller dosing cycle and I am personally really curious to see if the youthful phenotype is maintained. Will we see maximum lifespan limit breached? I am confident it’s only a matter of time.
Akshay: Thank you so much for that enlightening explanation. To those of us (me included), who are NOT familiar with research and development, this is most encouraging. Harold and you are obviously way ahead of everyone else in the field. I have complete confidence in both of you, and also appreciate what Josh is doing. You truly are going to change humanity, and we will all be the better for your hard work! Personally, I see nothing but upside in this endeavor and the results thereof. Congratulations on the successes you have already had, and I am sure there will be many more in the future. My parents and I believe, that, in very few years from now, the ageing disease will be a thing of the past for those of us, who want to live on, because of your work in this anti-ageing and age reversal field.
Thank you so much Shay! 🙏 I like Josh’s community because of the great encouragement we receive and also for the insightful discussions we have here. While Harold and I have confidence on taming aging I wouldn’t want to discount many other scientists more intelligent then us some are better funded then us who are also after the same goals. The point is that humans doubled their average lifespan in the last hundred years and are speeding towards breaking through the maximum lifespan barrier and at the same time working towards making aging plastic. No one can stop us now. When we do fully succeed on both counts we will need to adapt so that we can make our lives on this planet sustainable.
I just spoke to Harold 1 hour back and although both of us expect the effect to wear off it still hasn’t – today is the 7th day. He said he didn’t even rub it. He just took a little on the tip of his finger and dabbed it on the right hand. Now we are going to test on his left hand as that has a ‘before’ photo. Also he is going to apply to his face. We are capturing both on video and photos. We will share on the Newsletter. Harold told me he wants to make a topical product out of this regardless of its cost as there will be people who will benefit out of this. I can think of burn victims and diabetic ulcers that don’t heal leading to amputations, etc. So we will keep you posted on our work on that front.
Thanks for the explanation. Obviously my question has been anticipated by your experimental protocols. I continue to be greatly encouraged by your efforts!
Just read “Short term treatment with a cocktail of rapamycin, acarbose and phenylbutyrate delays aging phenotypes in mice” from the Interventions Testing Program. From their Methods section:
“Grip strength force was normalized by body weight measured on the testing date, so that the peak force was expressed relative to body weight.”
This study was with female and male subjects, finding a larger effect of the cocktail in males.
PRice thanks. One more study showing greater effect in males but the thing is in humans females on average outlive males so who knows it may not apply so much to humans.
Yes, you’re right Akshay. I got this study from a lifespan.io interview with Richard Miller.
It makes evolutionary sense for mice males to benefit more from treatments than females. The Rattus and Mus genera used in almost all rodent research aren’t part of the 6% in which fathers also provide offspring care.
There probably isn’t an evolutionary advantage for male mice to live much longer after sperm donation. Female mice don’t cache sperm.
It’s similar to studies in which treatments only benefited subjects who started out deficient. This interview hinted at how females’ healthspans and lifespans were already protected, with male mice benefiting more from 17α-estradiol treatment.
But that female protection may have limits in humans. Most whale species don’t experience menopause. In those that do, like Orca, menopause is thought to be evolutionarily determined in order to keep female children from competing for resources with female grandchildren and great-grandchildren. That’s a hypothesis, though, as those species’ male lifespans aren’t adequately measured.
What will it be for humans?
We have to find out.
Akshay said of GHK-Cu that “if a manufacturer is offering product of very high purity in sublingual form you should take it.” It is available from Super Smart https://us.supersmart.com/en/shop/scientific-research/ghk-cu-tripeptide-5-mg-H763#avis for $37.70 for 60 5mg tablets. 1 of 3 reviews is very negative, but it is also available from Amazon for $58.00 with 51 reviews, 4.1/5. I am considering taking it. Before taking it I will get an epigenetics age test from Elysium Health founded by Leonard Guarente at a cost of $499 https://www.elysiumhealth.com/products/index?customer_posted=true#footer-newsletter . Morgan Levine consults with Elysium Health and developed the test with the help of Steve Horvath (https://www.outsideonline.com/health/wellness/elysium-health-aging-index/). It is an improvement of Horvath’s original epigenetics age test by examining 100,000 DNA sites instead of just a few hundred. A subject submits a sample of saliva and gets the results back in about 6 weeks. After taking the sublingual GHK-Cu tablets for about 6 months, I will get another epigenetic age test for comparison to see if I got a little younger. I’m 86 now.
I would appreciate comments and advice.
Fascinating! Did you all test E5 epigenetic effects in vitro or go straight to animal models?
I posted a plan to use sublingual GHK-Cu tablets yesterday. It doesn’t show today. Why?
Lifespan.io : : :
– Prof. Richard Miller on the Intervention Testing Program –
This program examines the effectiveness of life-extending interventions in mice.
By Arkadi Mazin
May 5, 2022
{excerpts}
1
“….Canagliflozin is very frequently given to people because it’s good for diabetics. …”
It turns out that if you give it to mice, in *male* mice, it leads to about a 15% increase in lifespan and puts off at least five different kinds of non-cancer, non-lethal, non-neoplastic diseases in mice as well. So, it’s authentically an anti-aging drug.
2
What we found is that when you give rapamycin *and* acarbose together, in the males, you do better than either rapamycin by itself or acarbose by itself. And that combination of drugs together gives *male* survival a 29% boost. That’s the largest percentage increase we’ve seen in males or females.
—
~A lot more interesting and varied discussion in the article:
https://www.lifespan.io/news/prof-richard-miller-on-the-intervention-testing-program/
Hey all. Just wanted to say someone created an E5 sub on Reddit. Besides this comment section, I don’t believe there is any place on the internet to discuss Dr. Katcher’s work.
I don’t know if I can post a link, but googling r/YuvanE5 should cause it to pop up.
Update on Neel, from my parents, who are 81 and 78 years old (started using on 04-25-22), a little over 2 weeks in use. My Dad (Quantifiable – pictures): He has a LOT of age spots. He said his skin is smoother, many of his age spots have faded some, especially 3 on his face, which are not as noticeable any more. (Anecdotal): He says his energy level is up slightly, and his stomach troubles have eased somewhat. My Mom (Quantifiable – pictures): Her skin is smoother. (Anectodal – no pictures): had terrible, bleeding hemorrhoids. She said they have shrunk and no longer are bleeding. She says her energy levels have improved slightly. They plan on taking pictures once a month, so before and after will be available in a little under 2 weeks from now.
Having such enthusiastic supporters is a true blessing! Thank you so much Shay!! Please thank for your parents for kindly sharing their Neel experience. Please do email me the before and after photos when ready: atomicblissventures at gmail dot com
Hi, Shay:
What method of application did your mother use?
I also have issues with hemorrhoids every now and then.
Hello. Has a new E5 already started?
Hi Nanaka not yet but some interesting R&D is underway.
Now the summer is here in UK i am looking forward to grounding (earthing) in the garden. Research seems limited on this. But it certainly makes me & others feel great. Who knows if there are some small scale anti-aging effects we fail to discover ?
Derek you brought up nice memories of walking barefoot on grass early morning when it’s still wet with dew. There is definitely benefits. Earth’s surface electrons will be transferred into your body and the negative charge electrons from your body will be absorbed or neutralized by the Earth. Here is one paper you can look up: The effects of grounding (earthing) on inflammation, the immune response, wound healing, and prevention and treatment of chronic inflammatory and autoimmune diseases
By James L Oschman, Gaétan Chevalier, and Richard Brown
Hi Akshay! Any updates on Harold K’s left arm experiment? 🙂
Justin unfortunately not. The E5 powder he took with him did not survive the long flight and x-rays etc so we have to wait till we can launch our trial for E5 on skin. BTW our IRB human clinical trial for NEEL started today. We will be posting photos in our Newsletter.
Akshay,
Sorry to hear the E5 was damaged.
Has the E5 Harold originally applied completely worn off yet?
Looking forward to the NEEL results.
Thanks for keeping us all up to date.
Gerald till yesterday it hadn’t worn off. Will request him for latest photo. Thank you for your kind wishes.
Thanks for the paper details Ashkay. I live near a beach & it’s great there too. I remember seeing some dramatic pictures of it’s effect on RBC clumping somewhere.
Apologies Akshay !
Hello everyone. I see some people are regularly arguing about the agonist/antagonist-adding/removing-Yuvan/Conboy’s conceptions and their strengthens, weaknesses, opportunities and threats. I have been researching this dimension, since, I think, only approach to do a true rejuvenation reversal and dramatic extension of lifespan is to reprogram the body, but, the main cornerstone here is the word-SYSTEMIC! The latest interview with Vittorio Sebastiano shows how extraordinarily rapidly the science of aging is moving. At this time, Vittorio seems to be only one who, with his team, was the first to show that Y factors proprietary cocktail made by him works in humans. They have the technology that is by far the safest and probably the one that’s going to develop to clinical fruition most rapidly. Indeed, reprogramming with the use of Yamanaka factors seems to be exploding every day, more and more small companies are registering, but, that means nothing. Even Vittorio, in his latest talk said: “Am I worried about the fact that big money is being put into other entities or corporations, like the Altos Labs, Calico? No, because in the end, having a lot of money doesn’t guarantee success. The execution, the strategy, the foundational science are all very important, and we check all those boxes.”
No doubts, Y factors, especially, when Vittorio showed its safety, seems and sounds outstanding, but, we need to understand that reprogramming the whole body, literally every cell, is far from rationalism and realism. Even David Sinclair, who, just a year ago was thinking that even a gene therapy pill could reverse the aging process by several years and even decades, came to more adequate conclusion and he now considers reprogramming as a medicine for particular tissues, not as a full body rejuvenation. Vittorio Sebastiano: “Now, does that mean that this is going to be the cocktail that we’re going to use for every cell, every tissue for the rest of our lives? Probably not. We’re starting there because we know it’s the most powerful cocktail that gives the highest degree of rejuvenation in the shortest amount of time, so, first, we are studying this process.
We’re also learning that as a consequence of the expression of those factors, other factors are getting engaged, and potentially we may complement the cocktail with one or more of those, substitute some of them, or maybe replace the cocktail with something entirely different. The good thing about this cocktail that we’re using is that it works across many different cell types equally.” So, I introduced Yamanaka factors dimension, to underline it’s limitations from the standpoint of dramatic life extension, not to mention long term safety studies, even if the cell identity is maintained.
Now, back to Conboy’s+Kiprov collaboration approach, they are strictly against the version of pro youthful factors driving the aging process, instead, their conception is about the age elevated antagonists driving the process, which, when we are young, are balanced and playing one of the most critical functions, therefore, needed both agonists and antagonists, as Akshay has already explained it here wonderfully. When they are asked about the youth promoting factors or fractions, they obliquely, but still are mentioning Harold, Stanford, Alkahest and say that these factors are already discovered, like the oxytocin, gdf-11 and et cetera and that intuitive jump of considering the young plasma as a rejuvenation tool, is nothing, but false, how the biology really works and how humans are influenced by the intuitive nature of thoughts.
One fascinating thing about their work:Brain, liver and muscle of old mice are becoming statistically younger, almost indistinguishable from the young controls, also, senescent cells in the brain are almost disappeared, like in about a week and their thought is that they are not eliminated by the immune system but they are simply back to the normal cell behavior. After infusing old blood to the young mouse, in about a week, brain and liver are instantaneously old, but, somehow, at some extent, muscle remains young and resistant to the full of antagonist factors blood plasma.
Here are the questions: couple of years are gone, they are still not conducting the lifespan experiment, and the reason of that is the small veins of mice? They could use rats instead.
No any clock has even been applied-though the apparent epigenetic reset from the treatment is about 3-4 years in humans. Kiprov does not think the epigenetic reprogramming is “permanent”. The observations of recipients are that there are immediate benefits from a plasma dilution session, but they are observed to diminish in a few weeks. This motivates the repeated sessions. As Kiprov said, no anecdotal evidence is existing about the rejuvenation effect reflected on the appearance, no hair pigmentation repair, no skin elasticity improvement, no faster hair growth. It’s obvious, Unlike Conboy’s, who are claiming as long as the repair mechanism is back, you will become younger and live longer, Kiprov is almost sure TPE is not able to make these changes happen.
Their main standpoint-as long as the age elevated factors are diluted, literally all the youthful proteome platform is back to rejuvenate the body, that they are still encoded in our genome. My question here, if they have such a great tool to analyze both-negative and positive proteome fully, why still no any targeted pharmaceutical is made for blocking particular protein/factor? How do they know all the positive proteome is back to balance that they even do not know what these factors are?
In addition to that, Dr. Kiprov keeps it secret to say if this procedure can normalize Glutathione, SOD, Catalase, NRF2, MDA? He said he is not able to reveal details and that they are testing more and more parameters after every new study..A bit confusing to me.
I apologize for being that direct, but, even Dr.Kiprov seems to be aging at the same rate, even though he has been doing this procedure for years.
In short, if not taken as a bias, these are the reasons I do consider E5 as the only intervention capable of not just slow but reversing the aging process systemically and safely. To be more accurate and objective, I will link the 3 round counterarguments written by SENS research foundation, which seems rational, but they are all against the “conventional” young plasma treatments.
https://www.sens.org/parabiosis-the-dilution-solution/
I have nothing against Conboy’s and as Akshay said, E5 would not have existed if there were no their parabiosis study, but, I wanted to underline that the mechanism of this interventions are different and that the outcome of the human clinical trial of using therapeutic plasma exchange, does not seem to be reprogramming the body as intended.
Perhaps the benefits of “young factors” are not immediate
Tom in the rats we see their chronic inflammation levels drop within 7 days and Harold’s right hand improvement began on the 3rd day. I spoke to him yesterday in a Zoom call and he says it’s still looking younger. Anyway we have to wait for a trial to conclude the dose dynamics of E5 on skin.
Leo wow what an analysis. Both Conboys and us have a similar goal: to bring back the homeostatic ratio between the agonist and antagonist proteins tuning all our biological pathways. None of the studies and trials so far has shown dramatic systemic reversal except probably the male rat E5 trial. But our Lifespan study in females diluted that result. Nevertheless I do have clarity of what will take E5 to a point where we can dramatically see biological age reversal in pets and humans. It will take the time it needs to take but I grow more confident everyday.
Thank you so much, Akshay, you know how much I appreciate your words and of course, your confidence growing every day is so motivating, not to give up.
Pardon me, if the goals are similar, so Conboys are right and simply by diluting we no longer need to add some ectopically? I was going to have plasmapheresis procedure regularly, which costs 6000$ per treatment, that’s almost 45 000 for a year, but I do not see any rejuvenated people doing this procedure. I know some and even though they feel more alive nothing happens on their hair and skin and generally their visual, not even improvement. So I decided it does not worth at this moment to pay such a high price.
Nanaka I said goals are similar not procedures or it’s efficacies. I do respect the Conboys and am sure they will continue to improve their procedure. Biological age reversal has already shown to be possible in Dr. Greg Fahy’s human trial. In the next 10 years we can hope to see a significant age reversal. Regarding cost of treatment: Harold and I like to be as cost efficient as possible. We always think as a consumer first.
I apologize, yes I missed the word goal importance here. David Sinclair does mention Fahy example too but I do not know how a thymus gland regeneration could extend ones lifespan. That’s just a clock. But Greg Fahy is the only one who looks very young. Maybe growth hormone plays the role here. Thanks.
Hi Akshay. When talking about the exosome or other vendor plasma based treatments like Alkahest, they are trying to harvest these factors or exosomes from as young tissue as possible. I had a talk with Dr Ross about the exosomes and they said their donor is the youngest amniotic fluid and Alkahest tries to use less than 1 year old donors, that baby skin has 30 types of collagen and adult has significantly less. In short, they are all trying to take as young donors as possible. May I ask how is it possible that you are synthetically produce these factors and still achieve such an amazing results? I think these factors are found only in young? Of course, once again, if it’s not a violation of your IP. I am just too into mechanisms of aging and I find your blogs and articles extremely useful, thanks for that.
Azza thanks but I can’t discuss this in detail. Discovery isn’t of much use unless it can be translated and reach everyone who needs it or wants it’s advantages and benefits. So right from the beginning we were looking at how we can manufacture E5 on global scale without creating a 2nd slave trade of young kids. Harold came up with a brilliant idea which is now the crucible of this solution. And we have proof that it works safely. We are also working on the next gen version of E5 which will make it even more powerful and easier to mass produce. One has to think and plan atleast 10 years ahead to be deemed the leading solution in the market. We will not rest till we can achieve age reversal to youth safely in humans. Both Harold and I are relentless.
Thanks Akshay for your understanding and your answer, I do appreciate and completely understand. I like your relentless nature which is so crucial in the fighting of aging.
Thank you Azza.
Hi Akshay, will we still receive updates from NTZ about the current study and abut the new one if it has already started? If you are still doing female rats and if they are alive, they should have received another injection in May, if I am counting right. Thank you.
Hi Azza the next study first dose is slated this week. This a mixed gender study with alternative dosing cycle. NTZ will continue to update with results, photos and videos.
Thank you very much for your reply, good luck to you. Did all the treated rats die or still alive? Even though not as dramatic results, it’s still interesting how long they will live.
Got the NTZ update today, thanks.
Were effects on cognitive function (learning and memory) part of this first female-only follow-on study’s protocol? IAW, can you see whether E5 kept healthspan on pace with lifespan?
I think Barnes maze wasn’t done regularly but grip strength was and that was a stand out result in the treated very close to the benefits we saw in males. IL6 and TNFa showed lower response.
Is it now considered that science is beyond parabiosis studies. Surely nothing else is left to learn from this ? The fact that time must pass in order to confirm theories etc must be so frustrating for your team. I feel that natural frustration from us all on this thread. So what it is like for yourselves ? It seems a frustration borne from excitement though.
Derek in research one has to inculcate patience. If there is clarity of the path ahead, even if it will take one or two years, then one doesn’t feel frustrated. Continue to progress one step at a time. The only time pressure we have is on getting Harold E5 as soon as possible. I think we can try for early next year.
Wow Akshay, that would be great 2023. Enjoy Harold’s interviews so much. My favourite is the one with Brent Nally. A long interview interesting all the way.
Thanks for reply and insight.
Thank you Derek. I too enjoy his interviews 🙂
Hello Akshay. Before actually something like E5 becomes available, do you recommend taking of TGF beta1 inhibitor drug since it’s one of the more important aging driver protein as well as oxytocin?
Hi Azza, I personally do not like inhibitors. But oxytocin absolutely if you can get it in bioavailable form. Is it available as I would be interested myself?
Thank you Akshay. You personally do not like inhibitors because as I got from your previous comment, they are still needed, right?
I know some oxytocin stimulator precursors like SNP-oxytocin stimulator, OXY mind as well as oxy pure nasal spray. Also there are peptide oxytocin injections available. I also know a synthetic version analog called Demoxytocin. Though I am not yet sure which is more bioavailable and if it worth trying. Could you tell me why you have interest in this? Maybe it really is a good thing to add to regime?
Azza one of the biggest benefits of fasting atleast 7 days is that it launches the body into repair, recycling and regeneration of all our cells. I was reading on what secretion gets increased to effect this wonderful regeneration and saw that our body almost gets an internal bath with plasma circulated oxytocin. We have read about its benefits related to childbirth and social behavior and stress but it plays an important role in rejuvenation and regeneration. For example in muscle cells, bone and stem cells. Unfortunately it’s levels go down with age. Oral administration is ineffective as gastrointestinal enzyme chymotrypsin destroys it. Even in the blood enzyme oxytocinase destroys it within minutes. It’s half life is 3 mins. So seems to be very difficult to upregulate exogenously. Nasal spray is available by prescription but there are mixed reports in research papers on its efficacy in replenishing oxytocin. Wish there was a transdermal patch that could release it in our bloodstream every 5 mins.
Thanks Akshay, I hope e5 will increase oxytocin levels up too.
Yea I would expect E5 to bring hormones and neurotransmitters back to youthful secretion levels.
Thanks Akshay and Leo.
Although the expression of oxytocin and oxytocin receptors in the hypothalamus was not altered by L-carnosine supplementation, the concentration of oxytocin in cerebrospinal fluid was increased in CD157KO mice by L-carnosine supplementation. These results suggest that L-carnosine supplementation restores social recognition impairments by augmenting the level of released oxytocin. Thus, we could imply the possibility of a safe nutritional intervention for at least some types of ASD in the human population.
https://pubmed.ncbi.nlm.nih.gov/35215455/
Greg Fahy does take carnisone and generally, people take it as an anti-aging supplement. I have to read more abut it))
Hi Akshay,
A quick question regarding the NEEL gel. How much difference is there when it comes to 1. the time-release aspect
2. absorb into body aspect
between GHK formulations Dr Pickart himself sells on his website and Neel gel? Any rough estimates?
Thanks
Abu
Hi Leo, I don’t usually write comments. Only a reader of this blog. But your comment on L-carnosine is interesting. If you go to AMAZON reviews of every single non- essential amino acids supplement there is some benefits associated with it. For example, NAC & Glycine increases glutathione. l-cysteine improves hair/nail quality. l-lysine improves the skin. arginine/citruline increases nitric oxide are also often associated for longevity.
@Akshay, I’ve always wondered, if very slim people (BMI < 20) would actually need to fast for 7 days to induce the benefits you mention, especially if fasting is combined with exercise (to the extent energy levels allow it).
Ole, Valter Longo at USC found out in some of his earliest experiments/papers that the highest rejuvenation occurs with prolonged fasting. The optimum window was 5 to 7 days. He realized not everyone can do that so now he has come out with a compromise: a fast mimicking diet. But in his earlier seminal papers he described all the benefits that begin occurring throughout our body once we cross a certain threshold. Optimum hormesis.
For someone with that BMI and working out would surely cross that threshold sooner. May be in 3 days. In his 2019 paper Professor Longo said: “It gives the ‘OK’ for stem cells to go ahead and begin proliferating and rebuild the entire immune system,” said Prof Valter Longo, Professor of Gerontology and the Biological Sciences at the University of California.
“And the good news is that the body got rid of the parts of the system that might be damaged or old, the inefficient parts, during the fasting.
“Now, if you start with a system heavily damaged by chemotherapy or ageing, fasting cycles can generate, literally, a new immune system.”
Prolonged fasting forces the body to use stores of glucose and fat but also breaks down a significant portion of white blood cells.
During each cycle of fasting, this depletion of white blood cells induces changes that trigger stem cell-based regeneration of new immune system cells.
In trials humans were asked to regularly fast for between two and four days over a six-month period.
Scientists found that prolonged fasting also reduced the enzyme PKA, which is linked to ageing and a hormone which increases cancer risk and tumour growth.
“We could not predict that prolonged fasting would have such a remarkable effect in promoting stem cell-based regeneration of the hematopoietic system,” added Prof Longo.
“When you starve, the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged,” Dr Longo said.
I would also be interested if bioavailable oxytocin were available. So far I’ve found only GHK-Cu and epitalon as arginine salts version. Trying them both one package they seem to be considerbaly stronger than nasal spray of GHK-Cu and epitalon on skin rebuilt (at least combined with CaAKG) and they are sold in EU so no hassle with customs. How arginine salt of GHK-Cu compares to BlueGel? Where to sign up for your newsletter?
Have you guys seen Paul Robbins latest work about the use of exosomes to release useful factors and what is your thoughts?
“ We have using both naturally aged mice and mouse models of accelerated systemic and tissue specific aging to examine pathways that drive stem cell dysfunction with age as well as the ability of transplantation of functional stem cells to extend healthspan. Our results demonstrate that injection of young, but not old stem cells extends healthspan and lifespan, consistent with loss of stem cell function contributing to driving aging. In addition, we have identified extracellular vesicles (EVs) secreted by young stem cells as important for conferring the therapeutic effect on aging by suppressing senescence/SASP markers. We currently are developing and optimizing human adult stem cell EVs for clinical application to suppress senescence and extend healthspan.
SilverSeeker you can subscribe to newsletter here:
https://www.ntzplural.com/newsletter
Oral consumption of peptides doesn’t work as it gets digested. Gel is only good for the skin. Very little systemic benefit would occur. That benefit could get amplified if applied all over. Someone told me about a sublingual nano particulate version of ghk-cu so that could have a chance to work to some extent.
SuperSmart supplements has sublingual 5mg GHK but you have to call the phone number on their website
Tom in US it’s available on Amazon.
Akshay, AKG also doesn’t pass through stomach acids. Yet one day sports supplements industry paired it with arginine to increase survivability of arginine through stomach acids and blood level of arginine increased 8 fold from the same amount but as a side effect AKG reached blood by oral consumption for the first time (which normally is complete ZERO). Then they did it with ornithine and glutamine paired with AKG and the levels of ornithine and glutamine also increased 6-7 fold while AKG also reached the blood. The same was done with calcium/magnesium and threonate, then repeated with Ca/Mg and AKG. Now this was accomplished by firm targeting bodybuilding and sports first with BPC-157, and now with GHK-CU and epitalon as a salts going through stomach acids in enough quantities to make it noticeable on skin rebuild. They claim that it reaches about 3 times higher blood level from oral consumption compared to nasal spray. I tried their product and from comparison of epitalon nasal spray from other manufacturer I tried a year ago it’s seems that it’s indeed considerably better than nasal spray. It’s still very costly, but it’s seem to start deliver some result which is in my opinion worth the money (more noticeable result compared to nasal sprays for noticeable less money). No refrigerator needed, storage at room temperature. The field is very vivid and competetive. When BlueGel reaches EU finally, I would eagerly try how it compares.
SilverSeeker thanks for that information. I am sure readers here will find it useful.
Hi SilverSeeker,
What salt have they complexed epitalon with, and where do you buy it?
SubQ or IM injection of epitalon certainly works, as far as I can see looking at my biomarkers – but an oral alternative would be more convenient.
Thanks in advance
@Mark they describe on content table of the package as an arginine salt. Their name is Synthagen Laboratories, but their UK shop still sells BPC-157 only. In EU they launched Epitalon and GHK-Cu at the end of March. I didn’t tried shot’s version of epitalon as I couldn’t find the source that could deliver it properly freezed to my location so I do not know how strong it would be compared to o ther versions. My own experience with AAKG and CaAKG is that CaAKG is at least 3 times stronger on skin rebuild than AAKG (with 1 gram of CaAKG vs 3-4 grams daily of AAKG and yet two months of CaAKG yielded greater change than 6 earlier months of AAKG), don’t know how much of this is due to huge size of AAKG molecule and hence much lower bioavailability compared to much smaller CaAKG molecule (arginine has about 2 times greater molar mass than AKG), and how much of this is how body directs arginine to certain body parts. It’s rather ominous that Synthagen compare their product to nasal sprays and not the shots. Yet for those that do not have access to shots and cold storage infrastructure or want to avoid shots it’s seems to be improvement over nasal sprays. More advanced epidermal systems or the salts of Ca/Mg (which are not available (yet)…) may be better than big arginine paired molecules…
Thanks @SilverSeeker, I’ll look into the epitalon capsule.
Re: your comments on the effectiveness of Ca-AKG vs A-AKG, I’ve not noticed a difference in terms of epigenetic age between using the two; bear in mind A-AKG is 2:1 so compared to Ca-AKG you’ll have to take twice as much. Depends whether you mind having more Ca or Arginine in your system, and I for one much prefer arginine.
Hi Akshay,
I’d be interested in knowing what are the key bottlenecks in E5 production, since you don’t even seem to have enough to treat Harold properly yet?
Geography and logistics. It should get resolved soon.
Hello Akshay, nanaka posted here about exosome vesicles and I searched some information about kimera labs. This man, Dr. Ross seems to be completely sure parabiosis benefits are because of the exosome rna and dna proteins messenger. Can I ask if E5 is a completely different thing? I am asking because this therapy, I mean exosome therapy seems to be a good candidate for anti inflammatory diseases and for senescence cells to become healthy again, but there are not dramatic lifespan extension seen and also Dr. Duncan Ross adds that some of these molecules half life is maximum of 30 days, some even last as little as 4 hours. I hope E5 is a completely different thing and you found out something special not yet existing showed to fail. Thanks.
Azza I can’t comment on what’s in E5 yet as you can understand.
Of course, Akshay, I just could not formulate the question so as not to endanger your intellectual property. I’m just trying to make sure the E5 is completely unique and the only one considering its capabilities. I apologize and thank you.
I can only tell you that I can see the final version of E5 and it would probably be the most powerful age reversal therapeutic ever made. It will reset the gene expression, epigenome and proteome to how it was when we were younger. And unlike other powerful reprogramming therapeutics will do it very safely.
Sounds very promising, thanks.
Akshay – are you considering to perhaps release a topical version of E5? It seemed to have done wonders to Harold’s right hand – and in a very short timeframe to boot.
Hi Michael can’t make that decision till we have a small 5 person clinical trial. Which we will as soon as possible. If those results are as successful then we will start the process of building a factory to manufacture E5 in California. Parallely we will also conduct an IRB trial with 25 volunteers and confirm our regulatory classification. Fingers crossed. This could be a great way to benefit from E5 before it is approved for IV infusion.
Akshay, I know I sound like a broken record, but I’d love to be part of any clinical trial! 🙂
Hi Akshay. If you still need volunteers for an E5 topical application, I’d like to volunteer. I live in California, and am 67 years old, with the usual amount of skin damage from the sun (especially on my calves).
My thoughts exactly and the steps outlined make sense. I’m calling first dips on participating in the E5 topical trial but have an inkling you’ll require CA residency.
Not if you could fly to California for a holiday Michael – for the length of the trial 🙂
Not a bad idea, Akshay 🙂 I actually will have to go back at some point as I still have a bunch of things sitting in storage down in Los Angeles. Once things somewhat ‘normalize’ in regards to airline travel (whenever that happens) I plan on a trip to back there to sell a bunch of that stuff and put the rest on a container heading to Europe. Plus I definitely want to visit a few of the national parks just one more time before I finally shuffle off this mortal coil.
However in all seriousness, the trial would most likely last longer than a month, right?
Speaking of which, how is that patent application going? I’m looking forward to it because it’ll put an end to all this secrecy, at last.
Gregory USPTO is going to publish our patent in July
Could you please clarify what this information will give you? Let’s say their patent name is something like YVN-0522, and then what? I am just trying to understand why are you waiting for this so eagerly.
Patents are public, fully and completely, down to every little detail needed to fully reproduce the invention. If you want to keep your invention secret, it’s called a “trade secret”, and it’s much worse because, for one thing, it doesn’t come with an expiration date.
For example, I knew that the blue gel/NEEL is GHK-Cu even before Akshay said it here, because someone found the patent for it and posted it on /r/longevity.
So why to patent if someone in another continent can produce it for himself? Why to wait for 10-15 years? I do not get it.
Well, and this is a simplification, generally the original authors/discoverers do get some royalties from the ones interested in the production of their creation. This is the way big pharma works, and indeed the price of antibiotics whose patent has expired is way cheaper than the ones with patent alive.
If you want to learn more:
https://en.wikipedia.org/wiki/Patent
Could you please clarify where to? For example. I searched for alkahest patents on uspto and while there is a small information about it being albumin, I still can not see a full details on particular plasma fractions, how it’s isolated from human blood and how much and concentration is infused. I guess E5 will have a similar description?
Hello Gregory, could you please contact me via email? I would ask you something if possible. Here is my email address: [email protected]
I’m applying NEEL to my face and neck for 4 weeks. Unfortunately, I haven’t noticed any change in my skin yet.
What is your experience?
Hello there, Stephan! I’ve been doing the same as you, with special emphasis on the one age spot I had, near my temple. (I am 48 years old, female). The age spot is nearly gone. That’s the main benefit I’ve seen from Neel. My parents have seen more improvements, especially Dad. (They are 81 and 78). Dad is LOADED with age spots, face, arms, and hands. Mom has much less, but one large one on her nose, and a few others. Dad’s age spots are ALL much lighter, and that is easy to see. Mom’s are also lighter, but not as much as Dad’s. We all notice a general skin tightening effect. Have a great day, Stephan!
Hi Akshay,
The drug delivery method described in this paper might be of interest to you and possibly relevant to Neel. https://www.science.org/doi/10.1126/sciadv.abm8478eel.
Jim that link seems to open to an error page.
The correct url is https://www.science.org/doi/10.1126/sciadv.abm8478
This strategy may not work with ghk-cu as it can not survive digestion. But we are working on a nano formulation for delivery to the lungs by a pulmonary pump similar to the ones used by asthma patients. I
Sorry Akshay. Here is the corrected link
https://www.science.org/doi/10.1126/sciadv.abm8478
Thanks
Akshay we have bought three Neel and we have done it from Spain. It is incredible the problems that customs is giving us and we still have not received it, we are sending a documentation that they have requested after two weeks of having the product held there. You have to find a way to distribute it outside the US. Thanks.
Felix some customers have been able to receive it hassle free through myus.com where they pay custom duty online, in advance. Yes we are working on the paperwork but if you think Spanish customs are tough right now we are dealing with incredible paperwork for each country to be able to sell there. We finally had to hire a consultant to help us wade through all the formalities. Will get there eventually.
Hi Akshay,
Any ideas on how Neel compares to OneSkin? Their science seems fairly impressive judging by this recent article: https://www.pennsmithskincare.com/post/oneskin-slowing-the-velocity-of-skin-aging-really
Yes I agree Justin: OneSkin too is developed by a biotech and not a cosmetic company. The founders are PhDs and also have identified a peptide that has senolytic properties on skin. So this will be beneficial to older skin. I like the data they have shared so far. They too have conducted human clinical trial. I have personally not tried so can not say anything further.
Ashkay: Did you see this article that came out today???
https://www.scmp.com/news/china/science/article/3179905/chinese-scientists-may-have-found-vampire-secret-allowing-old
Hi David, Thank you I hadn’t seen that. They have tracked 164,000 cells over 5 years but mentioned only 1 mechanism involving activation of certain stem cells in the old mice. May the full paper May elucidate many more mechanisms? Every confirmation for young blood factors causing rejuvenation is a positive result for us.
When I lived in Almeria Spain, customs wanted a bribe for everything I ordered from USA
Hey, had I known that bribing would help here in Catalonia I would set up a monthly subscription! LOL 🙂
Hola Félix – te recomiendo que no envies nada directamente a España ya que los aduanas son los peores en Europa. Mas te vale usar un servicio de reenvio por ejemplo en englaterra, que le lleve un poco más de tiempo sin embargo se prevé que es más fiable.
Given this comment is aimed at NEEL aspiring purchasers living in Spain, please let me converse with Michael Mehrle in spanish. Thanks moderators.
Hola Michael, gracias por tu amable consejo. Pero tengo una duda: estoy en lo cierto si entiendo que, para sortear a las aduanas españolas, el servicio de reenvío debe partir de los EE.UU., pasar por el Reino Unido y desde allí llegar a España?. ¿Es correcto?.
Gracias anticipadas.
English transation for moderators:
“Hi Michael, thanks for your kind advice. But I have a doubt: am I right if I understand that, to avoid pitbullish Spanish customs, the forwarding service must start from the US, go through the United Kingdom and from there reach Spain? It is right?.
TIA.
Thanks, Michael. For that reason I suggest to Akshay that he enable a distribution method in Europe. US-UK-SPAIN…it’s too complicated
I live in Greece, which is a EU member. I have absolutely no problem receiving medications. For example, I have just received Everolimus shipped from India. The only thing I had to do is to sign a declaration that it is for “personal use”
Hi, I assume Dr. Katcher planned on writing (or already wrote) a second book, since the first one doesn’t answer the fundamental question about E5; is it fair to assume a release in the next few months, or is it further away? (More than one year away.) I could also be wrong, of course, and there is no other book.
to expect* a release.
Also, I know we might start sounding like a broken record, but any news regarding the JHU study? Thanks
Harold as you know writes well so another book may emerge in the future. JHU work is still at early stages and yet to pick up speed. Hopefully that will happen in the next 3 months.
It would seem at this early stage that it is now widely accepted that E5 has great human healthspan potential, that may result in less suffering from chronic illnesses. An extended healthspan and potential for some life extension. Albeit In a female rat experiment. Also if healthspan is decoupled from lifespan, is that not good. A Near 100% healthy life? My bottle is full. This experiment has been thus far very succesful, in my opinion.
Comments based on Josh Mitteldorfs thread re preliminary result analysis. Thanks again from a layman, for allowing me so close to the coalface of these experiments. Another new development.
I echo your thoughts Derek. But Harold and I havent given up on youthful healthspan leading substantial increase in lifespan.
While we await more news on E5, how are you self-experimenters faring with NEEL after more than two months? Any positive/negative changes yet, or is it still too early to tell? 🙂
I can only afford enough NEEL to do a half face test. A difference began to appear after only one month. I plan on posting a photo after 4 months use (in about six weeks) because photos are so dependent on lighting that a greater difference is required to make the effect obvious.
So, those who chose the full body test of cytokine changes should have some results by now. Could said reports be posted here?
Thank you Wayne for sharing your experience with NEEL and for undertaking such a challenging test with only half a face 🙏 We are receiving some great positive feedback from some customers regarding lightening or clearing of spots and received photos before and after of significant reduction of scar – almost can’t be seen.
I’m applying NEEL to my face and neck as recommended for two month.
Unfortunately, I can’t report any changes to my skin or wrinkles.
One reason might be my constant unprotected exposure to the elements (sun, wind, cold). which comes with my job as a adventure tour guide.
Stephan keep at it eventually you will notice the difference. We have had some remarkable photos and feedback mails so it’s working for many.
I can confirm that Neel is quite effective for me. Note that I am age 71 and the apparent mechanism by which the active ingredient works is to reset gene expression for many genes to a younger level. For that reason, one might expect an older person like myself to notice a greater difference than a young person.
Thank you Jim for sharing your feedback.
Hi Ashkay:
The picture of Harold’s hands and the comments about avoiding the FDA approval process by formulating E5 as a skin treatment brought to my mind another possibility.
As you are likely aware there is a very significant industry and a large amount of business being generated through home or office based infusion of supplements such as Vitamin B12, NAD. etc. My daughter is a nurse and after her daytime job often is called by customers requesting a home infusion of some of these. There are also clinics that customers can go to at a reduced price.
It seems to me that this would be an optimal solution for administration of E5. It eliminates the inordinately expensive prospect of large scale clinical trials (and the time required for them), still permits you to conduct the tests you consider necessary to insure efficacy and eliminates interaction and competition with big Pharma. Finally there is an existing infrastructure available to support the dissemination of the product.
Have you considered shifting to this method of accelerating access to E5?
Thanks,
Ed Quinn
Josh has a great group of followers here. Ed it’s certainly a good idea but we would need to go through the FDA for at least one disease of aging. Doctors do off label at their discretion which is very similar to what you are suggesting. E5 topical, fingers crossed, may not require FDA application and approval. That can make it available soon but we have to get our regulatory attorneys to confirm that.
Thanks for sharing your experience. BTW, I am 71 as well.
My wife and I are in our sixth week now and it’s pretty much the same. No visual changes on either of us, however no degradation either. We don’t spend any time in the sun when we can avoid it, so there are no exogenous factors that would interfere with any rejuvenation.
However I want to give it at least eight weeks before rendering any judgement. It took many years for our skin to age, lose collagen, become wrinkly, and less flexible. Reversing that process cannot happen in a few weeks simply based on the way the human skin goes through a cycle of renewal and healing.
If I don’t see any visible changes after three months then I may become more concerned. By the way my wife and I are in our mid 50s – so we’ve got plenty of wrinkles and sagging skin to show for 😉
Has anyone done the suggested whole body NEEL test? If so, were the inflammatory markers tested before and after? And if so, what were the results?
Hi Akshay,
Just wondering if you can give us any update RE: Neel patch? Is the plan still to release in 2022?
Also, I’m about a month in now of 3x daily application of the gel, definitely noticing my skin is much smoother. Gonna crack open my 2nd bottle today!
Cheers,
Dan
Dan,
Thank you so much for your feedback on NEEL. I am so glad that it has benefited your skin. We are getting many such positive feedbacks but there are some for whom it may take longer -like many months of regular application before finally the peptide overcomes all the damage and shrinking of dermal layers.
We investigated the patch technologies but none of them so far met our requirements of sustained release. So we pivoted to another exciting delivery method: pulmonary by mouth. We have an amazing team of highly experienced scientists now onboarded your develop this. We have two targets: through the lung for systemic release into the bloodstream and locally in the lung due to its powerful healing properties which would be a boon to smokers and COPD patients. Systemic release should provide all the incredible benefits we have read in research papers of Dr. Loren Pickart and Broad Institute from skin improvements to cancer protection, DNA repair, endothelial rejuvenation, autophagy/UPS improvements and neurological benefits like anti-anxiety effects. I would also like to know if anyone has applied the gel to their hair and noticed any benefits.
Akshay, as always thank you so much for your speedy reply’s! It’s exciting to get a a window into the development of these products and you do a fantastic job of it. Too bad the patches didn’t pan out but sounds like the new delivery system will be superior. Just to make sure I understand, would it essentially be an inhaler like one would use for asthma etc.?
I have been applying the gel to either side of my mini windows peak but haven’t noticed any change in hair growth so far. Would it also make beards grow in thicker?
Dan yes it would be like an inhaler pump by mouth as used in asthma. Our ongoing human clinical trial is only for skin but I am going by Dr. Loren Pickart who has mentioned hair growth and thickening of hair shafts. It should also work on beards.
I will continue to be diligent with the gel then! Thanks Akshay.
Also, I’m curious if you guys are able to bring anything from the proprietary development of the Gel regarding the way GHK-cu is delivered, across to the inhaler pump? Or because the delivery system is totally different you have to start from scratch?
It’s a challenging task because it is hydroscopic but we have probably one of the best teams working on it who have succeeded with much more difficult molecules. It will take time though. It won’t be overnight. Even after it is successfully made ready for pulmonary delivery there is a lot of testing that needs to be done before we can confidently move towards regulatory evaluation and production. The wait will be worth it if it brings youthful health and relief for lung afflictions.
Hi Scott what’s your age?
Akshay,
Will the inhaler pump be over the counter?
We have yet to find out.
Akshay, is it possible to buy another bottle?
Stephan it’s available at Neel.bio
When will free bottle be shipped?
Soon. Hopefully in August. You will get email confirming shipment along with tracking information.
Akshay: There has been an unavoidable delay in getting pictures to you from the progress my parents had made from the Neel applications to their faces and arms. There had been considerable positive chances by the end of July, in age spots, especially with Dad (who was loaded with them! Unfortunately they caught Covid in July and were also unlucky to have acquired the Covid rash that sometimes accompanies Covid. That rash and the red spots that came with it camouflaged any progress they had made previously. After that has cleared, the will resume taking pictures. The Covid, itself, was not serious for them, and they recovered quickly, in spite of being 81 and 78 years young. I tested positive, also, quarantined with them, but I had no symptoms.
“Chances” should be “CHANGES.” And the “the” before the words “will resume” should be “THEY.” I cannot type today. Maybe I have Post Covid Typitis? Hahaha.
Thank you so much Shay for so generously taking your time out to give feedback!
Harold received an email from a friend from Israel and he said that he had skin tags that disappeared with NEEL so that’s a new use that was shared. I didn’t know what was skin tags so I searched on the Net and Harold told me many people with advanced age get them.
Hi Akshay,
Just wondering if the topical E5 trials have moved ahead as I believe they were planned for August?
Hi Dan not yet. Harold and his team are working on it.
Ok, thanks for the quick update! Is it expected to be a rather quick trial overall? Really looking forward to the results. Also, I feel like if this were eventually released to the market that it would hollow out the cosmetic industry overnight. How would any these brands continue to market their products as “age defying” etc. next to something like E5, which ACTUALLY will defy your age?
Dan you certainly made my day 🤞let’s hope for the best.
From Dr. Horvath: “Umbilical cord plasma concentrate has beneficial effects on DNA methylation GrimAge and human clinical biomarkers” https://onlinelibrary.wiley.com/doi/10.1111/acel.13696 9/2/2022
“We use data from a safety study (n = 18, mean age 74) to investigate whether human umbilical cord plasma concentrate (hereinafter Plasma Concentrate) injected weekly (1 ml intramuscular) into elderly human subjects over a 10-week period affects different biomarkers, including epigenetic age measures, standard clinical biomarkers of organ dysfunction, mitochondrial DNA copy number, and leukocyte telomere length.”
Longevity Goes to the Hill Thursday morning ….
U.S. CONGRESS: SUBCOMMITTEE ON INVESTIGATIONS
AND OVERSIGHT
— THE FOUNTAIN OF YOUTH? THE QUEST FOR AGING THERAPIES —
DATE: THURSDAY, SEPTEMBER 15, 2022
TIME: 10:00 AM
WITNESSES
Dr. Jay Olshansky, Professor of Public Health, University of Illinois at Chicago
Dr. Laura Niedernhofer, Director, Institute on the Biology of Aging and Metabolism; Medical Discovery Team on the Biology of Aging; Professor, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota
** Dr. Steve Horvath **, Principal Investigator, Altos Labs
https://science.house.gov/hearings/the-fountain-of-youth-the-quest-for-aging-therapies?et_rid=856251125&et_cid=4397948
—
It’ll also be LIVE on youtube: https://www.youtube.com/watch?v=_M224pBQv-4
U.S. CONGRESS: SUBCOMMITTEE ON INVESTIGATIONS
AND OVERSIGHT
— THE FOUNTAIN OF YOUTH? THE QUEST FOR AGING THERAPIES —
** RECORDED SESSION AND DOCUMENTATION **
https://science.house.gov/hearings/the-fountain-of-youth-the-quest-for-aging-therapies
Leve thank you for sharing this! It is indeed encouraging to see White House committee discussing adoption of new set of biomarkers by regulators while adjudicating a aging related drug application.
I have used up my 100ml Blue Gel bottle by applying to my face for the past 5 months.
The result is rather disappointing, not convinced in buying another one.
BTW, will the bonus bottle ever ship?
I’ve been seeing positive reviews for OneSkin, have you tried that one yet? 🙂
It would be great to see anyone do half face with NEEL and half with OneSkin. From the two remaining female treated rats one has died at 45th month.
Thanks Akshay for the update. I wonder, do the treatment group rats die with bio-markers of youth? Or do they age rapidly at the end?
@Justin, I don’t really want to jump from one product to another. NEEL was supposed to produce visible rejuvenation within a matter of months, so if the majority of users aren’t able to see results then Yuvan needs to find out as to why. Perhaps the delivery method is flawed, or perhaps the product itself needs refining. At this point we have no data and I suggest Yuvan is proactive on that end.
@Stephan, what exactly did you expect to see. Can you be offer a bit more context to your assessment?
Perhaps certain age groups benefit more than others. That said, I’m 56 and after about four months do not see any significant changes. For example the sunspots on my hands and on my upper torso are still present and have not diminished the slightest. The deep crowfeet around my eyes look exactly the same as they did prior to commencement of the treatment (yes, I have photos). My wife feels the same and mentioned to me that she doesn’t see any changes on either of us.
We both remain cautiously optimistic but at some point the product would be expected to fulfill on its promise, everything else is wishful thinking. That’s not criticism aimed at Akshay/Harold/Yuvan – nobody is finger pointing here – it’s simply the reality of the marketplace. Anyone who has invested in the company obviously wants to see Yuvan succeed, and in order for NEEL ‘out in the wild’ against a legion of competing products it needs to deliver as advertised.
@Akshay, after five months, would it be realistic to expect noticeable changes? I recall a few months back that you suggested that it would take about three months. Perhaps it may make sense to set up a poll (e.g. on surveymonkey) to get a better sense of how NEEL users are fairing with the product.
Michael so far our positive reviews are far more then those who haven’t noticed any benefit. If you go to Neel.bio and click purchase you will be able to see the reviews. From Stephan and your experience not everyone seems to have the same response from NEEL. But fortunately many are having scars from many years go away, spots reduced, skin tone improved, complexion evening out, skin becoming smoother and reduction in wrinkles. It may also have to do with the skin condition. In Stephan’s case he has been outdoors a lot and so such years of damage may not go away in a few months. I am speculating. His skin may have got thicker – collagen may have gone up without yet being noticeable on the surface. There are human trials conducted by third party showing significant benefit to majority of the participants (not all) by GHK-Cu: https://www.researchgate.net/publication/312416949_Effects_of_GHK-Cu_on_MMP_and_TIMP_Expression_Collagen_and_Elastin_Production_and_Facial_Wrinkle_Parameters
Some have benefited by combining with exposure to red and near infrared light. A colleague uses this one:
https://platinumtherapylights.com/products/biomax-rlt?variant=15601444487234
When you aren’t seeing any noticeable benefit should you continue? I would leave that to you. But this peptide also helps in preventing development of cancer as seen in a few studies. Read up on it. There are other GHK-Cu products available for example by Dr. Pickart may be you can try that. May be his combination might work for you. It’s a powerful peptide doing many beneficial things to your skin as a well wisher of Stephan and you I wouldn’t want you both missing out.
Wish you both all the best.
@Michael
Thanks for your thoughtful comment.
Due to my body composition and fitness level, I’m looking much younger than I’m (late 60s). However, a closer look to my skin at my face and hands can reveal my cronological age.
I was hoping with NEEL, I can get rid off the wringles. It didn’t happen. The question is why.
I like YUVAN to succeed with NEEL and E5. Clinical trials are one thing, but we are also a community of voluntary biohackers that could provide useful insides and data. Maybe YUVAN thinks about ways to utilize this community in a better way.
I’m thinking of Josh’s DataBETA project, which, unfortunately, never saw the light of life.
Michael I had posted a long reply but it seems it did not get posted. Anyway here goes again. There have been many positive reviews if you go to Neel.bio and click purchase you will see them so many are benefiting. Some have their scars from many years go away, skin tone improve, complexion evening out, spots reduce or go away and wrinkles reduced. From your and Stephan’s response it seems the response may not be the same for all skin types. He has spent many years outdoor so may be it may not change in few months – I am speculating. But inside collagen may be going up without yet being apparent on the surface. Third party human trials showed significant improvements: https://www.researchgate.net/publication/312416949_Effects_of_GHK-Cu_on_MMP_and_TIMP_Expression_Collagen_and_Elastin_Production_and_Facial_Wrinkle_Parameters
Some benefit by using red and near infrared light like this: https://platinumtherapylights.com/products/biomax-rlt?variant=15601444487234
So after so many months without any noticeable benefit should you continue? I leave that to you. Studies show its cancer protection ability so may be you can try some other GHK-Cu product like Dr. Pickart’s to see if his combination works better for you. I am a well wisher of Stephan and you so wouldn’t want you missing out on its various benefits even with a competing product.
All the best.
Solar aging goes very deep and is often difficult to reverse. Neel may take time to show an effect on severely photo-aged skin.
Even Retin A takes a long time to show some improvement with photo aged skin.
Retin A, even long term, will not completely erase wrinkles formed by extensive solar aging. It only makes them less deep and therefore less noticeable. But it takes time….years.
Avoiding exposing bare skin to solar rays, thereafter, is a must to prevent further ongoing relentless damage.
To maintain the effect, a person needs to protect themselves from sun so that the collagen that has plumped/repaired is not destroyed, again.
The best way to prevent photo aging is prevention…wearing a large hat, covering exposed skin, engaging in outdoor activities earlier than 10 a.m and after 4 p.m. when sun is weaker, or by using more advanced European,korean or Japanese sunscreens.
My skin is not solar aged. I protect my skin from the sun. Neel had a brightening, tightening effect on my skin. I really have not used that much. I only use a thin layer.
I still have laugh lines around my eyes, and where I furrow my brow, but my skin feels and looks improved.
Nothing will make solar damaged skin look like a porcelain doll, again.
Your mileage may vary.
I am 71 years old. Here are some of the effects I have noticed with NEEL:
COSMETIC PURPOSES
Dark Spots on the Face: If there is a difference, it is very difficult to see.
Wrinkles: Fine wrinkles gradually mostly disappeared. But the effect was gradual and not easily observable if you did not pay close attention.
Deep Wrinkles: Slowly the skin tightened slightly, and appeared less deep
Saggy Skin on the neck: Observable improvement
Re Senolytics for Cosmetic purposes
In the past I had used a DMSO solution with senolytics applied once a week on dark spots. After about a year, a few light ones almost disappeared. Also, neck sagginess was reduced.
NON COSMETIC PURPOSES (but VERY useful)
Wound Healing: Extremely effective.
Healing skin irritations: Extremely effective
Numb fingers due to nerve damage on elbow: Improved
My Conclusion:
>NEEL (cu-GHK) is a MIRICLE substance.
>Since cosmetic improvements are due to “cell rejuvenation”. I would expect these improvements to be “permanent”, as long as treatment continues, even with lower dosages. I.e. Treating the cause, not the symptom.
>I doubt if it will have commercial success as a cosmetic, because its effect is slow, and therefore difficult to observe. As a result, very difficult to convince the general public. The general public is not very patient.
My Plan:
On the basis of my experience, the best approach is to use senolytics intermittently (maybe weekly), and NEEL twice a day. Removing the senescent cells will make NEEL’s job easier. I am confident that by using this approach for about a year:
>The skin sagginess around my neck will completely disappear.
>The dark spots might also either disappear, or be much lighter.
>The deep wrinkles will appear less deep (due to skin tightening)
I do have old photos and look forward to comparing with new in about a year.
Thank you Zisos for sharing such detailed feedback. I am hoping that it would work commercially as well due to word of mouth. Some products that really solve a problem become a household regular and are recommended in their circle of friends and family. It may not work for all as it seems from Heather’s post it may take years to repair all the damage and you are right many won’t have such patience. But there are some for whom there is dramatic improvement within weeks or couple of months. From those the ones who had a problem which was solved will recommend. Those numbers can be very big. There are 2 billion people above the age of 50 and growing everyday. In NEEL’s case as you rightly said it’s not just the cosmetic benefit but also skin health which is critical. 1 in 5 Americans will develop skin cancer – 9,500 are diagnosed every day! If that skin cell repair prevents cancer as is shown in trials that itself would be a great blessing. Plus I have personal feedback to give from my own family members. A 53 year old female relative after 6 months of regular use I saw recently seems to have skin of someone who is 30. She had wrinkles on her forehead and not just when she frowned they always remained but now they have almost faded. So for some the results are dramatic. Looking at her now her cousin started and in one month has finished 80% of a 100ml bottle just on her face. It’s changing her skin tone and evening out her complexion which is noticeable. I am beginning to think may be all anti aging therapies may work at different efficacies for different people. In the female rat trial it improved muscle strength significantly for all but for some it really prolonged their life as well. We will see as we get more and more data.
I will note that DMSO is banned for use in the US. It was considered a carcinogenic. This was in the late 1960’s, if memory serves me.
Use at your own risk.
DMSO is not banned now in the US. I fact, it has been approved by the FDA for some conditions. Please refer to this link: https://www.webmd.com/vitamins/ai/ingredientmono-874/dimethylsulfoxide-dmso
Having said that, it is true that when using on the skin someone must be careful. First, must use pharmaceutical grade, not commercial grade. Second, must make sure that skin is very clean, because DMSO is extremely effective in pushing substances deep into the skin.
I have actually used it for about a year with selolytics. I have stopped using it not due to safety concerns, but for different reasons: It irritates the skin, and has a terrible smell.
@justin I have also used NEEL for couple of weeks then I gave up because my skin was breaking out and it irritated my skin. I have had used my fair share of creams and gels etc and usually the first application often tells about the future. Usually, if the very first application does not react well to body I have noticed it is wise to use that product at all. I did not find NEEL to be a comfortable product to use at all. Significant irritation. Dryness as well. Could any of these hypothesises be true:
1. Maybe variation in skin type is getting in the way. And some skin types are just not absorbing / reacting well to NEEL? Some experts in cosmetics industry might be able to help in that case.
2. NEEL is just isn’t as effective? Maybe it does make things better just not as much as the papers say? For example, there is a paper that is talking about hair growth etc. But Dr pickart himself is bald. If it worked it would have worked on him? So there probably is certain limits to using this product.
Abe we recommend everyone using NEEL to also their usual moisturizer this should take away any dryness. Having said that some skins do have reactions to some products and you are right best way is to avoid using it. Regarding its benefits well there are placebo controlled studies involving more than 270 volunteers in different trials that validated its benefits. An institution like Broad which is fostered by Harvard and MIT discovered its incredible array of benefits. Plus we do have so many reviews from customers for whom it has proved beneficial. It’s certainly won’t like some miracle potion giving overnight results. For those for whom it’s suitable it will keep doing its job in their dermal layers rebuilding lost repair capacities.
As some of you that use NEEL are following this thread I wanted to share an important message:
IMPORTANT INFORMATION
NEEL is a powerful gel with deep permeation so it is important to wash with a cleanser, soap, shower gel that you use BEFORE you apply NEEL as any make up or cream or bacteria or virus on the surface may also get entry into the skin potentially causing skin reactions. Also it is important to use a moisturizer wherever you have applied NEEL AFTER washing away NEEL at any other time during the day. This will prevent dryness. Apologies for so much washing and applications but if we want to fully enjoy the benefits of a powerful peptide without any unwanted effects we will need to make this extra effort.
Okay, I will give it another try.
Can we still order NEEL?
Yes
Stephan please read my reply to Mehrle. In 5 months you have used only one bottle or multiple 100ml bottles? If it’s only one bottle than you might not be applying enough quantity on your skin. For larger quantity one needs to massage it till it’s fully absorbed. 100ml should not last more than two months. I observe my family using it so I noticed how it’s getting over.
Michael I had posted a long reply but it seems it did not get posted. Anyway here goes again. There have been many positive reviews if you go to Neel.bio and click purchase you will see them so many are benefiting. Some have their scars from many years go away, skin tone improve, complexion evening out, spots reduce or go away and wrinkles reduced. From your and Stephan’s response it seems the response may not be the same for all skin types. He has spent many years outdoor so may be it may not change in few months – I am speculating. But inside collagen may be going up without yet being apparent on the surface. Third party human trials showed significant improvements: https://www.researchgate.net/publication/312416949_Effects_of_GHK-Cu_on_MMP_and_TIMP_Expression_Collagen_and_Elastin_Production_and_Facial_Wrinkle_Parameters
Some benefit by using red and near infrared light like this: https://platinumtherapylights.com/products/biomax-rlt?variant=15601444487234
So after so many months without any noticeable benefit should you continue? I leave that to you. Studies show its cancer protection ability so may be you can try some other GHK-Cu product like Dr. Pickart’s to see if his combination works better for you. I am a well wisher of Stephan and you so wouldn’t want you missing out on its various benefits even with a competing product.
All the best to both of you.
Michael I had posted a long reply but it seems it did not get posted. Anyway here goes again. There have been many positive reviews if you go to Neel.bio and click purchase you will see them so many are benefiting. Some have their scars from many years go away, skin tone improve, complexion evening out, spots reduce or go away and wrinkles reduced. From your and Stephan’s response it seems the response may not be the same for all skin types. He has spent many years outdoor so may be it may not change in few months – I am speculating. But inside collagen may be going up without yet being apparent on the surface. Third party human trials showed significant improvements: ‘Effects of GHK-Cu on MMP and TIMP Expression, Collagen and Elastin Production, and Facial Wrinkle Parameters’
Some are benefiting by combining red and near infrared light like Biomax 900.
So after so many months without any noticeable benefit should you continue? I leave that to you. Studies show its cancer protection ability so may be you can try some other GHK-Cu product like Dr. Pickart’s to see if his combination works better for you. I am a well wisher of Stephan and you so wouldn’t want you missing out on its various benefits.
All the best to both of you.
@Akshay – sorry for the late reply, I have been slammed all week. Anyway, a quick summary response:
We are definitely applying sufficient product (across the entire body). One bottle usually lasts us two weeks, which would bring it to one month per bottle. Sounds about right.
We actually tried Dr. PIckart’s product over a decade ago but without any noticeable results. What seems to work for us a little bit is LifeLine Pro Plus, however we have discontinued it for now to only see the results of NEEL.
The fact that collagen may be accumulating and only lead to visual improvements later down the line is a possibility I don’t want to discard.
We still have a bunch of bottles left as we bought many with a few more on the way. There’s no downside to continuing obviously so we’ll keep you abreast if anything changes in the months to come.
Thank you Michael. All the best!
Here are some positive reviews:
S. M.
Results:
1.) After 1 week, there was a noticeable difference by touch in the smoothness of skin on the face, forehead, and back of hands.
2.) After 1 month, there was a visible difference in the smoothness of skin on the face, forehead, and back of hands.
3.) After 2 months, previously hyper pigmented spots were barely visible. Small wounds in the hands acquired in an accident healed completely in 2.5 weeks.
4.) After 3 months, the incidence of bruising on the back of my hands is greatly reduced. My perception is that the thickness of skin has increased slightly.
I continue to use the product after 3 months of use and will gladly serve as a reference.
By A.V.
I am 79 years old , female, and came out of last winter with deep cross hatching lines on my face which made me look very old. I used neel twice a day for about a month before seeing any real change. Now I use it on my face, neck, arms and legs with improvement everywhere, but most especially on my face. Perhaps that is because my face gets more product per square inch! I look MUCH younger than i did last Spring and am no longer “bummed out” about my appearance. It has lightened brown spots to some degree on my body, but the bigggest change for me has been the reduction of lines and wrinkles.
By M.
37 yo male that had several dark rough skin patches on my ankle / foot area. For years, have tried many different creams/moisturizers and nothing worked. Tried NEEL and after 2.5 months the dark spot started shrinking. After 3 months it looked like brand new skin like the rest of my foot! Thank you Dr Katcher for this amazing product. I can sumbit photos of the progress week by week if interested.
Akshay, are you still planning to launch NEEL for customers within the EU, February 2023?
Hi Ole, yes we are hoping to do that in first quarter.
From what Harold Katcher is saying in this new interview (22 Sept), E5 (once available) should make your skin look young again: https://www.youtube.com/watch?v=b8mV2I3Ga68
I got dips on the first case as soon as it’s available 😉
Hi Akshay,
I just read this article and wondered, whether this is something, that could help you with the E5 production.
https://news.nus.edu.sg/novel-technique-to-grow-meat-in-the-lab-using-magnetic-field/
“In response to a short 10-minute exposure to the magnetic fields, the cells release a myriad of molecules that have regenerative, metabolic, anti-inflammatory and immunity-boosting properties. These substances are part of what is known as the muscle “secretome” (for secreted factors) and are necessary for the growth, survival and development of cells into tissues. We are very excited about the possibility that magnetically-stimulated secretome release may one day replace the need for FBS in the production of cultured meat.”
Kat I didn’t know about this so thank you so much for referring this! Josh’s readers continue to impress me with their knowledge and research. I was aware of similar effect via phototherapy but magnetic fields too seem so intriguing. The entire universe is held together by electromagnetic force.
Comments by Dr. Charles Brenner on this paper on Twitter:
https://threadreaderapp.com/thread/1679213673771057152.html
So I participated in this thread early on when the development was announced, but decided to go away and let the dust settle because everything was super secret and couldn’t be talked about.
Now there is a product available for at least limited distribution, so presumably things are being talked about in more detail.
The initial product is Neel, which I gather is some sort of topical GHK-Cu based product.
This perplexes me. There must be at least dozens of GHK-Cu based topicals on the market right now. More than half of them claim to have some sort of secret sauce that gives them better dermal penetration, which I’m guessing is Neel’s claim to fame?
To be blunt – what sets Neel apart from all the other GHK-Cu topicals? Forgive me my laziness, but this thread has grown to such massive proportions that combing through it is a considerable task.
Merlin, I made my own topical GHK-Cu 10 years ago using a chemical supply house and mixing hyaluronic acid (around 400 KDal molecular weight), water, and the GHK-Cu. It healed wounds quickly, but it was a mess. I haven’t tried since then until Neel came along, but I can tell you that Neel has worked for me. It made a significant difference in the skin on the top of my hands over a four month period. I will share before and after pictures on request.
Stephen we are so happy to learn that NEEL has benefited you. Your before and after photos would be so valuable and greatly appreciated. Please do email me if you don’t mind: atomicblissventures at gmail dot com
Stephen I’d sure like your pictures!!
Thanks in advance.
Hi, Leve
I sent my pictures to Akshay so that he can provide them to any of you that wish to see them. It’s not a miracle, but it certainly improves skin condition with a little patience. You may be surprised!
Thank you for responding! I will contact Ashkay direct.
I have been following the events on Josh’s Blog here
for 6 years and I enthusiastically wish to see and
understand all developments. Good, bad or indifferent.
The way Josh and Ashkay have kept everyone up-to-date
is just so commendable.
Thanks again!
Merlin allow me to reply. Ghk-cu peptide like most peptide can get easily unstable or inactive if not handled well throughout the supply chain, production, storage. The formulation should protect its stability. The purity should be as close 99% as possible to avoid unwanted impurities. The formulation benefits greatly from development in the lab by biotechnologist s vs cosmetic formulators. As in the lab a lot of confirmatory and in vivo permeation, stability and efficacy studies are done to optimize the formulation. We source our excipients from a multibillion dollar pharmaceutical major and they are pharmaceutical grade not cosmetic grade. Unlike cosmetic companies we invested in an IRB approved human clinical trial to accurately measure response in various skin types of 25 volunteers. A biotechnology product by default should prove superior than cosmetic product. I can share two examples one for ghkcu a product by the scientist who discovered it Dr. Pickart and other is also developed by scientists in lab and made with a peptide called OneSkin. These will prove superior then run of the mill cosmetic products with 30 ingredients one of which is ghkcu. I would wager most would have inactive peptide in it.
Forgive my skepticism, but I’ve heard this story before:
“Our proprietary process ….. ”
“We use the finest materials …. ”
“Our optimized formulation delivers …. ”
Look, I’m going to buy the product and try it and I hope my skepticism is unfounded. But this sounds very much like every pitch I’ve heard for this sort of product. And I simply don’t feel that the initial hype for what touted to be a revolutionary product lives up to the GHK-Cu cream that has resulted.
Merlin your skepticism is not unfounded. There is no miracle topical cream that overnight transforms skin. 99% would just plump up the skin temporarily. We never touted our topical gel to be a revolutionary product. We do think ghk-cu peptide is incredibly powerful probably one of the most powerful in our body going by the data unearthed by Broad Institute. But those effects can be aspired for if it can be successfully taken systemically. Oral doses are not possible, it has a very short half life so injections too wouldn’t be practical. So we are currently investing in developing pump for pulmonary delivery of the peptide from the lungs into the bloodstream. In the meanwhile we thought since skin is the largest organ why not develop a topical version. If you do buy the gel please do wash your skin with soap or shower gel or whichever is your regular cleanser and then massage NEEL gel till it is fully absorbed. Keep it for atleast 30 mins without anything else. Separately please do use a moisturizer everyday to prevent dryness. No matter how good the product is such repair takes time so expectations should be managed accordingly. How much time will depend on the skin condition. The more the aging or damage the more time it will take to rebuild dermal layers. But I will share with you what has true potential to be a revolutionary product under development with us: it’s a biologic therapeutic which we call E5. It has shown unprecedented reversal on epigenetic clocks in mammals. We are now testing on larger mammals. It does require FDA approval to be prescribed so will take years before it will become available. If one is convinced by the data from various trials one can look at joining a Phase II or Phase III trial as a volunteer if one is keen and is above 65 years in age. It has the potential to alleviate suffering of many with chronic diseases onset by aging.
Hello Akshay, I’ve been following since your first E5 results were announced. I’ve bought NEEL and do see a difference. My skin feels a lot smoother and soft. My father is 73 years of age and would love to apply for the phase II or III trials. Please add me to the list. 🙂
Thank you Jesus so much for sharing your feedback about NEEL and your faith and support for E5. We will be certainly looking for volunteers in that age group. Can you tell me your father’s location? As you the Phase II is still some time away but you will here about it’s announcement on NTZ newsletter.
Hi Akshay, thank you for your reply. Really appreciate it. Yea, we are in Las vegas NV. But traveling for this would be no problem for us.
Oh, I’m a believer in GHK-Cu. It’s no miracle but it is useful.
Thanks why I run courses of 2mg/day injected subcutaneously – 4 weeks on/4 weeks off.
I certainly believe I’m getting a systemic effect with a subcutaneous injection. A topical application on top of that can potentially be useful as well to get some localized effect.
Good morning to everyone.
I’ve just seen the report on Sima, the last of the rats. Yes, she looks great for her age, and pretty active.
Just one question if anyone can answer. The protocol of that study included E5 every 90 days till the last of the rats died. But Sima seems not to have got any E5 for the last 6 months. Yet despite of that she hasn’t lost her sight. Why did the protocol stop? Why didn’t Harold and Akshay keep the 90 days dose?
If someone answered I would be grateful, I am really curious. Kind regards.
Hi Ines, the PI took the decision based on her advanced age as to whether she will be able to take the 4 injections of a dose. But Sima had other ideas 🙂 She is so popular at the Lab everyone comes in to say hi and spend some time with her – she laps up all the attention. She is indeed a remarkable lady. May be we should request the PI to continue with her dosing?
Hello Akshyay! Thanks for your information. Actually she doesn’t look her age and seems pretty active! Why not dose her again? It is obvious E5 didn’t do any harm to her….And if social interaction made her the lab pet, sure she and the human staff are enjoying that and social interaction plays a role (just like in humans and other mammals) loneliness is a killer for us as well, why not having her around some more months now that she achieved human friends? The whole study is so intriguing Akshay, two rats made the difference, and Sima even more, why? Keep us up dated on both!!
Thank you!
I’m a big fan of rats. At one point I went to watch wild rats most nights. I agree that they are extremely sociable animals, experiments show they are altruistic, and they adapt to new environments very quickly. I’m amazed how they, with short rearing times and lifespans, can generate a culture (collection of knowledge) and pass it to their offspring.
For this I’m glad the surviving rat is getting the social interaction she needs now her friends have died. It puts a chink in the armour of the study, though. It’s unfortunate that the handlers even know which rats got E5, and the possibility that they could unconciously have treated the groups differently is a problem. I noticed that even the method of measuring grip strength, which required multiple attempts to get the rat to stand in the right place and pull on a platform, could be subject to bias if unblinded. The idea of ad-hoc alterations in dosing schedule could be the basis for criticism, too.
I’m saying this as someone who deeply wishes E5 to be a success, so please believe it comes from that perspective, not as a naysayer.
Tim the rats are coded on their tails that clearly identify their group plus they are kept in separate groups. The PI and her post docs are very thorough knowing how important this research is and will be subject to peer review during submission to a journal. Regarding grip strength the difference is so great between the two groups that it’s difficult to mix up just on that factor: treated were 260% stronger. Plus we had 3 team members taking each measurement to remove any possibility of bias. Harold always want to know the truth whether good or bad as this is not just an academic endeavor but something that he will be injected soon with. So he would want to know for sure that it’s safe and it really works.
Maybe 4 shots every 90 days is too much? Dosing is a stage II trials aim.
Hi, glad to see you back. I have many questions but as you seem to be quite busy I’ll keep some for later. You have mentioned that the Indian lab works faster than the US lab, but I can’t remember if you already explained what they are working on; surely, they aren’t all petting Sima all day. I also wondered if you made any progress on the topical E5 trial; it might be easier to set up now that you’ve had the Neel trial going, I assume; but on the other hand, you already stated quite a few times that your E5 production still is a constraint, so who knows? And as usual, thank you for taking the time to answer our questions; that makes this whole E5 adventure very interesting to follow.
Hi UnUtilisateur the Mumbai lab has just completed a mix gender study in rats and the results are very good. We found that there is difference in the rate of aging and rate of rejuvenation between the genders. Females take a little longer to respond to E5 but surprisingly they not only catch up but in our last grip strength test done day before they were 10% stronger than treated male rats 🙂 So Ines great news is E5 works well with both genders. To complete the study we also sent DNA samples from blood draws to Dr. Steve Horvath’s Clock Foundation and we will soon be sharing those results but as a hint they are quite exciting. I know there has been recent debates about the accuracy and value of epigenetic clocks but from our experience I can say they are the gold standard for testing biological age. Their readings continue to be in sync with our other biomarkers with regards to over all percentage of age reversal. Dr. Horvath is one of the most important, hard working and brilliant scientists of our generation and will some day be validated by a Nobel prize. The E5 topical trial is slated to start next week in Mumbai. We will keep you updated on the results – good or bad. Harold and I are misfits amongst the Ivy League PhD founders but atleast we don’t shy away from sharing the downs as much as the ups.
Some of the most amazing people in the world are misfits, 🙂 Don’t be ashamed by that! We were all placed on this earth to be great at something, you both found out what that something is, and you are doing it your way, which I’m sure everyone in this forum would agree is the best way!
Thank you Dean for your kind words! -very encouraging.
You know why I called us misfits. I was trying to avoid mentioning it but I guess this forum members are almost like family who have been with us through thick and thin. Well a Harvard University scientist who has himself not developed any anti aging therapy recently called Harold a fraud and made a serious allegation that he must have inserted a young rat instead of Sima. This is so hurtful and that too without getting to know Harold or his integrity. In fact Sima can be matched from earlier photos and videos as we code and mark each rat and I am sure upon close observation we can identify her as they always have some unique mark or feature on them. Plus perhaps we can have Steve Horvath confirm her chronological age. None of us are from Harvard and we have nothing against anyone from there but I can vouch our team is self respecting, honest and diligent. We always want to know the truth. Outside our team I hope they can believe in the integrity of Prof Steve Horvath. He has now confirmed twice the significant biological age reversal on his highly accurate epigenetic clocks. I guess their skepticism comes from disbelief that aging is reversed by a small bunch of researchers on a shoe string budget. May be as misfits and outliers we have to work harder to prove ourselves. As we generate more data in 2023 I hope one day we will be able to convince these Ivy League skeptics.
Just do good, you’ve already proved your worth. Screw them and reach for the fountain of youth! Your work has proved your worth. Anyone that can’t see that is just erogant or jealous.
🙏
Hello Akshay,
You sound upset at being mistreated. You shouldn’t let it worry you. I noticed you have a sunnier and more optimistic disposition than I do. My take is that academia is not a place of dreaming ivory towers, it’s more like a collection of little cliques with dogmatic zealots who hate each other’s guts. Probably something you said implies the incorrectness of part of the attacker’s credo, and that can’t be permitted…
When I was doing doc and post-doc, I talked to friends in different disciplines about their day-to-day lab life. The usual set up is that the professor (for us, the boss, not just any lecturer) has some particular dogma of his own and anyone who tries to challenge it will not pursue their career much further in that lab. The research teams at different universities had different ideas, and the professors often loathed each other.
One of my friends did genetic research on fruit flies. They were trying to be the first to establish what a particular gene did with knock-out studies, and only first was good enough. Other teams would visit to try and spy on what they were up to, and they would mislead the visitor (I assume by what documents, reagents, equipment were lying around) so they wouldn’t catch on and steal a lead.
You are better off outside that environment.
Earlier you answered a question of mine about your experimental setup, thank you. I was asking for a reason. I had sent your initial paper to a few colleagues of mine, but also to a one-time friend from Cambridge days. My colleagues are engineers like me, and were all at least interested. The other, now working at a big French government virology institute, and I thought well qualified to understand the science, was depressingly off-hand and dismissive. Her attitude was just to glance briefly at the contents apparently in order to find something about the techniques which enabled her to brush it off without further consideration.
I think when your work is more broadly disseminated you will get a lot of this, and need to be prepared for that and expect it. Anything that could be seen as a methodological weakness will provide fodder for those who just wish you would go away. I hope you have people who can critique in a positive way, which will armour you against the nastier critics who will surely come. Did you ever come across Stephanie Seneff? She was good at supportive criticism, and I note she is still around and making waves.
I’m glad to hear that Harold will soon be taking E5. I only wish I could too. If ever you get a trial running in Europe, let me know and I’ll be there like a shot, if you will have me.
Hi Tim,
Wow what an explanation of world of academic research for someone from outside it. Such major allegations without any effort to find out more about the person or the protocols was surprising to me and I won’t deny hurtful as someone from an Ivy League background may get an audience that will believe what they say. But from your explanation it seems common occurrence and I guess we will be better prepared for more to come. Personally I believe in results. If the results are repeatable and also in humans than it would be the best answer to such atrocious behavior. Phase II of human trials may need to be multi -centered.. As soon as you hear results of phase please do write to me with your biomedical details. Thanks Tim.
Hi everyone here is a new paper that shows benefits of young plasma in old rats:
https://www.biorxiv.org/content/10.1101/2022.12.01.518747v1
Good paper. Important as it is a different team getting similar results.
Hi, Akshay:
This comment should not be “hurful” at all !
Making claims like that, without any facts to prove it, in the end only hurt themselves. So it is not just jealousy. It is also stupidity, as this in the end will hurt the person that made the comment, when his comment will be proven ridiculous.
Of course, this is not the only jealous person around.
I remember Aubrey de Grey commenting on the results of your study that “it is too good to be true”, again without pointing to any weakness of the study. This is also a sign of jealousy (without stupidity). And I am sure there are more.
But nothing like that should hurt. In fact, if anything, it should make you laugh.
What would REALY hurt, is if someone actually found a serious weakness of the study that renders the results worthless. If that happened, you and everyone following you here would really feel disappointed. But nothing like that has happened.
May be you can tell us who made that comment, so we can also laugh at them.
Thanks for the great news. I agree with Dean Bellone, “misfits” might just be what this field needed, your studies’ results will be your credentials.
Thank you UnUtilisateur.
Hi, I’m back with more questions. I think Dr. Katcher said that it only took a few days for E5 to show all its effects on his hand, is it fair to assume that therefore, the topical E5 experiment might only need one application, and then it would just be a waiting game where you monitor how long the effects will last? Or would there be multiple groups, some with multiple applications and some with just one? I also wondered if either you or Dr. Katcher would take part in this study and whether you would get the full E5 injections later on. You don’t seem to be very old, but the inclusion of both people from India and the US might be interesting as some medications work better for some populations than others.
Hi UnUtilisateur there will be variable application protocols to compare and see which protocol shows the optimum benefits. We both will not be able to participate in the topical E5 trial as neither of us are in Mumbai during the trial. But I expect there to be more follow on trials if the first one succeeds. The next one would be an IRB approved trial with a dermatology CRO in the USA.
Akshay:
I think the word maverick is more fitting, as it pertains to you and Dr, Katcher, than “misfit”.
Thank you Heather
Congratulations on this wonderful news
Thank you Jim.
Wow Akshay, so many good news! I can’t wait to read about the results of the mixed gender experiment! Of course you information triggers many questions: Are you going to let the rats live and continue with 45 days dose? Harold wanted to spare them from being analized, and continue to let the live, I guess to set a new lifespan record. Was the female response a matter of frequency and dose? Did that affect estral cicle (so, was there any sign of it). Being able to jump from 60s-70s-80s and beyond back to the 50s again is great and a great achievement in itself, but going back to reproductive age improves overall happiness. And if estral cycle was resumed, you simply would have solved Alzheimer!
Are you going to try anything with a little bigger (and luckier, as this improves health) mammal? Or are there still issue with E5 production?
Thanks again for the information, it is amazing being able to follow this sort of process while most of labs are so secretive. So kind Akshay!
Hi Ines,
No we can’t expand this mixed gender study into a lifespan study as we have limited resources and they need to be allocated as per priority. Sima has already done a great job to show us the potential of lifespan potential. Our main goal from mixed gender study was to compare gender response to E5 head to head. And we have those results. The females started slower but caught up with males including in their epigenetic tests. So that’s a positive finding. We certainly are very keen to move to larger mammals. There continues to be a problem with animal plasma we get from here versus Mumbai. We are trying to figure what that is and hopefully Harold will as a back up we will source from our other lab. In 2023 our main target is to reverse chronic kidney disease in dogs and cats. Some things are falling into place that will enable to accomplish this goal. We do not use induced kidney injury models in the young animal as most other trials do. We only enlist older animals that have spontaneously developed CKD. Reversing a chronic disease while making a larger mammal younger will become the highlight of 2023 and give us the confidence to move to NHPs and humans. Wish us luck. We also hope to publish our bioRxiv paper with Steve Horvath in 2023.
Hi Akshay,
I’m curious to know, why you choose to test E5 on mice with spontanous CKD.
If the tiny tubes have been destroyed (typically due to an acute infection, eating a toxic mushroom, autoimmune disease etc.), how would E5 rescue those tubes?
What is the mechanism in E5 that would restore the function of the tubes?
My father has suffered declining kidney function for 10 years now due to Wegeners Granulomatose.
Currently he is treated with the chemodrug Rituximab every half year. It would be wonderful to have him off Rituximab, but given his age of 85 years, he will most likely never benefit from E5, unfortunately.
I appreciate that you share so many details about you and Harold’s work with E5. I think we are many on this blog that appreciate all of your work and especially openness.
Thank you so much Ole! We have never tested on mice only rats. And CKD we plan to test in cats and dogs early next year. We are nervous and excited. Nervous because first trial in much larger mammals. This will give us a big answer as to whether E5 will work in humans with the same efficacy or not. Excited because if it does work in larger mammals it should be able to reverse a chronic disease and that will benefit millions. Quoting from a paper: Renal tubular epithelium has the capacity to regenerate, repair, and reepithelialize in response to a variety of insults. Previous studies with several kidney injury models demonstrated that various growth factors, transcription factors, and extracellular matrices are involved in this process. E5 should provide those. It may not happen overnight but with repeated doses we should be able to repair and regenerate the tubules. Your father is still not on dialysis so if our veterinary trial is a great success and we do see kidney function improve then we can confer with his doctors and enroll him in the Phase I trial in humans. I wish him good health.
Akshay,
Since you are perusing CKD as a clinical endpoint for E5, you may want to check out the following organization: https://www.kidneyx.org/. Their stated goal is to accelerate cures for kidney disease. They may be able to help you with funding for clinical trials, or navigating through the FDA approval process.
Rick I love this forum and always make it a point to respond because of wonderful members like you. Thank you so much. This may turn out to be quite valuable. Your kind contribution to Yuvan 🙂
Thank you for the explanation Akshay. Much appreciated!
As you know, elderly CKD disease patients are increidble vulnerable partly due to the fact the kidneys perfom so many actions as compared to eg. the heart, which is much simpler organ.
CDK patients are given EPO to raise the number of red blood cells, but the margin must be kept very narrow. Raise it just slightly above the level, which is considered normal for non-CKD persons, and the risk for strokes increases exponentially. Due to stiffening of their arteries, blood level values must be kept somewhat below normal range, and we all know that it leads to lack of energy and suddenly you have this downward spiral, with less energy, becoming more sedentary, gaining weight. Basically a trainwreck in slow motion.
How wonderful it would be, if it turns out that E5 can produce a systemic effects across all tissues. Fingers crossed and keep up you incredible important work!
Thank you Ole! 🙏 From your insightful description it looks like a one way street once the disease starts. How incredibly sad to witness that.
If the decision has been made to break protocol for Sima (the last test rat), is there any reason not to start the post mortems on the rats that have already died?
This is important data for further research.
Will check with PI. There must be a reason to start post mortem only when all rats have died.
I think this is interesting, Sima is 3.7 years old
“Arguably the most accurate data comes from one large study with thousands of animals in which maximum longevity was 3.8 years”.
I would like to emphasize the thousands.
If only with a sample of 8 rats and with the very first protocol and even not following it faithfully, as Sima hasn’t received any dose since the last 6 monts, Sima is about to break a record, this could be the beginning of something.
https://genomics.senescence.info/species/entry.phpspecies=Rattus_norvegicus.
The same link expresses that once, one female under caloric restriction managed lo sirvive till 4,6 years. But again, just one female.
Despite the results (other treated rats died much before some controls), I am cautiosly optimistic, as this is the first experiment. When Shinya Yamanaka managed to handle that recipee of four factors to turn back the age (and identity) of cells, it wasn’t an obvious succes. In fact he was able to turn back the age of 1 cell out of every 1000 cells, aproximately, or even something less than that, much refinement of the process was needed to get the skills and the routine that now seems to be reprogramming a handful of cells in a modest lab today.
So let’s see what happens next. If Sima holds on a couple of moths more, It would be impressive.
Ines that’s a really good post! I didn’t know the stats you quoted. You should be on our communications team 🙂
You deserve somenone that produces less erratum in any text. But thank you Akshay.
I know I sound like a broken record, but still have never received my free extra bottle that was promised for early orders? Did they ever go out?
Hi Dean, not at all a broken record- you have full right to know what’s happening on it. Everyone should receive it by next week.
*** Loss of Epigenetic Information Can Drive Aging,
Restoration Can Reverse It
Featured Genetics Neuroscience·
~January 13, 2023~
Summary: Epigenetics can drive aging in an organism, independently of alterations in the genetic code itself. The breakdown of epigenetic information results in aging in mice, yet restoring the integrity of the epigenome reverses signs of aging.
Source: Harvard
!!
An international study 13 years in the making demonstrates for the first time that degradation in the way DNA is organized and regulated—known as epigenetics—can drive aging in an organism, independently of changes to the genetic code itself.
!!
The work shows that a breakdown in epigenetic information causes mice to age and that restoring the integrity of the epigenome reverses those signs of aging.
Findings are published online Jan. 12 in Cell.
https://neurosciencenews.com/aging-reversal-epigenetics-22248/
– – – –
— C E L L —
Article:
Loss of epigenetic information as a cause of mammalian aging
In brief:
Aging is characterized by changes in
cellular identity and function over time.
This process is driven by changes in
chromatin factor localization during DNA
break repair, which alters the epigenome
and advances the epigenetic clock.
Expression of a subset of Yamanka
factors, OSK, can reverse these changes
and modulate aging.
—
++ Abstract ++
All living things experience entropy, manifested as a loss of inherited genetic and epigenetic information over time. In yeast, epigenetic changes result in a loss of cell identity and sterility, both hallmarks of yeast aging. In mammals, epigenetic information is also lost over time, but what causes it to be lost and whether it is a cause or a consequence of aging is not known. Using a transgenic mouse system called “ICE” (for Inducible Changes to the Epigenome), we show that the process of repairing non-mutagenic DNA breaks accelerates age-related physiological, cognitive, and molecular changes, including the erosion of the epigenetic landscape, a loss of cellular identity, cellular senescence and advancement of the epigenetic clock. Epigenetic reprogramming through ectopic expression of Oct4, Sox2 and Klf4 (OSK) restores patterns of youthful gene expression. These data support a model in which a loss of epigenetic information is a cause of aging in mammals.
____________
Yang et al., 2023, Cell 186, 1–22
January 19, 2023 ª 2022 Elsevier Inc.
https://doi.org/10.1016/j.cell.2022.12.027 ll
_________________
~~ 50 Page Article ~~
https://www.sciencedirect.com/science/article/pii/S0092867422015707?dgcid=author
After 25 years of articles by some of the top aging biologists in the field, the idea that aging is an epigenetic program is still “too hot to handle” in a top journal like Cell. So pro-aging epigenetic programming — which is clearly directional and not purely random — is reframed as “loss of epigenetic information”.
When will they ever learn?
Exactly. As my friend Nicolas pointed out that the article mentions the reprogramming as reinstalling the software but software is a program. instead the process is labeled as antagonistic pleiotropy.
“Transcriptional reprogramming of skeletal muscle stem cells by the niche environment” Published 2/1/2023
These McGill researchers did a good job disproving both irreversibility of epigenetic changes and randomness of aging programming.
Hi, Akshay! Thanks to all of you again for all of your hard work! How can I get my parents on the list for consideration to participate in future human trials for E5? They are 78 and 82 years old, mobile and in reasonably good health, and are willing and able to travel and remain in the trial area, or return, as needed. Thank you.
Hi Shay if we get confirmation of topical benefit from the on going trial of E5 then your parents could enroll in the next topical trial in US. Email me at atomicblissventures at gmail dot com
Thank you, Akshay! I will do that, by e-mail, and provide you with better contact information for my parents. I have their permission to do that.
Hi Gerald, thank you for buying Neel from Amazon! Later please do leave a review as that helps.
Akshay,
Just a crazy idea, but have you tried sourcing your pig blood from a fetal pig processor like Nebraska Scientific (https://www.nebraskascientific.com/)? They don’t presently provide this service, but they do have access to both fetal pig and cord blood. You might be able to get a higher percentage of the plasma fraction that you are looking for from this fetal source.
Rick that is a great idea but the idea was to use a waste product of the meat industry as our raw material. So that E5 is affordable. A typical new drug can cost millions in a year. We are working on ways to even further enrich it. Secondly we are at our peak around puberty that’s why we have not sourced from cord blood.
Akshay,
Fetal pigs are also a waste byproduct of the meat industry, so cost should not be an issue. If the plasma fractions that you are looking for are not more abundant in fetal blood, then this avenue is not worth pursuing. Thanks for considering it.
I see thanks for that information. I wasn’t aware. Yes around puberty is the ideal spectrum we want to mine.
Rick our mechanism of action is a reset of the cell’s phenotype to the age or lifestage of the donor. So fetal or chord won’t be a good target for lifestage. There have been attempts by others without any notable success. We also believe in using a source that is easily accessible. But who knows may be in future when we have extra funds and resources Harold may try that out of curiosity.
Hi Akshay. I came across this paper
https://genomebiology.biomedcentral.com/articles/10.1186/s13059-023-02888-y
by Joao Pedro de Magalhaes. In it it fully agrees with Josh & Harold developmental theory and touches many things and ideas, amongst them, cancer and age. It also mentions the effects of an eventual reprogramming (with whatever method) pointing to the fact that just bringing back the clock may no reverse presbyopia, for instance. Once a body has reached some phenotype, the reversal may be complex or impossible, as some changes in phenotype affect growing tissues, like eye lenses. it is difficult to de-grow.
It seems that the epigenetic theory of ageing is now mainstream. Things changed in few years.
All the considerations concerning an hypotetic body having been rejuvenated brought my mind to the rats and Sima.
were their bodies already analizad? Were the trated rats more or less prone to cancer? What was Sima’s cause of death?
I’m always asking Akshay. Are you about to launch a paper?
Thanks before hand Akshay
Hi Ines did you get my reply?
If not here it is again:
Hi Ines, yes he is warming up to program of aging but still considers it as antagonistic pleiotropy which it isn’t. Aging is part of the ‘software’ design that we inherit to perpetrate recycling. Dr. Vadim Gladyshev’s paper showed us why Nature has incorporated recycling into the software of almost all life forms: in early embryogenesis there is an event that wipes all errors in germline cells. This is critical for survival of species as accumulation of errors over a very long lifespan can make a species vulnerable to being wiped out by an epidemic. But we can take inspiration from the very very rare lifeform that has been able to adapt itself out of this need for recycling. Like the Gingko Biloba tree. It remains young and resilient even after a 1,000 years. Yes this year we are hoping for multiple publications. Our Horvath paper is already submitted to a leading journal and we are soon submitting our Lifespan study paper that has data of Sima and her compatriots also to a journal by next month. There is necropsy data in it and on early preview it looks quite good for the treated animals as the organ and tissue related abnormalities seen in control animals can not be seen in the treated and yet it is puzzling as they did die. As we iterate further hopefully we will achieve optimum treatment to further extend youthful lifespan. Knowing the treatment dynamics it doesn’t seem to be an unreachable goal. My inspiration is the Gingko Biloba tree 🙂
Thanks so much Akshay. So kind to answer so quickly.
It would be interesting to see how much damage in DNA do both groups accumulate. It would be key if the treated group had less mutations in DNA as it would mean that there is not only one way (the OSKM) to erase out those, that can trigger cancer among other diseases, but blood factors.
I can’t wait to read the papers, please, keep us updated.
All the best.
Will do. Thanks Ines.
Hi Akshay,
I am looking forward to the two new papers!!!
Ines point about the “damage in DNA” is very insightful.
From what I gather the rats got long life and health span together from your comments.
Have you had any movement in the cosmetic end of E5?
Thanks for any info,
Gerald K.
Hi Gerald,
Yes we too are looking forward to the publication of both the papers this year. In our first paper we are hoping to add our latest clock results from GlycanAge. So this was very exciting for us: two clocks developed by reputed scientists Dr. Steve Horvath and Dr. Gordan Lauc, both measuring changes in very different parts of our biology: methylation and Glycans on IgG molecules and yet both clocks showing a biological age reversal of 50%! I don’t think any other longevity intervention has demonstrated such reversal or confirmation. We are hoping to add the GlycanAge clock results to our paper with Dr. Horvath. Highlight of the second paper is that despite a lower response compared to males in the females in the lifespan study treated rats consistently lived longer than controls, were almost 3x stronger than the controls and one of the treated Sima now holds the world record for maximum lifespan for her species! They did die though and so the necropsy comparison will be of interest to all of us. We will figure out a way to maintain the peak response so that the youthful lifespan can be continued for many more years. We are not satisfied with a world record of only 4 years. It should be 8 or 12 years to exploit E5’s full benefits. I can not add such great update for topical yet but NEEL gel is now available on Amazon and for a limited time of 3 weeks is available at an incredible discount. Every day the price will increase a little till it reaches MRP so this a great time for anyone in USA who may wish to buy. Our safety trial in old dogs is in full preparation mode. In the safety trial we can not enroll dogs with disease but they are naturally old. We are trying to test as many biomarkers as we did for our first rat study which was 30.
Thanks for the exciting update, Akshay. We are looking forward to the results of the autopsies and the safety trial for the dogs.
I’ve shared Neel with a couple of relatives. It continues to prove itself, though it appears that it requires 4 months to achieve optimal results and then continued use.
Thank you so Stephen! We persevere on the support of all of you. Hope one day I can repay to all our loyal supporters. Yes the time it takes to show results depends on age and condition of the skin to start with. But if a skin peptide has evidence from highly reputed institution of DNA repair and cancer protection we should just make it a part of our daily regimen. The introductory offer is discounted by 35% so stock up and ask friends and family to stock up. Yes if the dogs age goes back by even 30% OMG we would be ready for humans! BTW despite 2 vaccinations and a booster Harold got Covid so let’s pray for his speedy recovery.
Also do not forget to leave feedback on Amazon 🙏
Hi Akshay, thanks for the sale. I moderate an anti-aging group, and told our members about the discount. It seems to be shipping worldwide – is that right? I would like to link to the study mentioned in your promotional material on Amazon. Google can’t find it. Can you provide a link?
Nissenbaum, M.A. (2022, July —). Assessing the Cosmetic Changes in the Facial Skin Utilizing Non-Invasive In Vivo Skin Imaging Instrumentation after Use of a Topical Cu Tripeptide Product in Subjects with Moderate to Severe Photodamage. Identifier 20212157.
Cheers,
Nick.
I started using NEEL 8 months ago in an attempt to fade the aging spots caused by bleeding under the skin (which has become much worse for me over the past 5 years. The age spots have not faded……..but the bleeding under the skin has now been almost completely eliminated. I have had only one small spot in the past 3 months. I can’t be sure the NEEL is responsible but I haven’t changed anything else.
Thank you David for your valuable feedback. Ghk-Cu peptide has been validated by third party research for powerful healing properties. I would request you to make your next purchase on Amazon and do share with others your experience so far in a review as that would definitely help us but also help others who have similar skin issue. Wish you even further healing and youthful, healthy skin.
I would like to thank David Jones and Wayne Johnson for leaving a review on Amazon. This helps us a lot.
Akshay. Wish I could do more than 200 ml, but with 2 minor-aged children and meager monthly Social Security checks…
Hope Neel sales get you to the debut of topical E5.
BestRegards,
Wayne
Thank you Wayne. I am sharing some good news with you by email.
Akshay, I’m happy ro report that I’ve used NEEL for month now and begin to see improvements in skin tone, wrinkle depth and general tightening of the skin. I do consider using NEEL on larger skin areas, but I’m wondering, if the copper contents could potentially lead to copper toxicity, if used over a prolonged period and on larger skin areas?
Ole thank you for sharing your experience with NEEL-glad to hear it’s benefiting you. Application on skin is not a way to enter molecules in bloodstream otherwise there would be no need for injections or oral pills. Some transdermal patches claim to do this but our evaluation wasn’t successful that’s why we are looking at other delivery systemic option. So no worries there. For additional comfort you can consider taking a zinc supplement.
Hello Akshay. It showed 50% reduction but we do not know if continued, they would live more and more or rats would have died as in female lifespan trial. Is this correct? It’s a pity that we still do not have anything that can even double the lifespan…
Hi Katerina,
Yes totally agree – it is a pity. We are not satisfied at all by such lifespan increase. We aim for doubling or tripling the known maximum lifespan. Is it possible? I think so. What we have is so powerful that on average two different clocks calculated reversed biological age by 50%. Humans have been trying to do that from thousands of years. Now it’s a question of improving the potency, adjusting the dose, etc. to see what leads to increase in lifespan by multiples. Then we have to do the same for our pets and humans. Will it work the same? Well surprisingly there is very small difference in the protein coding genes between mice and humans and the secretome circulated in plasma is even more similar as it is highly conserved. We have proven the latter in our lab by getting the 50% reversal with cross species plasma fractions and is part of our IP. So lots of lab hours ahead but so is the fire to make it happen.
Thank you Akshay. Generally I am super pessimist and critical in every dimension, however, as I see how rational you are, it does not even sound as overhyped and exaggerated. The question is if changing secretome can affect all aspects and hallmarks of aging, a little bit confused here. All the best.
Katerina, thank you for your kind evaluation. Changing secretome isn’t everything. There two primary sources of change in the cell’s gene expression and protein production: from inside it comes from the transcription guided further by the spliceosome. Unfortunately the most important and the vast majority of our transcription is highly under studied: majority doesn’t code. We have focused in the last 7 decades on the minority protein coding transcription. But as we are learning the majority of the transcription in humans is involved in regulation at multiple levels bringing about changes in gene expression and proteome. The second source of major changes comes from the cargo of the secretome. This too is universal. Every lifeform is made of cells and every cell secretes. So people miss one incredible advantage we have versus other drugs: we get VIP entry into cells and the nucleus. Whereas in comparison it took them 2 decades of research to figure out how to get the mRNA for Covid vaccines into the cell. We can literally send over as many change agents that we want safely (now we are trespassing a bit into our IP). So E5 is competing with legacy transcription. It’s not an easy battle and so far despite reversal of age by 50% and increasing muscle strength by 3x our treated still die. The problem is that amount of spliced transcripts are almost limitless. Let me share one paper with you for your reading pleasure: https://www.cell.com/cell-systems/fulltext/S2405-4712(17)30547-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2405471217305471%3Fshowall%3Dtrue#%20
But you know how solutions are born? By understanding the problem fully first. I wonder if even the senior longevity scientist have such clear view of where and what is the cause of pervasive changes that come uninvited with aging leading to death (Nature sees it as recycling having made reproduction so compelling). We are constantly thinking on how to leverage the powerful antidote we have discovered to overcome the legacy transcription. Is it impossible? From what we can see so far apparently not. We hope to reach an inflection point where Harold believes we may reset the transcription and spliceosome clock itself. Any evidence of that would be incredibly exciting. We are filing more patents as we take another step towards improving E5. I have some exciting ideas yet to be tested which I can’t disclose now but have the potential to be transformational for E5 therapy. In the meanwhile we continue to test it on larger mammals towards human application. Even in its current state if it can reverse a chronic disease or improve and increase youthful healthspan it would still have a market.
That’s why I do consider you and Harold to be the only scientists who saw light in the very dark and “no way to escape” room from the day 1. I wish Harold a super speedy recovery.
Thank you Leo! I will pass on your wishes to Harold. You have always been a true believer in us 🤝
Thank you for your explanation. This is beyond my possibilities to understand but I will try to read it many times. Thanks!
Akshay, I received my first bottle of NEEL blue gel today and would like to know, if I can use it in combination with my vitamin C skin serum?
Hi Ole, first of all thank you for your purchase of Neel. Hope it gives lots of benefits to you. Leave a review if you can. I do not have data for that interaction if possible use them separately.
Hi Akshay!
Thank you for your good and interesting work with Harold.
I have also ordered a couple of bottles of NEEL (2X100 ml).
I am in my 50ties Today I use regular moisture cream in my face and neck(including resveratrol). I am happy with that but hope NEEL may rejuvinate the skin a bit although I look like I am in my 40ties today I would say…
I plan on using it on face and neck and one hand for comparison. Would that be a good strategy og would you reccomment the whole body ? Is there some systemic rejuvination in NEEL or will I have to wait for the E5 for that ?
Just an update from me:
The NEEL came earlier than expected wo I have been using i for a week now. 3 times a day. I am using it in the face only.
It feels like drying out my skin a bit, so before night-time I put some ordinaly moituring cream (with resveratrol) on top.
Seems to be some pigments in the NEEL influencing skin tone slightly but no noticible changen (rejuvinating) seen so far.
Good instructions on the bottle so I will keep on 3 times a day for a month, the daily.
Hope to see some effect in not to long also.
Thank you Are for purchasing NEEL. I am glad you are diligent with your applications and are using a moisturizer- we encourage everyone using NEEL to separately use a moisturizer atleast once a day. The improvements have already begun but skin cells take about every 28-40 days. With each turnover there will be some incremental improvements. Depending on your skin’s health it will take that much time to become discernable. First change you should notice is on skin tone. Unlike other cosmetic products Ghk-Cu has properties of enhancing DNA repair, rejuvenating elastin and collagen so one should consider making it a part of one’s daily skin care routine. Afterwards you can reduce the number of applications to twice a day and later to once a day for maintenance. Wish you great looking skin! If you do notice any improvements please do leave a review as it helps.
Hi Akshay!
Just a status report from med her having now used the NEEL in the face for almost 2 months.
I have a few “darker spots” in my face and I thought I saw some changes on the biggest a couple of week ago, but I am not sure.
I was hoping that my wife should give some compliments by now noticing how fresh I look, but nothing so far.
In order not to run out of stock I bought two more 100 ml bottles and a 30 ml bottle so that I have for traveling this summer as well.
I will continue usage and hopefully there will be incremental improvements although I see no sign of any rejuvination so far. In a couple of months I will evaluate pictures I have taken to get a better comparison.
I root for you and Harold both to the NEEL and the E5 and wish you the best of luck for the dog-testing of E5 and hope this new pig-possibility you talked about may improve time to market. Keep pushing, time flies 🙂
Thank you Are. Thank you so much for your continued faith despite not noticing improvements! Hope you are using sufficient quantity? A 100ml should last a month. I use 6 to 8 squirts just for my face. Regarding rewards for your perseverance I encourage you to read review left by Zisos on Amazon. It will be eye opening regarding use and timing of NEEL gel. He has also shared a photo. So Zisos you must know is one of our first backers/investors in Yuvan but he doesn’t shy away from sharing honest feedback. His experience can be a roadmap for any with accumulated skin damage over many decades and of course due to aging. Once again thank you for your kind wishes and wishing you beautiful young skin.
Hi, Are
Regarding NEEL, I would say this:
Rejuvenation does not happen immediately. The process is so slow, that it is almost unnoticeable. I have noticed in a few months that small wrinkles started becoming smaller, until they completely disappeared. If a person sees me every day, that person will notice nothing. However, after a year of twice daily usage, I saw huge difference. I had a big “turkey neck” (skin hanging under the chin / around the neck), that was reduced by 70-80% in a year’s time. Wrinkles around the eyes completely disappeared. And eye puffiness substantially reduced. To see the amazing effect of NEEL, someone needs to be patient. Unfortunately, the damage that accumulated in decades, cannot be fixed overnight.
As far as dark spots are concerned, NEEL was not very effective until now. I saw some change, but it was not huge.
Also you can use NEEL for all sorts of skin issues. Minor wounds will heal much faster. Apply it on cold sores (herpes) as soon as you start feeling it, and it will go away very quickly, without reaching the maturity stage. All in all, I find it a miracle substance. However, it is easy for someone to get discouraged, since you cannot see the difference from one day to the next.
I suspect many people get discouraged, and discontinue use before realizing the substantial benefits of NEEL in the long run.
Thank you Zison and Akshay !
I think I use about the abount you describe, Akshay, in the beginning 3 times a day, whereas now it is 1-2 times a day. I have used about 150 ml in almost two months.
I agree with you Zison that it is easy to quit when you dont see results in say the first month. I will continue, I just bought 230 ml more and I will continue. The bottles are very neath.
The 30 ml I will refill and use for traveling.
It does cost a bit for the NEEL, maybe a possibility could be a larger simpler refill botle (say 250 ml) that maybe could be a little bit cheaper per ml to keep people continue buying ? Maybe people buy anyway? I will buy it regardless, and maybe it dont matter.
Keep on the good work and good that you support Akshay and Harold, Zison and I can assure you that if the E5 works as i hopefully does, the return of investment will amasing!
Thank you Are for your kind words of support to Yuvan and Zisos. Refill pack is a good idea but to ensure quality of the product remains intact for longer periods we use airless bottles which may not be possible for a refill pouch or jar. But right now Amazon inaugural pricing is still much lower than retail price (it keeps rising everyday till it reached retail price) so one can take advantage of that. Also subscriptions should also give further discounts.
Ole May be it could help. Someone has to find out.
I agree 100% with Zisos regarding NEEL’s efficacy. The changes are not noticeable at all on a daily or weekly basis, but over a 3-4 month period you will see a significant improvement in skin texture and appearance if you’ve been taking photos. For the underlying tissue it takes longer but does help.
Hi Are
I actually use around 30-40ml of NEEL on my face and neck each month. Applying it on wet skin makes the application process very convenient. Additionally, I incorporate an AHA peeling treatment into my weekly skincare routine. My belief is that by removing old and excess skin, I can make room for new and rejuvenated skin. However, I’m uncertain about the actual effectiveness of the peeling.
As far as I know the only way to remove excess skin is through a facelift operation. While a facelift provides immediate results, it doesn’t address the overall health of the skin, which tends to revert to its previous state over time. Moreover, facelifts are expensive and carry certain risks, as is the case with any surgical procedure. On the other hand, using NEEL is a gradual process, but it promotes the development of healthy skin that promotes a youthful appearance as you age. In other words, you look younger as you grow older.
While NEEL might appear a bit expensive, it is actually a bargain if you compare it with alternatives.
@Are and others using moisturizers to hydrate the skin, stay away from cheap moisturizers containing oils, as these will just upset and break down the skin barrier. Ideally, choose a moisturizers which has the correct ratio of ceramdies, fatty acids and cholesterol to support a healthy skin barrier.
I recommend Emu oil – works great as a moisturizer.
I wonder, if combining OneSkin with NEEL would generate synergestic effects on old skin? I assume that people over the age of 50 must have accumulated some degree of cell senescence through the different skin layers and do we know, how NEEL acts on cell senescence and SASP? Even a fraction of senescent cells can potentially poison the neighbouring cells.
Thank you guys, Akshay, Ole and Michael.
Good getting clarified that NEEL does not work as a moisturing cream such that feeling dried out is natural when I did not take my “regular” moituring cream on top.
The quality difference of moituring creams I have not thought of. Thanks for informing on that. Browsing for supplements hopefully having some senolytic effect on Swanson I came over a mointuring cream containing resveratrol:
https://www.swansonvitamins.com/p/swanson-premium-resveratrol-wrinkle-cream-hyaluronic-acid-2-fl-oz-59-ml-cream
This cream feels OK so I use that mostly. I will check your parameters befor buying more next time, Ole! Thanks.
I also buy fisetin, querecitin and curcumin from Swanson to hopefully get som senolytic effect…
In the Norwegian farmed salmon industry I have noticed how much the biologists seem to be able to maipulate the salmon. I have no biotec competence but intuitively it should be possible to manitulate ourselves… You, Akshay and Harold seems to be the best so I am rooting for you and the E5 🙂
Thank you so much Are. Random mutations and evolutionary adaptations can be considered as manipulations which allowed our species to survive and thrive and gifted us with superior intelligence. Now this intelligence is taking over and the adaptations and manipulations will happen at a much faster pace than evolution. But our species also harbours greed and selfishness. We have to hope that these negative traits do not exterminate us and our planet before we can derive the benefits of our biological adaptations and manipulations.
Gerald that’s difficult to predict. We have to take it one step at a time: first we need human clinical trial evidence after that we have to get it ready for production to ensure consistent high quality product that’s stable at room temp. Then setting up supply chain and manufacturing facility for mass production. Then soft launch and then launch on various marketing channels including Amazon. The good news is that if we do not make any medical claims then we may not need to go through FDA IND approval process. Wish us luck.
Hi Gerald we haven’t measured circadian rhythms so can not give you a definite answer but my guess would be yes.
Best wishes to Harold. Hope he’s on the mend.
Thank you Derek! You will be glad to know Harold is a fighter: even with high fever he was so chirpy the doctor almost discharged him lol. He should be home soon. All of our prayers are with him 🙏
Indeed they are. Thanks for the news.. His enthusiasm is admirable.
You are welcome Derek. I feel like all of you supporters are part of our company and one day we will all jointly make history. When we do we all have to meet in person to celebrate 🙂
Hi Akshay,
Wishing Harold all the best in his recovery.
Thanks for suggesting reading the paper “Universal Alternative Splicing of Noncoding Exons” !!!
It gives me a better idea of what Harold and you are facing.
Looking forward to the dog trial results.
Will you be using Larger shorter lived dogs?
I ordered some of the Neel product from Amazon.
We have several skin areas that may benefit from it.
Gerald K.
Hi, Akshay! When my parents, who are similar in ages to Harold, had Covid, electrolyte drinks seemed to help them a lot! My parents and I pray for Harold’s speedy recovery!
Thank you Shay! That’s a good idea. Will make sure he gets them.
Hi Akshay. I read several of your comments and as I got it, your medicine can become precise enough to achieve outstanding benefits in terms of lifespan extension, not just healthy golden years.
This is gorgeously important and motivating, but may I ask you why your current state did not extend the maximum lifespan of treated group, not even close to regular parabiosis experiments? What could be an issue and do you have a real idea how to make it work?
Your huge fan.
Wish you success.
Hi Azza, thank you for your longstanding support. I explained this to some extent in my messages above about the battle we are fighting with legacy transcription and how pervasive it is. But it is a big breakthrough if one understands what the problem is as only then one can hope to find a solution. I do have IP on what will improve it by 5x. Now have to test it. But this process will continue on and on even after we have a product out in the market. I have one more plan that can potentially keep us constantly in rejuvenated state but this will take longer to develop and require bigger funding. But I have no doubt we will be able to test this too. At the same time we all should be happy that our therapeutic even at its current potency is reversing biological age on two different clocks by 50%, improving muscle strength by 2.7x and breaking world record for maximum lifespan. The latter is indeed remarkable. Nature/evolution has guarded this with a hundred arrows. We have never witnessed any human live beyond 123. Even our current E5 can breach that with youthful health. Future versions could have potential to increase youthful lifespans by multiples and not just decades.
Thanks Akshay. I wish you not only a huge but rapid success as well.
I just watched a new interview of Matt Kaeberlein on Tom Bilyeu show. He said that age related inflammation is really affecting a functional decline but he doubts that it’s a main thing aging is manifested as and he does not think that the fundamental feature of biological aging is chronic inflammation. He said that mTOR inhibition with Rapamycin extends lifespan robustly in every organism, including in Yeast and yeast does have an extremely rudimentary immune system, and Rapamycin but mTOR inhibition still works there. He also mentioned that there should be a universal action how mTOR is affecting aging in yeast and in mammals.
If you have some time, could you please share your opinion on this? What do you think how mTOR inhibition works? How it can affect plasma components? Because some people claimed that Y reprogramming or E5 is still unable to show better results than Rapamycin does currently(34% lifespan extension). Seems like mTOR is driving a programmed aging? Dr. Alan Green believes so as well.
As one of the many non-scientist spectators in this forum I always try to be extra careful to not post any comments outside of my scope of knowledge or my understanding of what boils down to being a host of extremely complex biological processes that result in what we term as ‘human aging’.
That said, since I took an interest in gerontology and life extension back in the mid 1990s one thing has always been extremely clear to me and I believe it is one of the few ideas that have stood the test of time:
We are in a race against time and our collective goal here in the third decade of the 21st century should not be to achieve immortality. Instead we should seek to leverage as many of the scientific advances as we can to slow down our own aging process to the point where we are able to take advantage of the next advance, and then the next one.
By doing so we basically step back in time just a little, extending what remains of our respective biological lifespan just enough, to hopefully catch the next curve of advances if you will.
That’s been my M.O. over the past 30 years and despite a serious illness a few years ago I’ve been doing well, so has my wife. In summary I hope that E5 will be available soon enough so that I get to bump out my future day of death just enough to catch the next bandwagon.
If it fails – what’s the worst thing that can happen? I’ll die on the day I was always supposed to. As a trader I would call this as a bet with very limited downside (money and time spent – the premium) in return for unlimited upside. So in a way E5 is like buying a call option on immortality 😉
If you ever read ‘The First Immortal’ by James Halperin then I’m sure you get the general idea.
After you twenties are gone, the probability of death increases dramatically. Human natural lifespan is 38 years. After that, we are living in a borrowed time.
I do not know how old you are, but now tell the same to 70-80 years old person and wait what the answer will be. There is no guarantee and not even light that we will have as dramatic and superb intervention that will make us young again safely, of course, except E5. Not even Y factors, I guess. So what you are saying, is simply an act of surrender and getting used to the reality that we are all going to die so live life to the fullest every single day!
Hi Akshay,I have had best success in Covid cases with Vit C , 15 grams,intravenously,+ Glutathion 1000mg-2000mg i.v. Vitamin D ( Calcifediol 100000i.U ,Zincorotat
60mg, Quercetin 2×500 mg.After day 6 dayly Heparin Injections. As the Spike kills all Bifido, I would add a LaktoBifido Supplement.I had no hospitalisation and no Long Cov.In Germany there is a Phosphadidylcholin for Infusion ( Nano PPC, Viktoria Apotheke, Saarbrücken), that also prevented hospitalisation, and Long C , if given during infection, and cured Long C, when given after the infection .
To the commenters, who are only satisfied with dubbling or trippling of lifespan: I am 75 , and I would be the luckiest man on earth, if I could get 50 again, with all the fitness and sharpness.and endurance….
Many thanks ,Best wishes to Harold.
Peter Ross
Azza, mTOR functions as a sensor to switch on growth or repair. They are like a gas or brake pedal both can’t be pressed together. When we are young it works really well optimizing between the two. As we grow older it leans towards growth which leads to repair falling behind damage. So when rapamycin inhibits mTOR it upregulates repair to some extent. Nrf2 is one of the most powerful repair pathways which is inversely related to mTOR. It augments very powerful antioxidant enzymes, autophagy, protein production support machinery, DNA repair, NAD+, etc. I do both: take low dose rapamycin once a week and upregulate Nrf2 couple of times a week by taking pterostilbene, andrographolide, Sulforaphane, myrosinase and quercetin. I also take spermidine and oleuropein with them. But when you do a heavy weight lifting work out in the gym you also need growth to rebuild those torn muscles. That’s why chronic inhibition of mTOR is also not good. Also this benefit is in a narrow range. Will Rapamycin make us young again? No. Will E5 make us young again? Yes it works at a much higher level: resetting gene expression and protein production selection. So it has the potential to make us young again.
Thanks a lot, Akshay. I am no expert but as Vera Gorbunova mentioned in one presentation, Rapamycin does also regulate the expression of genes. It upregulated positive maximum lifespan genes and downregulated negatively associated genes.
Yes Azza, Vera is right and I am a fan of her research but those changes are happening due to the inhibition of mTOR and so have a narrow set of changes linked to mTOR. Whereas E5 gains entry easily into cells and directly regulates almost every gene and protein that was changed by aging up or down to match that of the donors age. That’s why with E5 we see more than 30 biomarkers reversed to youthful levels, memory and grip strength improve significantly and also breach the world record for maximum lifespan. Another thing you must check in the rapamycin study is at what age they began the intervention. E5 begins at human equivalent of 75 years and still does all these changes.
Thanks Akshay. I am not trying to compare E5 with Rapamycin. Just wanted to point this latest study.
In this one, they did a comparative transcriptomics on 26 species with diverse lifespans. They identified thousands of genes with expression levels negatively or positively correlated with a species’ maximum lifespan (Neg- or Pos-MLS genes). Neg-MLS genes are primarily involved in energy metabolism and inflammation. Pos-MLS genes show enrichment in DNA repair, microtubule organization, and RNA transport. Expression of Neg- and Pos-MLS genes is modulated by interventions, including mTOR and PI3K inhibition. Regulatory networks analysis showed that Neg-MLS genes are under circadian regulation possibly to avoid persistent high expression, whereas Pos-MLS genes are targets of master pluripotency regulators OCT4 and NANOG and are upregulated during somatic cell reprogramming.
Azza, that’s why I take rapamycin. Till we get E5 that’s the most powerful anti aging intervention available. Its gamut of changes would be similar to what we see in hormesis. Besides the changes you mentioned mTOR is also inversely related to Nrf2 so it would also activate all the repair genes. The challenge is that as we grow older more and more of our proteins immediately after production are negatively regulated by miRNA assassins. So we expend our declining energy to produce these proteins only to have 60% terminated by miRNAs binding to them (as per one study). Resultant we don’t get full fruit of the positive gene expression changes. We are yet to do this study but I would expect E5 to reduce transcription of these protein assassins. The other difference we should compare is the change in those genes by what percentage as that modulates the depth of change. Personally I like rapamycin more than metformin – I have tried both separately to note their physiological effects. I feel loss of energy with metformin but the opposite with rapamycin. The change is noticeable. I don’t know what has been the experience of others here who take it?
Hi Akshay,
A few ago, you said people like me who exercise a lot and practise fasting do not need to take Rapamycin and Metformin. They achieve similar effects on the mTOR pathway due to their lifestyle choices.
Do you still stand by this?
Hi Stephan, you have a very regular weight training exercise and fasting regime from what I recollect. I am trying to remember how many times you run, at what speed and for how long. But yes if those are at their optimum as they also work via hormesis there is not much incremental gain that I see from taking rapamycin and metformin. I fall under the majority that are unable to be as regular as you are and so can benefit from them. Did I suggest upregulating Nrf2?
Hi Akshay,
I don’t run at all but hike the mountains on average 250 km a month. Yes, I’m very committed to resistance exercise, which I started at 58. It was the best decision for my health, physically and mentally. Without it, I would not be able to still lead multi-week canoeing and hiking tours in remote Northern wilderness in my early 70ties.
If I recall correctly, you didn’t mention upregulating Nrf2. From one of your latest comments, I learned that you take more than a dozen supplements to do so.
Just wondering whether there is a shortcut.
Stephan that synergy is required for ensuring sufficient bioavailability. If you don’t run there is shortcut for that: sauna.
Thank you. If I have the time I’m going 2 – 3 times a week to the sauna. If not, I do alternated hot and could showers.
I take it once a week Akshay and I too feel very improved energy. I think it’s a product of lowering age related inflammation and shutting down SASP and other hyperfunctions.
Interesting study you mentioned about the proteins. Does it mean we still produce them but become “resistant” because of miRNA? So proteins are what runs our body and metabolism every second?
Sorry if too incompetent.
No you are right Katerina (not at all incompetent 🙂 So aging onslaught is so pervasive it not only changes gene expression decreasing helpful proteins and increasing ones that would become harmful when expressed more than needed but it also attacks proteins before translation, during translation and after translation.
Thank you Akshay. It’s now clear how all this destabilization happens. The one interesting thing, however is the fact that aging starts even at gastrulation, therefore we can not consider it as a continuation of development. If nature wants us to be strong until our puberty, why it makes us age during the process of gastrulation?
Hello
What is the best way to buy Rapamycin, and how much should I have each day?
Thanks!
Hi All of you who are following our research if you would like to vote for us – it will take less than one minute if you have a LinkedIn account – than please do so here:
https://www.linkedin.com/posts/startup-founder-world_activity-7051343810810810368-ECEn?utm_source=share&utm_medium=member_ios
Thanking you in advance. Please mention here if you do vote so I scan thank you personally.
Voted Akshay! Is there a place to view this presentation though?
Cheers!
Thank you Dan! I can email you
Voted 🫶🏼
Thank you Leo!
Hi there, I voted, but I would like to see what I voted too!
Thank you Ines! Emailed you already.
Voted.
Well said Katerina. I get disheartened when I still see articles by major scientists mentioning entropy and stochastic changes for aging 🤦🏻 https://www.biorxiv.org/content/10.1101/2022.02.06.479300v1.full.pdf
And what is the grand conclusion: that aging can not be reversed! We have already demonstrated that it can in mammals on two different clocks developed by highly reputed scientists.
In one interview, Josh mentioned that they all refuse to call it program because it’s bad for funding. So maybe that’s an issue? Or why they still call it antagonistic pleiotropy-in fact, a type of wear and tear)
Voted
Thank you Zisos! Our first backer!
Hi Toby,
I am not an expert on rapamycin myself but Dr Alan Green has been treating patients for years and recently gave this very informative interview on how he treats his patients with rapamycin for longevity. You may want to reach out to him.
https://youtu.be/zWJQecgNloU
Voted! Akshay, please email presentation to: [email protected]
Thank you Ole. Sent.
Love your reply, this is getting so exciting! Keep up the great work.
Thank you Dean!
Hi Akshay,
This is my first post here, but I have been a lurker on Josh’s blog for almost a decade. I am a huge fan of yours and Harold’s work on aging. (I am not an expert, so I have avoided posting here to not disrupt the conversation.) I have voted for you on LinkedIn and I am wondering if you could share a link to your presentation here, or maybe send it to my email?
Thank you!
Thank you Derek! And thank you William! Thank you for following our work. Can you share your email? Or if you have mine send me a hello.
Akshay, why aren’t you making your presentation public?
Stephan no special reason – only because it’s not meant for public distribution. As you know our colleague Nicholas sends out our latest updates via a newsletter.
Good Luck. I’m at [email protected]. I’m in Yorkshire though not in Montenegro (me) !
Thank you Nick!
You got my vote, now you owe me the link 😉
Thank you Stephan. Sent.
Hi Akshay ,
I forgot to include my email address on my previous message. Thank you for keeping us informed and generously sharing your time with us . My email address is [email protected] .
I am looking forward to watching your presentation.
Voted.
Thanks Akshay for your email and sharing with us so much exciting news.
Hi Akshay. Following your great work for several years. Just made a LinkedIn account and voted 🙂
Thank you Adam!
Voted. My email address is [email protected] Thanks
Thank you Felix!
Voted Akshay, thank you very much for your work and discussions here. Link for presentation [email protected]
Hi Akshay, could E5 be refined to affect the glymphatic system and clear waste more efficiently from the brain. As we age, the glymphatic system gets impaired and leads to the accumulation of metabolic waste and neurotoxic proteins. Recent research has found that increasing the amount of long aquaporin 4 might increase waste clearance via apigenin or sulphaquinoxaline (which is not safe for human consumption).
https://academic.oup.com/brain/article-abstract/145/9/2982/6671408?redirectedFrom=fulltext
https://elifesciences.org/articles/82232
Also, in 2020 researchers used a double mutant in which the insulin signaling (IIS) and TOR pathways were genetically altered. Because alteration of the IIS pathways yields a 100 percent increase in lifespan and alteration of the TOR pathway yields a 30 percent increase, the double mutant would be expected to live 130 percent longer. But instead, its lifespan was amplified by 500 percent. The increase in lifespan would be the equivalent of a human living for 400 or 500 years. Imagine if a future version of E5 could achieve this.
https://www.cell.com/cell-reports/fulltext/S2211-1247(19)30858-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124719308587%3Fshowall%3Dtrue
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Hi Ghalib,
I don’t like any mutant or induced model study as past events show it’s very difficult to translate. But yes I agree with you that is being able increase our maximum lifespan is not far away. If in the young the glymphatic system works efficiently in clearing metabolic waste then we can expect the same with any therapeutic that systemically reverses biological age to youth. So I would be optimistic about E5 doing the same. If it’s to do with autophagy then E5 does upregulate autophagy. If there is a specific assay to test this waste clearance we would be happy to run it in our next study.
Akshay,
I assume that you you have seen the announcement for the Maximon Longevity Prize 2023.
https://longevity.technology/news/applications-open-for-maximon-longevity-prize-2023/
I hope that you plan to apply for this prize. The judges appear to be important movers in the longevity field. Win or lose, an application could be useful in raising your profile in the longevity community.
Thank you Rick. I wasn’t aware it had opened for applications. Will certainly check it out.
Epigenetic fidelity in complex biological systems and implications for ageing
ABSTRACT
The study of age is plagued by a lack of delineation between the causes and effects within the ageing phenotype. This has made it difficult to fully explain the biological ageing process from first principles with a single definition. Lacking a clear description of the underlying root cause of biological age confounds clarity in this critical field. In this paper, we demonstrate that the epigenetic system has a built-in, unavoidable fidelity limitation and consequently demonstrate that there is a distinct class of DNA methylation loci that increases in variance in a manner tightly correlated with chrono- logical age. We demonstrate the existence of epigenetic “activation functions” and that topological features beyond these activation functions represent deregulation. We show that the measurement of epigenetic fidelity is an accurate predictor of cross-species age and present a deep- learning model that predicts exclusively from knowledge of variance. We find that the classes of epigenetic loci in which variation correlates with chronological age control genes that regulate transcription and suggest that the inevitable consequence of this is a feedback cycle of system-wide deregulation causing a progressive collapse into the phenotype of age. This paper represents a novel theory of biological systemic ageing with arguments as to why, how and when epigenetic ageing is inevitable.
SOURCE:
https://www.biorxiv.org/content/10.1101/2023.04.29.538716v1?rss=1
Akshay, I finally got past the reCaptcha.
Here are three papers you might find useful.
CKD Kidney regeneration in rats by blocking IL-11.
https://www.nature.com/articles/s41467-022-35306-1
Extra Cellular vesicles and anti-aging
https://onlinelibrary.wiley.com/doi/10.1111/acel.13337
and a BioArVix paper on doing the E5 anti aging experiment by a somewhat different methodology.
https://onlinelibrary.wiley.com/doi/10.1111/acel.13337
And for those with recaptcha 2 blockages – it only works with the 2 most current releases of browsers. Older browser releases get an error.
Hi George, thank you for sharing those papers. We saw almost complete restoration to health of aged kidneys in 165 days with two doses of E5. One of the mechanism of action will be reduction of chronic inflammation. Your 2nd and 3rd link for papers is the same. Can you share the correct 2nd link?
We are doing some exciting research work and will soon share the results here.
Thank you George. Prof Rudy Goya is a good friend of Harold and me and a co-author on our first paper on E5. His results do confirm why E5 which is much more potent than young plasma gives us such exciting results.
Here is the missing link. (No pun intended.)
https://www.biorxiv.org/content/10.1101/2022.12.01.518747v1
a little disappointing that young plasma has proven to be only a healthspan rather than a lifespan extending intervention. Better than nothing, but we can already extend healthspan. Hopefully E5 will be better.
E5 has shown a 50% reversal in biological age of two different clocks: one measuring methylation changes and the other measuring changes in Glycans on IgG molecules in rats. Shown 2.7x improvement in grip strength compared to old control. Plus significant improvements in 30 biomarkers related to aging. One of our treated rats is now the world record holder for maximum lifespan. Now we have to see what it does in old dogs next 🤞
The significant extension of maximum lifespan in a single rat is highly encouraging. All the other biomarkers could just be a reflection of improved healthspan.
I agree Mark. All these biomarkers can be improved with the supplementation of glycine and NAC. It’s wonderful that you discovered E5 but will you also discover how to concentrate exactly the same factors needed for dramatic lifespan changes? As Irina Conboy said, there is a hierarchy in plasma proteins so you need to change just some and the rest will follow the tasks. I think BBB is a big issue for E5. Maybe that’s why it increased rat’s lifespan as it shown to reverse the methylation age in hypothalamus. Just like 19%.
Azza BBB is not a problem for E5. Brain is a unique organ vs other organs. So methylated may change differently. Functionally we do see memory improve significantly. Do the 30 biomarkers we tested go back to youthful levels with GlyNAC in naturally old rats? If yes then we should have someone do bioage clock tests to determine how much reversal it causes. Breaking a maximum lifespan is a big barrier to cross as it is strongly guarded by Nature. However it would be really exciting to increase that by multiples. So one strategy we want to check is maintaining the youthful peak and see when death occurs. So far in our old rat studies we have a dosing cycle that peaks and drops back by around 50% of its gains and then the next dose again takes it to another peak. If we tweak the dosing to try and keep them in constant youthful state then I want to see what could cause death. May be it may lead to much bigger record of maximum lifespan.
“All these biomarkers can be improved with the supplementation of glycine and NAC”. Grip strength cannot improve to juvenile levels with Glynac.
Looking forward next experiment in dogs.
The effect of E5 in the kidney, as if those kidneys were being rebuilt along 155 days was amazing. That organ was ageing back! Like many others I suppose.
I can’t help but wonder what would have happened to those rats if they had kept getting E5 every 90 days. Or every 45 days. Would some of those rats, the ones in Sima’s group, be still alive? Sima spent 6 months with no E5 (Am I wrong Akshay)? Any perspective of supplying a group of relatively short lived animals with E5?
And still, have authorities approved any human trial?
The other day I read a Jesús Ávila interview (Spanish researcher interested in Brain rejuvenation and good friend of Dr Izpisua Belmonte) . Interestingly enough, after kidding about Juan Carlos Izpisua being less prone to share information since he entered Altos, he suggested that Izpisua was no interested in pursuing trials approvals in USA, but offshore, where it was much easier.
That really shocked me.
I enclose the link here.
Easy to read with google translator.
https://www.niusdiario.es/ciencia-y-tecnologia/ciencia/20230215/jesus-avila-neurocientifico-alzheimer-rejuvenecer-cerebro-farmaco-nasal_18_08725739.html
Hi Ines,
You are right the improvements in aged kidneys is fascinating to watch in every study. Yes Sima spent last 6 months without E5. Yes I just mentioned the same thing regarding dosing cycle and constantly maintaining youthful state to Azza. This is one experiment yet to do but currently all resources are focused on the upcoming dog trial. Offshore human clinical trials are more common than we think. Even big pharma sometimes do Phase I offshore to save a year and enter FDA straight with Phase II.
Copper peptides block DHT. How much will my DHT-levels decrease with daily use of NEEL gel for prolonged time? Anything to worry about?
Aging as a morphostasis defect: a developmental bioelectricity perspective
AUTHORS: Léo Pio-Lopez and Michael Levin
ABSTRACT
Maintaining order at the tissue level is crucial throughout the lifespan, as failure can lead to cancer and an accumulation of molecular and cellular disorders. We argue here that the most consistent and pervasive result of these failures is aging, which is characterized by the progressive loss of function and decline in the abilityn to maintain anatomical homeostasis and reproduce. This leads to organ malfunction, diseases, and ultimately death. The traditional understanding of aging is that it is caused by accumulation of molecular and cellular damage resulting from energy metabolism and mitochondrial function, and that cell growth and lifespan are limited by replicative senescence due to shortening of telomeres. In this article, we propose a complementary view of aging as a morphostasis defect, specifically driven by abrogation of the endogenous bioelectric signaling that normally harness individual cell behaviors toward the creation and upkeep of complex multicellular structures in vivo. We first present bioelectricity as the software of life, then in a second part we identify and discuss the links between bioelectricity and rejuvenation strategies and age-related diseases, and develop a bridge between aging and regeneration via bioelectric signaling that suggests a research program for addressing aging. In a third part, we discuss the broader implications of the homologies between development, aging, cancer and regeneration. In a fourth part, we present the morphoceuticals for aging and we conclude.
SOURCE: https://osf.io/wkhx4/
Yes, thank you. Another friend sent me this ms as well. I need to understand it and respond.
Thank you Kat for sharing this paper. I am a huge fan of Michael Levin. Finally we have his thoughts fully orchestrated on aging the way he sees it. Brilliant work!
Akshay, how is this morphostasis connected to factors in the blood plasma? I mean the connection with your theory?
Hi Nanaka our biology is too complex for me to answer that fully but it seems like a complementary system. Having said that we do lose polarization of our cells as we age and the causes are to do with overall epigenetic drift. Ion channels play a key role in that. Channel function can be modulated by changes in membrane potential, ligand binding, intracellular second messengers and metabolites, protein–protein interactions, phosphorylation, and many other factors. Many of these factors are related to epigenetic changes of the ion channel genes. So when the cell has a younger phenotype the all of these factors function at optimum levels to maintain cell polarity and the viability of our bioelectrical systems. Loss of cell polarization is seen in both aging and cancer.
Thank you Akshay. Very well explained, that makes sense. So it’s basically what we call Epigenetic drift and loss of cellular identity but from the standpoint of Ion channel and bioelectrical memory, right? And how is transcriptional program we all inherit from our ancestors connected to the polarity?
Thank you Nanaka. This transcriptional program we inherit is the cause of epigenetic drift.
Hi Akshay. Here’s a thought. AFAIK, all the electric potentials in living cells are the result of chemical reactions. So, when looking for root causes, why not just forget about bioelectrics.
Hi Wayne that’s a very interesting postulation. Josh has such an amazing group of followers!
Here is my evaluation of the bioelectric survey article and E5. There seems to be a hierarchy of aging control, of which E5 is some where in the middle. E5 seems to be effective on tissues that are still capable of active growth and/or replication. Whether or not it can activate regeneration in organisms has not been tested.
This is important, as the article points out the correlation between an organism’s ability to regenerate, and its rate of aging, relative to its size and complexity. This implies a level of aging control above E5. I note that early 20th century research I studied years ago included an experiment with nerve transplantation to to an area that needed to be regenerated in an organism that could not regenerate caused a limited and disorganized attempt at regeneration. (Nerve tissue has a high level of bioelectricity.) This is another correlation. E5 itself causes kidney regeneration. There seems to be cross-linking between anti-aging mechanism and regeneration mechanism, and regeneration is “quicker” to test.
What ionic pathways lead to regeneration and anti-aging are still to be determined. Finding out how E5 actually works will be the first paving stone on the path to ending aging.
How to go further? Probably the quickest path is to research regeneration, using that correlation between regeneration and aging. Some ideas on studying regeneration:
IL-11 blocking causes regeneration of kidney tissue in mice. One experiment might be to infuse regenerating part(s) with IL-11 to see if it disrupts known regeneration patterns. For example, chop up planaria and see if they re-form new planaria in an environment containing a high level of IL-11. Does it break the regeneration pathways?
Another is to do the same in regenerating salamanders.
Another is to chop up a bunch of planaria (planaria are cheap and easy to work with) and the filter the media they are regenerating in for fractions – a la E5 – and see if any fraction can trigger regeneration in animals that don’t normally regenerate. If any do, you have a starting point to determine the biological pathway(s).
There are proteins that cause cell cultures to form miniature organs. Does that stimulate regeneration in vivo?
Just some ideas for studying the issue. They may all be worthless. YMMV. . .
George, E5 technology is an arbitrage. Signaling and regulatory molecules circulating in the plasma of the young are injected into the circulatory system of the old. As those molecules enter the impaired cells they reset the proteome of that cell back to how it was in youth. Thereby rejuvenating those cells. As Akshay explained in his latest article on Autologous Regulation, this does not stop the legacy transcription in the cell which after a point would begin the degradation all over again. The question here is if the pro youth molecules are injected repeatedly would make the transcriptome to how it was during youth. If yes then it would take decades before the cell would get impaired again. As Harold said, E5 is a semi-permanent solution.
At this time, I see E5 as the only systemic solution.
Also have huge hopes on the methods of constant E5 circulation in our blood thanks to the ideas of Akshay.
Leo as always is the most up to date on everything related to E5!
Rick for some reason I couldnt post my reply yesterday – it kept getting blocked. Here is trying again: Safety trial start small with 5 old dogs. They are 10 year old. Their avg lifespan is 12-15 years. Phase I has 21 old dogs and cats. For veterinary application we are using our regular E5. The humanized porcine plasma was only being considered as a bridge to accelerate human clinical trial. Although it can be scaled eventually we want yo use regular E5 after it is fully tested in NHPs.
Hi Akshay, do you have any fresh news to share? I know that I speak for everyone here if I say that every day when I check my emails, I hope to see a dozen notifications from you; reading all these discussions is quite addictive.
Hi UnUtilisatuer, hopefully we should have some exciting news to share by end of July early August when we get preliminary results of our trial on old Beagle dogs. Primary end point is safety and toxicology and secondary endpoints are many biomarkers including dog bioage clocks to determine to what extent did their biological age reverse. This trial is being conducted by a veterinary CRO. The same Professor of Dermatology at Royal Victoria Hospital, McGill University who conducted human clinical trial for NEEL has agreed to conduct a human clinical trial for topical E5. Harold and his team are preparing E5 for the dog trial and the team of scientists that developed NEEL are creating a version of E5 for enhanced topical permeation. Fingers crossed. A Professor of Genetics and Chair of the Department of Genetics of the worlds number one University is joining our Scientific Advisory Board. He has already opened our eyes about humanized pigs: pigs that have been genetically engineered to have human immune system. This can accelerate our human clinical trial of E5. If we get great results on safety and efficacy from the old dog trial then I would be open for Harold and me to try E5 injections derived from humanized porcine plasma.
Thank you very much for the update, looks like this year is going to be a very important one for Yuvan (and very interesting for us readers); hopefully all goes well and we get to see you both rejuvenated by your discovery soon. As usual I have a few questions though: is the immune system a concern for regulatory agencies only, or is it more of a technical burden, something that needs to be taken care of during the production of E5 and that would go away with humanized pigs’ blood, or even something that diminishes the safety or efficacy of E5? I mean, does it have anything to do with the rats from the previous experiment dying even though they behaved youthfully? You tell me if my questions are dumb, lol
No negative immune reactions are much more immediate and death after a long life is not is not caused by it. Although Harold brilliantly discovered cross species application of the highly conserved signaling molecules in plasma regulatory bodies like FDA and EMA would be comforted by a humanized source to doubly ensure safety. In all our trials on hundreds of old rats we did not have a single adverse event or any negative immunogenic event. How can manage that is part of our patent.
Wow, what a news, Akshay. Looking forward to hearing more about the outstanding results from old Beagles. May I ask you if there is any special protocol for them? Or the same pattern as in rats?
Thank you Leo. We have to find out. But in dogs we may not need to give a dose every alternate day for 4 days. We may be able to dose in one session.
George Snoga your ideas are always interesting.
Thank you Akshay. You know how wholeheartedly I support you 🙏🏻
Akshay,
I just saw a question and answer session with Steve Horvath at “Ending Age Related Diseases 2022” that was recorded last August. Dr. Horvath indicated that there was a “replication study” of Dr. Katcher’s original experiment to verify his results. Since it has been 10 months since Dr. Horvath’s statement, can you give us an update on the progress of this study?
This is the mixed gender study where tested on another clock developed by Professor Gordan Lauc and his amazing team at GlycanAge. Their clock calculated average 50% reversal of biological age in our treated rats. Interesting things is that the Horvath clock measures changes in methylation to calculate age and GlycanAge measures changes in Glycans on IgG molecules so very different parts of our biology but both arrived at similar results. I can’t think of any other longevity therapeutic that is tested on two clocks and with such results. Dr. Horvath is a great supporter when The Guardian newspaper carried this story on our female rat Sima from our longevity study:
https://www.theguardian.com/science/2023/feb/08/anti-ageing-scientists-extend-lifespan-of-oldest-living-lab-rat
He was quoted by the reporter calling the results “stunning”.
The Glycan study is interesting Akshay. Do you know if there is a paper to be published in the offing? Is it also a lifespan study?
Thanks
Hi Mark, no this wasn’t a lifespan study but a mixed gender study to evaluate if there any gender differences. Yes the Glycan clock data is going to be part of our paper which we have submitted for publication.
Akshay, any results from the post-mortem for the E5 rats?
Yes you will get to see when we upload the paper to bioRxiv soon
Akshay,
I was wondering if you might be able to share a few details about the Beagle trial? How many beagles? Average age of the beagles? Exclusion/Inclusion factors for the trial? How many treatments? How long will the trial run? Will you be using E5 made from humanized porcine plasma? etc.
In the past you mentioned that Dr. Katcher was using pig blood that was a byproduct of the meat industry to keep the cost of E5 down. Do you have an idea of how using humanized pig blood is going to affect the cost of E5?
Thanks,
Rick
Akshay,
Are there any updates on the phase 1, safety, beagle trial of E5 that you can share with us?
Any progress on the phase 2 dog/cat trial or potential human trial that you might be able to share with us?
Thanks,
Rick
Hi. If you need a volunteer for the human E5 topical trial at Mcgill, I am near enough and would be happy to do it.:)
Scott what is your age?
Hi Akshay. I am 56.
Zisos that is a great reply to Are. You bring out nuances about NEEL that even we did not realize.
Hi Akshay!
A appreciate the feedback both from you and Zizos. I am still using the NEEL and think I may see some improvements but I will not say anything for certain now.
I will do some pictures after the summer and do some less anectotal checks and come back.
I agree with Zizos that it is a danger that peaople loose faith too early. I am in for the long run. By the way it seemed Zizos were also doing som senolytics. I now started NMN myself 300 mg dayly + 100 mg Fisetin, then some curcumin or querecitin. Do you guys have any toughs on senolytics? I hope it can give some benefit while we wait for the E5 🙂
Hi Are, I am personally not a big fan of senolytics. I try to upregulate autophagy which can rebalance senescent cell numbers. One of the ways I upregulate it is by activating Nrf2. This has many other benefits besides autophagy. It releases powerful antioxidant enzymes to manage ROS which increases with age, detoxifies through liver enzymes, improves protein production which is hampered with age, increases NAD+ via NQO1 and HO-1, improves mitochondrial function, increase SOD, glutathione, dampens chronic inflammation, protects to some extent against neurodegeneration, reduces stress of advanced glycation end products. It is inversely related with mTOR so when we inhibit mTOR via rapamycin or metformin bulk if the benefits arise from activation of Nrf2. Nrf2 response levels go down with age. But too much of anything is also detrimental so one should activate it only occasionally like 2 or max 3 times a week to make up for the loss due to aging.
Akshay, do you have any idea what can replace Xanthohumol in your Nrf2 protocol? It’s toxic to dogs, so I would love to know what role it does have and what can be used instead of Xanthohumol to rebalance.
Sulforaphane with myrosinase can work for dogs? Or Quercetin or Andrographolide?
Thanks Akshay. I do give them all. Including Oleuropein and Boswellia. I just wanted to know if Xanthohumol does anything special for Nrf2 or Ubiquitin-proteasome.
It’s great but it can be substituted by the others I mentioned. For ubiquitin proteasome system enhancement you are already giving Oleuropein 👌
You probably have the healthiest dog on the planet 🙂
Haha) Thanks to your recommendations and directions only.
Your deserve!
Hi Akshay,
I grow my own Broccoli sprouts to have a fresh supply of Sulforaphane and go three times a week to the sauna. Do I overshoot in respect to nrf2 activation?
Hi, Are
I was trying senolytics (a DMSO solution with fisetin, quercetin, dasatinib and azithromycin) for about a year before NEEL. I also continued for about a month after starting NEEL. It had some success with dark spots, but not much else. I stopped it due to very bad smell of DMSO. Also, when I was applying it, it irritated the skin.
Thanks. Was considering topical senolytics but won’t try now.
> If we get great results on safety and efficacy from the old dog trial
> then I would be open for Harold and me to try E5 injections derived
> from humanized porcine plasma.
Looking forward to seeing before and after pictures!!!
Hi Akshay,
>The same Professor of Dermatology at Royal Victoria Hospital,
> McGill University who conducted human clinical trial for NEEL has agreed to >conduct a human clinical trial for topical E5. Harold and his team are
> preparing E5 for the dog trial and the team of scientists that developed
> NEEL are creating a version of E5 for enhanced topical permeation.
>Fingers crossed.
If all goes as hoped for,
how soon might we see a cosmetic E5 available for purchase on Amazon?
Hi Akshay,
I have been following this thread for a couple of year now and I just wanted to commend you, Dr Katcher, and your team for all the hard work you have done.
I have had some very good results and am very happy with the NEEL product. I am enthusiastically looking forward to any further advancements you are working on.
Best Chris
Thank you so much Chris for your feedback and encouragement! Regarding NEEL gel we would request all our friends here who have had some benefit from NEEL gel to leave a review on Amazon.
In the non FDA pipeline we are working on some exciting developments that will be shared over this year and which will provide great benefits to all of us till we get a chance to take E5. On E5 our entire team is working hard towards the launch of old Beagle dogs trial this month. We want to make them really young, healthy, happy and jumping around like the 1 and 2 year olds 🤞
Akshay, what is the goal and endpoint for the beagle trial?
Check for inflammation reduction?
Rejuvenation result?
Regeneration of tissues (like kidney, ect.)?
Maximum longevity trail?
Something else?
Thanks,
George
Hi George, all of what you said except maximum lifespan. Primary endpoint is safety and toxicology to test various dose strengths and frequencies. Secondary endpoints are more than 20 – as you know we like to test exhaustively to get a sharper perspective of what’s happening- in rat studies we tested 30 biomarkers including functional. We are especially keen to check kidney markers. There are two clocks for dogs we are interested in to get third party confirmation of reversal of age: Horvath dog clock is ready and GlycanAge dog clock is under construction and we are requesting all organizations that support pets and aging to financially support their project of building an accurate dog clock. Not only will it help veterinary aging research like ours but also all the dog owners that may want to know how much improvement did their dog receive from the treatment. Dr. Matt Kaeberlain is an advisor on their project.
Consider evaluating brain endothelial cells in a future study?
“These findings underline the strong susceptibility and malleability of endothelial cell (ECs), which are directly exposed to secreted factors in both brain parenchyma and blood, to adapt to changes in their microenvironment. ECs, despite comprising <5% of the total number of brain cells, are a promising and accessible target for treatment of aging and its associated diseases."
"Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types"
A good suggestion PRice.
How is the beagle trial coming along?
I read “Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction”. Is Yuvan producing E5 in the US?
Embryonic stem cell-derived extracellular vesicles rejuvenate senescent cells and antagonize aging in mice
ABSTRACT
Aging is a degenerative process that leads to tissue dysfunction and death. Embryonic stem cells (ESCs) have great therapeutic potential for age-related diseases due to their capacity for self-renewal and plasticity. However, the use of ESCs in clinical treatment is limited by immune rejection, tumourigenicity and ethical issues. ESC-derived extracellular vesicles (EVs) may provide therapeutic effects that are comparable to those of ESCs while avoiding unwanted effects. Here, we fully evaluate the role of ESC-EVs in rejuvenation in vitro and in vivo. Using RNA sequencing (RNA-Seq) and microRNA sequencing (miRNA-Seq) screening, we found that miR-15b-5p and miR-290a-5p were highly enriched in ESC-EVs, and induced rejuvenation by silencing the Ccn2-mediated AKT/mTOR pathway. These results demonstrate that miR-15b-5p and miR-290a-5p function as potent activators of rejuvenation mediated by ESC-EVs. The rejuvenating effect of ESC-EVs was further investigated in vivo by injection into aged mice. The results showed that ESC-EVs successfully ameliorated the pathological age-related phenotypes and rescued the transcriptome profile of aged mice. Our findings demonstrate that ESC-EVs treatment can rejuvenate senescence both in vitro and in vivo and suggest the therapeutic potential of ESC-EVs as a novel cell-free alternative to ESCs for age-related diseases.
SOURCE: https://www.sciencedirect.com/science/article/pii/S2452199X23001937
Hi Akshay,
I was wondering if E5 might reset the circadian Rhythm to a younger age?
Was there any indication from the E5 rat studies?
Thanks for your response.
Hi Gerald not sure if I replied earlier. We haven’t tested circadian rhythm changes but I would be surprised if they remained disrupted as seen in aging after E5 treatment. Something to find out.
Chemically induced reprogramming to reverse cellular aging
ABSTRACT:
A hallmark of eukaryotic aging is a loss of epigenetic information, a process that can be reversed. We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity, a process that requires active DNA demethylation. To screen for molecules that reverse cellular aging and rejuvenate human cells without altering the genome, we developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay. We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.
SOURCE: https://www.aging-us.com/article/204896/text
Kat this is certainly a very interesting approach towards cellular reprogramming but personally I would be much more excited after I see this succeed in vivo. I had made a presentation which included a research paper from Dr. Joao Carvalho https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174973/
where he states that even a partial reprogramming of the cell can lead to cancer some time in the future. Sinclair et. al. mention that not stem and IPSc like genes were activated so that’s encouraging but it would good to see that recreated in mammals and with lifespan study.
Hi Akshay, I have a question regarding the plan to use humanized porcine blood/plasma as a source for E5 : won’t this source make E5 a no-go for people that follow a kosher or non-animal lifestyle, ie Muslim, Jewish, Buddist, Vegan/Vegetarian, etc. Not trying to rain on your parade, but this seems like a path that could exclude a significant portion of humanity.
Cheers,
Ron
Hi Ron,
E5 can be sourced from any mammalian plasma not only porcine. Also we are just harvesting valuable molecules from a waste product so such a molecular therapeutic would not be considered as meat by vegetarians.
They would be excluding themselves. If this is what creates rejuvenation in humans, they would have to rethink their priorities and make a decision.
Dear Akshay,
I am a veterinarian in Austria, EU,and interested in E5 for rejuvenation of old dogs in my practise. I think, it will be much easier to get a pemisson for the application of E5 for animals than for humans.And if it is declared as wellnessproduct, it should go through the customs in EU.Will that be possible earlier than the appl. in humans?(which is sorrowly for me still years away)
Best Regards.
Dr.Peter Ross
Dear Dr. Ross,
Yes veterinary regulatory approval of E5 should be much faster than human but I doubt it may pass off as a wellness product in EU. It may need to be approved by EMA. Glad to note your interest. When we are planning to conduct veterinary clinical trials in Europe I will reach out to you to see if we can work together.
Hi Akshay / Josh,
Bill Faloon has a web site age-reversal.net that he is putting together with a database
similar to the one proposed by josh several years ago.
It appears that it will track what individual are doing and how it affects their aging,
I am wondering what works best in relation to Diabetic Glycosolation at present, and if the systemic approach might be the answer to diabetes. Benfotiamine and Lipoic acid are considered promising by some. The Continuous Glucose Monitors etc also seem to be a godsend. I do not have the condition personally but a family member has. The future at last seems brighter for so many chronic conditions. Hope big Pharma behaves itself. Best wishes to all.
Another important piece of the puzzle. It is clear the extracellular vesicles are not monolithic, this implies that there are different EVs for different function. While some other tissues don’t seem to be affected by the trialed EVs, that does not mean that those other tissues are immune to EVs for rejuvenation, but that the EVs that would affect those tissues weren’t present in the trialed EVs. For example what EVs are produced by the early growth of the thymus may be very different in function from those produce in the heart.
This fits in with the E5 rat trials. While E5 rejuvenated the rats, the life span only increased relatively marginally. Apparently, some parts of the soma were not being rejuvenated, despite appearances, and then became the limiting factor(s) in the overall lifespan. What parts and what will trigger their rejuvenation are still open questions. (At least here in the peanut gallery!)
An aside to the speculation that EVs are released into the air to help invoke heard immunity. Decades ago (sorry, no link – didn’t think I would ever need it in my far future), there was a paper that showed that tree used some form of aerosol to do exactly that form of inter plant communication against pathogens. What the chemicals were was not determined, just that they existed.
Finally Josh, I wish you could do something about the reCaptcha you have set up. If you aren’t running the latest version of Chrome, you can’t post. You don’t get a reCatcha to fill out to prove you are human, you are just cut off as a robot. I current keep a separate computer just to be able to post here. (I run Linux on my main computers; Chrome is never up to date in Linux.) I’m posting here because even the new computer with a current Chrome won’t get past the ReCaptcha.
Thank you, George. It’s a really good point about different kinds of EVs. I’m sure that cells are smarter than we now realize, and they decide which EVs to pick up and which to exclude. So this is the beginning of a very promising line of research, only the beginning.
I’m sorry about your experience with ReCaptcha. I’m beholden to Ben at ScienceBlog, and he’s beholden to WordPress. I didn’t set up the security, nor do I have a dial I can turn to change the level of security for commenters. I’m sure you agree that digital security takes an inordinate amount of our time, a dispersed cost that every corporation you can think of us forcing us to bear for them.
It would appear that many of the questions about E5 have been answered:
https://www.biorxiv.org/content/10.1101/2023.08.06.552148v1.full
It involves young sources. It is an exosome plasma fraction.
Hi everyone, I know I sound whiny but it’s been something like a month since we’ve last had an update and a few years since the whole thing started, and the suspense is killing me; does anyone actually know when the patents will be, uh, patented, or released or whatever the proper terminology is in English? This story needs some kind of “conclusion” (but barring that I’ll gladly read any new bit of information too, of course).
Oh and am I the only one who didn’t receive a notification (an email) for JM’s last two posts?
Hi guys,
Have you seen this?
https://www.technologynetworks.com/proteomics/news/breakthrough-in-brain-rejuvenation-identifies-anti-aging-plasma-factor-377876
A mollecule present in plasma called PS4 is resposible for brain rejuvenation. I wonder if E5 could contain this molecule.
Responding to the post on the Aug 6th, 2032 page and latest paper link. (Can’t get in any other way.) I have read the paper. It does not include the Female Sprauge-Hawley trial to death information. However, on page 7, there is a comment that platelets were exclude3d from the E5 extraction. But if you go the the May 2020 page, there is a recent post from David Ragazzu with a link to another paper that contains information concerning Platelet Factor 4 being able to go through the blood/brain barrier, and have a rejuvenation effect of brain tissue and function.
Might be a factor to be added to E5, for more thorough rejuvenation.
>>Might be a factor to be added to E5, for more thorough rejuvenation.
Exactly. Just remember that hypothalamus rejuvenated at 20% rate while other organs rejuvenated even 70% with E5. If I remember well, a possible explanation given here is that some plasma factors could not penetrate well in hypothalamus tissue. It seems that is not the case for PF4. So if E5 doesn’t have PF4 molecule, then it could be considered a missing piece in the E5 formula to be more powerful.
PS: My name is David Ragazzi, not Ragazzu. Sorry for the typo in the former message. 🙂
New Harold Katcher video…
Is anyone receiving email notifications for new posts to this thread? I think there might be a problem as I haven’t received a number of the latest posts.
Akshay, what’s your opinion on chemically induced reprogramming? I do not know the first 3 molecules but the last three are very well known Sodium Butyrate, Valproic Acid and Forskolin. What would happen if we would take the last three I mentioned for a few days? Maybe histones will acetylate and it will spread some Euchromatin to the genome? Thanks
For some reason I do not get emails for new messages like I used to before. My friend Larry told me about messages on this post. Azza chemical reprogramming will have a limited effect with chances of off target changes as well. This is also true for other types of induced reprogramming.
Hi Akshay,
Do you need to match the gender of the animal used in E5 to the gender
of the person getting the treatment?
Thanks in advance for your reply.
Update on NEEL
I have now used the NEEL for half a year. Although slowly and steadily I will say there is an incremental improvement.
As I am approching having used half of the last bottle I was going to buy more at Amazon, but the page was taken down. Akshay, would you know anything about that ? I would hope it is still possible to buy, but it dont look like that. I was planning to buy a new batch for continous use.
I must have gotten one of the last bottles.
You are a lucky guy 🙂
Sad if our guys are running out of money on the E5 and have to spend all time chasing investors.
To me the way forward seems to be “flushing” young esovesicals into the body and hope for the best anyway. Then hopefully the proof will be in the pudding…
If this is to be run through the FDA “efficacy” process I guess we will be dying while waiting for approval… :).
Hi, Are. Yes. It is no longer listed on Amazon. I tried ordering some from Walmart but they said “Out of Stock until further notice.” I see some available online for very high prices. GoSupps seems to have some for sale, for a decent price, but I know nothing about them. I may try one bottle from them and see what happens.
Dr Katcher seems to be pretty mad at the lack of funding (?) right now. I wonder if a last ditch effort is in order. Something like channeling all resources towards making enough E5 for one person, and then using it as a proof of concept. But maybe I’m reading too much into his exasperation?
To me there seem to be companies doing “something” in regards to this, and having effect like he testimonials at https://www.wellbeingint.com/ or Sally Kaufmann. The enormous verification processes required by the FDA seem to having been avoided. Its sad if our guys are running out of funding, but to me the way forward seem to be Harold doing a full cure himself based on the best possible guess from what we now know. The proof is in the pudding anyway…
I’ve seen a few companies offering these treatments or someting similar but it seems that they only give small quantities of EVs or cells which probably isn’t sufficient to overcome the body’s own signaling. It’s like they are sitting on a gold mine but they don’t really know its value because they don’t have the right framework to work with; they think “regenerative medicine”, with very specific applications when they should think “rejuvenation”, with full body treatment in mind.
I would think so too regarding the dosage.
sandra kaufmann said i a podcast she does extracellular vesicles once a month and stated the she believes they are behind at least 80% of positive results from gene therapy…
Its an annectode but all science start with annectodes, and combine this with the faboulus work carried out by Akshay and Harold, E5 in my oppinion represent a good lead and maybe the highest potential for short term benefits in this area of all leads. Sad if they run out of money…
I think that in the moment Dr. Katcher apply E5 on himself and the results were fascinants, show himself to internet, TV shows and investors will flood into his house to get more information about.
It’s simple, every anti-aging lab and scientist claims that their discovery have results on animals. But most people are skeptical why until moment, no human show impressionant results.
Aksay and Katcher should try that, it would be the best proof of concept. Not only pictures, but for those that could say that is makeup, plastic surgeries, etc, they should collect biomarkers before and after infusion.
As I said, everyone is claiming that found the youlth formule. But people are tired of seeing results on animals or just statistics in papers. People want see fascinant results in real life people!
I think that in the moment Dr. Katcher apply E5 on himself and the results were fascinants, show himself to internet, TV shows and investors will flood into his house to get more information about.
It’s simple, every anti-aging lab and scientist claims that their discovery have results on animals. But most people are skeptical why until moment, no human show impressionant results.
Aksay and Katcher should try that, it would be the best proof of concept. Not only pictures, but for those that could say that is makeup, plastic surgeries, etc, they should collect biomarkers before and after infusion.
As I said, everyone is claiming that found the youlth formule. But people are tired of seeing results on animals or just statistics in papers. People want see fascinant results in real life people!
I wonder how much money we are talking about, to get human trials going with E5? It would be a shame for this to just stop here due to lack of funding. There may be a way to get funding going again with the right people involved, including the people who visit this blog! Many of us could help in various ways, I am sure. Does anyone have an idea how much money is needed to get this going again?
Regarding NEEL gel. Amazon bot has erroneously flagged it as a restricted drug when it is safe cosmetic product. Unfortunately it takes really long to appeal. We have shared with them a legal memorandum from our regulatory attorney that confirms it to be a cosmetic product. So hopefully someone senior enough at Amazon will relist it soon. In the meanwhile one can always buy NEEL from our website: Neelgel.com
Regarding NEEL one our regulars on this blog has been diligently applying NEEL all over his body since a year. Probably the only person I know who has done that. He can name himself if he wants. He has emailed me about incredible improvements he has noticed. He sent me before and after photos of his face and it looks 20 years younger to me. He says that his strength and energy has gone up considerably: for example he needs to carry two buckets of water for a regular task in his garden. Earlier it had become quite strenuous but now he says he can sprint back with them. He also mentioned improvements in other aspects which I won’t mention here but hope you get the drift. He said over the year nothing else was changed except the application of NEEL. Anyway this is just a n=1 kind of anecdotal data but it’s really exciting to imagine what will be the effect of an oral pill that’s under development with us. Takes me back to the reason Harold and I decided to develop products of Ghk: the Broad Institute gene mapping study that showed Ghk reset 1/3rd of our genes to youthful expression.
Thanks for this update. Akshay.
Many friends were wondering why it was removed from Amazon.
It’s almost impossible posting a reply here recently as it continues to get flagged a Google verification failed error with message that you are not human. So if you don’t see my replies the reason is this. I am trying to post this:
Dear Shay and our supporters here thank you so much for worrying about us 🤗 we are in between funding rounds and the VC funding has come down by 70% since its peak in 2020 for biotechnology in general so that compounds the lack of funding. We also need to fill a gap in our management team: we need a senior executive who has taken a drug from lab to clinical success. Once we recruit such an executive our funding search would become easier. We are actively hunting for this executive. If there is anyone here who would like to invest and I will qualify as accredited investor please write to me atomicblissventures at gmail dot com. Currently our dog trial is delayed due to an entire batch of plasma that we collected over many months not clearing QC tests. We are in the process of sourcing from alternative suppliers. We also improved our QC assay. So in the next couple of weeks we should have enough E5 to start the dog trial and the topical E5 human clinical trial.
Yes, that Google thing is not good. One gives up. My comment is that NEEL is not possible to ship outside US on your page ?
Maxwell Biosciences have found a single molecule that seems responsible for heterochronic parabiosis effects. It is very fragile and elusive but they have made a synthetic version that is stable and they are going to human trials in 2024
Maxwell Biosciences believe they have found the rejuvenating factor in young blood: “LL-37 – also known as Human Cathelicidin Antimicrobial Peptide.” It would be a super-drug except it’s too unstable. They have developed a cheap stable small molecule they call MXB-22,510 that mimics LL-37 and are going to human trials next year.(2024). They call it a “synthetic immune system”. It’s causes most human pathogens both viral and bacterial to be quickly eliminated replacing both antibiotics and antivirals. They believe Immune senescence is the main driver of aging, and expect this drug to increase human life expectancy from 74yrs to 120yrs by 2033. https://maxwellbiosciences.com/healthspan
The above should have been in quotes to avoid plagiarism, but I don’t recall where to attribute it.
Investigating the synergistic effects of agents that upregulate Klotho and LL-37 is a sophisticated and nuanced area of research. While specific studies focusing on the combined effects of these agents on Klotho and LL-37 upregulation are limited, we can hypothesize potential synergies based on their known mechanisms of action and biological roles. Here’s an overview:
Vitamin D3 and Omega-3 Fatty Acids: Both are known for their immune-modulating effects. Vitamin D3 upregulates LL-37 and potentially Klotho. Omega-3 fatty acids, through their anti-inflammatory actions, might enhance this effect, potentially creating a synergistic environment for both LL-37 and Klotho expression.
Vitamin D3 and Curcumin: Vitamin D3’s role in upregulating LL-37 could be complemented by curcumin’s broad anti-inflammatory properties, which might indirectly support Klotho expression. This combination could have a synergistic effect on reducing inflammation, a key factor in aging and immune function.
Curcumin and Omega-3 Fatty Acids: Both have potent anti-inflammatory and antioxidant properties. This combination could create a favorable environment for the expression of anti-aging genes like Klotho, and possibly for antimicrobial peptides like LL-37, by reducing oxidative stress and inflammation.
Sodium Butyrate and Vitamin D3: As an HDAC inhibitor, sodium butyrate can alter chromatin structure and affect gene expression, potentially enhancing the effects of Vitamin D3 on both LL-37 and Klotho expression.
Generated by a Custom GPT designed for active agent up-regulating Klotho. It would imply that there should be some benefit of combining Vitamin A, and D3, Curcumin, Omega 3, and Sodium Butyrate.
Hi Akshay, I hadn’t drop here for a long time, but I read Harold ad you last paper, which even yield more questions to me. I am not going to post them here.
recently I foun dquiean interesting paper about the possiblity of cultivatinc EV in bioreactors
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9506336/
Do you consider this as a mid term possibility?
I hope you’re going forward with your dogs trial, please. keep us updated.
All the best
I had suggested about this in another topic in this same blog (in end of 2023), but… wow! I see that even 2022, this already was addressed!
A major paper concerning E5 in Nature – Aging, April 2024. Contains results including isolating miRNA loads of EV that seem to have much of the active effect of E5, among other things. See this link https://www.nature.com/articles/s43587-024-00612-4