Age Reduction Breakthrough

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.

Cartoon by Maddy Ballard

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 genebrca1. 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.”

Human-rat clock measure of relative age defined as age/maximum species lifespan.

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:

  1. 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
  2. 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.

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.

697 thoughts on “Age Reduction Breakthrough

  1. 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.

  2. 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!

  3. 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

        • 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

          • 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!

          • 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.

          • 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 😉

          • 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.

          • 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

          • 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

    • 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 😉

    • 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.

  4. 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.

  5. Apparently excess levels of SOD play an important role in the greater danger of Covid-19 for older people…

        • 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.

  6. 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.

  7. 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?

  8. 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…..

      • 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.

  9. 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.

    • 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…

  10. 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.

  11. 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.

  12. 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?

  13. 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.

        • 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.

        • 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 🙂

          • 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. ;/

          • 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,

          • 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.

  14. 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.

  15. 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

  16. 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?

  17. 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?

      • 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.

  18. 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.

  19. 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.

  20. 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.

  21. 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.

  22. 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.

    • 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.

  23. 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.

  24. 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.

  25. 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.

    • 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.

  26. 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.

          • 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.

  27. 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.

  28. 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.

  29. 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.

  30. 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.

  31. 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.

  32. 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.”

    • 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.

    • 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.

          • 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.

          • 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.

          • 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!”

  33. 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

  34. 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.

  35. 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

  36. 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

          • 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.

  37. 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. 🙂

      • 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.

    • 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.

  38. Profound thanks to people like Harold, Akshay and Josh who have imagined what might lie over the crest of the hill.

  39. 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.

        • 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.

  40. 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.

  41. 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 “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.

  42. 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

  43. 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.

  44. 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.

  45. 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.

  46. 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.

  47. 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.

  48. 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.

  49. “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.

  50. “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!

  51. 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.

  52. 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.

  53. 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!

  54. 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?

    • 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.

  55. 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.

  56. 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)”.

  57. 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.

  58. 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!

  59. Pingback: Josh Mitteldorf: “Aging is an Inside Job, Our Bodies Are Rigged for Controlled Demolition!” – Kevin Barrett

  60. 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 😉

  61. Pingback: _on Kevin Barrett’s Truth Jihad Radio | NO LIES RADIO

  62. Pingback: The Future of Life Extension Part 1: We are much closer to a cure against aging than you think – Life Extension Network

  63. 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.

  64. I would appreciate being able to view the pictures and being on any list of potential investors or trial participants

  65. 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…

  66. 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

        • 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.

          • 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

          • 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!!!

          • 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.

          • 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.

          • 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.

          • 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.

          • 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.

          • 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

          • 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.

          • 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.

  67. 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.

          • Thank You Akshay, please, keep us posted about the dog trial and Elixir release. Good luck to you!

  68. 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.

          • 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?

    • 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

          • 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!! 😉

  69. 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.

  70. 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.

          • 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

    • 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.

  71. 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.”

  72. 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

      • 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.

  73. 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?

          • @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.

          • 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 ,

  74. @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.

          • 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.

          • 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.

          • 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?

          • @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.

          • @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.

          • 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, 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!

    • @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.

  75. 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 😉

  76. 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 😉

      • 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

  77. 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.

    • 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 ,

          • 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.

  78. @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.

  79. 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

  80. 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).

          • 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.

        • 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.

          • 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)

  81. 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.

  82. 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.

          • 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

          • 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.

          • 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.

  83. 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.

  84. 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.

  85. 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.

  86. 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

        • 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

  87. 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.

    • @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.

  88. 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

          • 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.

  89. 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! 😉

        • 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.

          • 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.

          • @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.

  90. 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.

          • 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.

          • 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.

        • 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

  91. 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.

  92. 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.”

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