Rumors of Age Reversal: The Plasma Fraction Cure

I say “rumors” because there is no publication and results from just 6 rats, all of which were sacrificed for the sake of tissue biopsies.  Worse, we have no announcement of what the active agent(s) were that rejuvenated the rats, so discussion of mechanisms will have to wait. I’m writing this largely from personal and scientific trust, while recognizing that even the most careful and honest scientists can deceive themselves.  “You are the easiest person to fool,” Feynman warned us.

Some of you may recognize the name of Dr Harold Katcher, who is one of the most prolific and best-informed among many well-informed readers commenting on this blog.  I’ve known Harold for about 10 years. We came together because we have the same idea about what aging is. The difference is that I have only the evolutionary reasoning, the logical shell.  Harold also has the background in biochemistry to fill in the details. Filling in the details is what he has been doing, and this week he convinced me that he has the most promising age-reversal intervention yet devised.  His treatment protocol is in preliminary stages of testing, and because the ideas that he and I share are out of the mainstream, it has not been easy for him to get funding. Now that he has preliminary results, perhaps that is about to change.  He is committed to bypassing the standard channel of Big Pharma, proceeding on his own with appropriate partners to assure that the the technology gets to a wide public at affordable prices–but it is early to think in these terms.

The heretical idea that unites Harold’s thinking and mine is this:  Aging is controlled through evolutionarily conserved mechanisms. Some of the same genes and proteins that control the rate of aging in yeast cells serve the same function in mammals, which may live a thousand times longer than yeast.  This implies that aging isn’t just random damage to individual cells; rather it is tightly regulated at the systemic level. Maybe there is a central clock, or maybe there is a consensus that is reached body-wide. But in any case, there is communication, assuring that different parts of the body keep to a common schedule.  The natural place to look for this communication of the age state of the body is through signal molecules in the blood.

Thus our hypothesis, Harold’s and mine, is that even an old body remembers how to be young, if only it gets the message in the appropriate biochemical language.  If an old mouse were to have the blood of a young mouse coursing through its veins, the old mouse would become a young mouse. Parabiosis experiments, sewing together mice of different ages so that they share a common blood supply, originated in the 19th century, but they took a leap into the 21st century beginning in the Stanford laboratory of Irv Weissman.  His students spread out to Berkeley and Harvard, and the successors to these programs are studying the rejuvenation potential of various blood plasma components.  (It’s not the red blood cells or the white blood cells. It’s not any cells at all, but the proteins and RNAs and short peptides that are dissolved in the blood’s clear liquid background, called plasma.)  Some of the best-known people working on this idea are Mike and Irina Conboy at Berkeley, Amy Wagers at Harvard, Tony Wyss-Coray at Stanford. Two companies (Ambrosia and Alkahest) have begun selling transfusions of young blood to wealthy old folks, brave or desperate enough to experiment on themselves with untried technology, and to pay for the privilege.  

Harold doesn’t have the funding or the university infrastructure that these people have, but by his report he has leapfrogged their research.  He claims to have isolated the crucial molecules in young blood plasma, and that it is feasible in the not-too-distant future to synthesize them, so we’re not all running like vampires after 20-something men and women, bidding up the price of their blood.

His experimental results are preliminary, but impressive.  On the one hand, there are big questions that remain; on the other hand, I’ve never seen success like this from any other intervention.  (The possible exception is the Mayo Clinic’s work with senolytics, extending the lives of older mice; but the two approaches are so very different and what we know about the two is so different that there is no basis for saying one is more successful or more promising than the other.)

So, what were the results that we find so impressive?  I’ve linked to his own chart of results, and I’ve asked Harold to tell us in his own words.

To tell you the truth, when I first was invited by my partner, Akshay Sanghvi to conduct research at a laboratory in Mumbai (India, formerly ‘Bombay’) I had a very definite idea of what I wanted to do.  I wanted to transfer the plasma of a young rat, to replace the plasma of an old rat, which I have called Heterochronic Plasma Exchange (HPE).  This idea was originally based on heterochronic parabiosis, which apparently resulted in rejuvenation at the cellular level in mice, but without  the bizarre and cruel aspects of sewing two animals together; and yet, it should have more profound effects as 100% of the old animal’s blood could be replaced–while in heterochronic parabiosis, a young rat is half the weight of an old rat, so that the combined plasma circulation in the parabiots is considerably less than 50% young plasma.   If it is assumed that there are ‘pro-aging’ factors in the blood plasma of old animals, those factors would remain. By using HPE however, sufficient rounds of plasma replacement should leave the old animal with nearly pure ‘young’ plasma. The greater concentration of youthful factors and the absence aging factors should push the cells and, eventually, the body to youthfulness.  

Although transfusion technologies for humans are mature and quite safe, transfusing small animals requires state-of-the-art lab techniques. 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, and at first nothing seemed to be happening. But after two months (about 4 years in human terms) the rats showed signs of rejuvenation.  We were encouraged. Rather than continue with the herbs, though, we formulated the elixir that we report on here. This is our first iteration, with dosage and timing determined theoretically, yet to be optimized in the lab.

We have addressed several different problems:

  1. Identification and purification of youth-inducing factors and a process for their large-scale production. Our processes are scalable from microliters to metric tonnes
  2. Raw material supply: we have gone beyond the need to obtain blood from young people, our sources are virtually limitless
  3. Removal of the effects of ‘pro-aging-factors’.  We have discovered a way to do that, one hidden in plain sight.

Here are our results.  Notice the striking and simultaneous occurrence of increases in mental speed and physical strength coupled with lower inflammatory markers and blood glucose levels.  Also encouraging is that these changes began days after the IV treatment, and the markers that were improved but not quite down to youthful levels continued to improve right up until the day of their sacrifice. It would appear that the changes induced are permanent, but it will take additional experimentation to confirm this.

Clearly, our next steps are

  • repeating and extending our rat results to include molecular and epigenetic signs of aging (Steve Horvath is developing a methylation clock for rats).
  • extending results to dogs (in collaboration with Dr Greg Fahy)
  • Looking for other molecular changes, including telomere length and various mitochondrial parameters
  • and, of course trying the elixir in humans.   

I am looking ahead to envision an elixir that brings you back to apparent youth in a week and a day with no side effects.  Time will tell, but I feel that the results we have at this point justify optimism.

— Harold Katcher

I’m full of questions, but Harold tells me these will have to wait until intellectual property is secured.

  • For some interventions, the body is made stronger and levels of tissue growth repair are restored to youthful states, but there is a cost in elevated cancer risk.  This is something that will take time to determine, and perhaps working with mice would be better, since they have higher cancer rates than rats.
  • I would guess that a fully youthful phenotype will require restoration of the thymus, which shrinks severely with age both in rats and humans.  The current report doesn’t mention thymic regrowth.
  • What would rejuvenation look like in humans?  Physical strength and mental acuity are a great start.  Would my eye lenses soften to youthful levels?  Would I grow new discs between my vertebrae (and regain the 2″ Ive lost in the last decade)?  How about teeth and hair?
  • I’ve read that many blood factors are transient, with a half-life of seconds to minutes.  I can imagine long-term effects from epigenetic reprogramming through blood factors, but I’m surprised this could happen without a continuous IV feed.
  • And, of course, I’m curious about the content of the elixir.  Thousands of different compounds have been isolated from blood plasma, and hundreds that differ between young and old.  I think of the Conboys as leaders in this field, and when I spoke to them less than two years ago, they had been unable to identify a small subset of key factors that would induce changes in the rest.  Harold has said, “these factors are ‘bio-similar’ to factors already present in the blood, they work by natural means…”

The bottom line

I respect Harolds caution in protecting his discovery out of the reach of Big Pharma.  On the other hand, so many questions are not being addressed because his resources are limited.  This is indeed a very promising start, and let’s hope that the appropriate connections come along so that further experiments can proceed without delay.

244 thoughts on “Rumors of Age Reversal: The Plasma Fraction Cure

    • That interesting article – and I hope to see more info how it all will be developing soon enough – reminds me about certain research which I expect most ppl here are unfamiliar with. I will retell the main plot without going into details (https://www.ncbi.nlm.nih.gov/pubmed/16358576). It is about reversing aging in salmon. Salmon lifecycle starts in a creek, salmon proceeds to go to sea and grow, then some switch flips and two things starts to happen: salmon journeys back to mother creek while aging rapidly. Even though salmon is phylogenetically very far from humans salmon’s aging is very similar to human aging: diabet, atherosclerosis, etc. When in mother creek salmon procreates and dies from aging. However a certain population of salmon managed to live much longer, being able to return to sea instead of dying. So salmon 1. ages & dies due to program 2. ages & dies in way similar to humans 3. in certain population aging is reversed, death avoided. Russian scientist decifered what happens. A mollusc – pearl mussel – reprograms salmon! Mollusc spends initial part of it’s lifecycle in salmon’s gills as parasite – or rather symbiont. In most of salmon’s oreal mollusc spends several month in the gills and after that drops to ocean floor to start next part of lifecycle. However in northern waters it’s so cold that mollusc does not have enough time to fully grow during salmon’s lifecycle. So mollusc produces some elixir & injects it into salmon’s blood and as result salmon is cured from aging. (Notice pearl mussel itself demonstrates negligible senecsence). Work to isolate mollusc’s secret in the lab has been done. …and here it all stops. Money to analize mollusc’s secret & find the anti-aging component is not forthcoming. End of story.

  1. I’m enthused but color me skeptical until I see confirmations of Harold’s initial results. Too many exciting/promising treatments have come and go over the past decade, probably more than I can count. In the meantime our body’s aging process keeps marching on – tick tock tick tock…

  2. Hoping for the best but I suspect we will be disappointed. Until then I will continue with Rapamycin, Metformin, exercise, intermittent fasting, and NMN.

  3. Maybe aging is all gene based. Winston Churchill drank, was over weight, smoked like a chimney & probably ate all the wrong foods yet lived to 95.

    • Lifespan after about age 90-95 is indeed based largely on genetics. For the lucky few, they can smoke and drink and still live to be centenarians. For the rest of us, food, exercise, and medication all matter.

      • I agree with you that we can improve our age chances if we eat sensibly, exercise, avoid mucking up our systems (smoking, drugs, etc.) & medications (some now gene based)

  4. Say, when I first heard the results, I was astonished. It’s not that I expected it to fail, I didn’t, but I didn’t expect it to succeed as well as it did. So clearly I made some correct assumptions along the way. So will it work, or will it fade away to obscurity? This all depends on whether my view of aging is correct or not (and several other things as well, which I would love to explain once I feel ‘safe’). The basic thesis is that cellular age-phenotype is not a product of a cell’s history, and that the cellular aging that accompanies the aging of the organism, is not the cause of aging but the result of aging. By this logic, if I can change the age-phenotype of the cells by using the body’s own messaging system, then the age phenotype of the organism will follow. As that seems to be the case, I’m most likely correct in my hypothesis, certainly these proof-of-principle experiments support it. So then if what I already stated is the case, then proper age-reversal in merely a matter of engineering. And that’s the stage we’re at. There has never been anything like this before, because there has never been the proper understanding of aging before.

    • Really encouraging results Harold. If I can ask though, you say that ‘cellular age-phenotype is not a product of a cell’s history’, but how would they accumulate in the first place if not by a change in the gene expression of the cells that secrete them? Or are we looking at another process that kick-starts it?.

      I read that you are also looking forward to the new Horvath clock for mice. I was actually watching some talks of his lately, and in one he mentioned a study that showed transplanted hematopoietic stem cells reset the epigenetic age of the recipient to that of the donor. Most interestingly, this age differential remains over time and it is not fasten by the ‘aged’ environment of the recipient.

      Source here: https://youtu.be/uquZph42iSU?t=1950 (paper cited on the slide)

      So, if we take epigenetic age to be a driver of ageing (I know not all agree on this and many see it as a byproduct), then it appears to be intrinsic to the cell or at least the cell lineage. We know though that Yamanaka factors alter it, so external stimuli could potentially affect it.

      Just some questions that pop to mind. Really glad otherwise to read about the success of your project so far.

      • Adrian – let me take a shot at answering this, because you get a lot of things right, and the answers are quite subtle.

        1) Yes, of course, aging is at some level controlled by cells because cells are what the body is made of. But the cells don’t age independently, they are coordinated. As I said above, rather cryptically, there are two possibilities, either (a) there is a central clock (some have proposed the hypothalamus) that sends the signals that tell cells what age they should be or (b) the “clock” is quite dispersed, and cells age and send signals about their age which tell other cells to get older or younger, so that synchrony is maintained. This mechanism has never been decoded, and my guess is that both (a) and (b) play a part. The thymus, the hypothalamus, and telomeres all act as aging clocks, and the small proportion of senescent cells also plays a signaling role. There are probably other mechanisms as well, perhaps 6 to 10 interlaced clocks that mutually consult one another.

        2) The 4 Yamanaka factors can reset a differentiated cell to become a zero-age stem cell. But that’s not what we want. We want to set the clock back PARTIALLY, and there is no natural process that does this. There are recent reports that small doses of the Yamanaka factors can set the clock back part-way, but this is still a new technique, far too uncertain to try in vivo.

        3) I wrote the following too hastily, before looking at the new article. Please see below. Horvath’s story about an infusion of stem cells resetting the body’s methylation clock is more complicated. It’s about bone marrow transplant patients, and they do seem to experience remarkable epigenetic rejuvenation for a few years, but after that, aging catches up with them with a vengeance. There aren’t enough of these cases for us to know the story more reliably than this.

        • Josh, about the 4 Yamanaka factors, I thought the experiment had been partially but successfully done in vivo on mice by Delmonte in the Salk Institute in La Jolla. You talked about it in December 2016.
          Do you have any information about further experiment in this field?

          • I regularly check google scholar for followup studies, but there isn’t anything significant. So I would discount their findings very much.
            Although I believe Josh is and advisor to a startup that is trying to exploit Yamanaka factor based rejuvenation

        • A follow-up long-term study of human HSC transplants:
          “Epigenetic age is a cell-intrinsic property in transplanted human hematopoietic cells”
          https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12897
          “The present study shows that the DNAm age of donor blood is not influenced by the environment of the recipient’s body, whether younger or older, and that the DNAm age continues to increase after transfer to the recipient’s body as if the donor cells were still in the donor’s body. This trait persisted even 17 years after the transfer to recipients who were 1 and 3 years old at the time of HSCT. This suggests that the DNAm age of human hematopoietic cells is not affected by BM niche cells or other factors in the recipient’s body. “

          • So does this mean that the cell environment does not play a role in ageing? The donor cells kept acting like they were in their original home?

          • This specifically applies to hematopoietic stem cells (HSCs) which are different. Sadly, the report about that difference came out of Amy Wagers lab, published in Nature and Blood, when the first author Shane Mayack was accused of faking data and fired. The papers were retracted and we don’t know the actual results – but Shane said that HSCs didn’t change with a young environment solely on the basis of blood factors, but required the assistance of rejuvenated bone-marrow stromal cells to rejuvenate and it took considerable time. Some earlier reports showed the same thing. What the truth is, I don’t know – wish someone would find out – me perhaps. Worse came to worse we could select and amplify somatic-cell derived HSCs (that is, induced to pluripotence, and then coaxed to form HSCs, from the patient herself, sequencing those single cells to assure genomic quality. Every problem has a solution.

          • Thanks. Very good paper. My speculation is that the mDNA clock is propelled by something related to the PI3K AKT mTOR pathway that is basically tied to daily food intake. So the clock is tightly coupled to something that is very hard to tamper with.
            Lack of PI3K AKT mTOR is embronic letha and even at an adult age you dont survive without food.
            Also many cancers have the PI3K AKT mTOR pathway upregulated and mDNA age accelarated, too, while on the other hand rapamycin and calorie restriction slows down mDNA age.

            Maybe knowing what drives the clock could help find something that can set it back a little.

        • Thank you for your comments Josh.

          The key take away for me re. the bone marrow transplantation study is that, at least epigenetically, cell lineages seem independent of each other and not affected by their environment. I may be putting too much weight on just one study and on epigenetic age as a whole, but currently I believe this is the closest we are to uncovering the ageing clock.

          There is the possibility, as you say, that ageing is ‘distributed’ across different interrelated clocks. But knowing what we now know about cell biology and how the body is able to cope quite well with time over decades, only to rapidly decline after a certain age, I find it hard to believe how this is not driven by gene expression. If not ultimately gene expression, what else?

          Closest to this is probably senescent cell accumulation. And this does appear to be the clearest proximal cause of ageing. But then we also have to wonder, why do they accumulate from a particular age onward, and why does this age vary widely between related species?

          Of course, I welcome any other directions of study, but personally, I think eDNA age is where the ‘money’ is.

          • Agreed Adrian. But those epigenetic marks are just book keeping, what writes them and erases them and why? The very simplest semblance to life, is the virus. In particular, at one point I studied the coliphage, T-4 . The genome of this organism is a single DNA molecule and the genes ‘begin’ at one end and end at the other. What do I mean by this ? The first genes at let’s say the 5′ end are transcribed by the bacterial genome (the virus infects the bacterium E. coli) are celled ‘immediate early’ genes and produce proteins which now change the host cells transcription apparatus, so that it now it reads viral promoters not bacterial and produces an enzyme that destroys host DNA (its own DNA protected by hydroxymethyl cytosine in place of cytosine residues) (the first epigenetic marks?). And then that causes the transcription of the early genes, which alters the cell to allow the transcription of the middle genes and finally to cap it off, the late genes are called upon to lyse the bacterial cell in which the virus has made ~200 copies of itself. So here is a linear sequence of nucleotides, coding for proteins, but more importantly (Heresy!), coding a four dimensional structure we call a ‘life’. I believe we work much the same way, just much, much more complex. We are born, not with a set of genes, but with a ‘life’ that unwinds, a play that unfolds, with plenty of room for ‘ad-lib’. I believe I have shown that by rejuvenating cells, we can rejuvenate the body, bring it back to a part of the program already played, like rewinding a tape.

          • If you think about it Adrian, we share almost all our genes and proteins (or very similar ones) with every living thing on the planet, and yet we live to completely different ages, have different life cycles and build completely different bodies. So there MUST be a large amount of scope for change in gene expression, allowing for all sorts of outcomes. This is good news in terms of life extension and health; it should all be highly malleable.

          • That’s a good analogy with the virus life-cycle Harold. I think that, likewise, we can be thought of as carriers of ‘life’, our species, and this program may not necessarily care for what’s best for our own bodies, as much as it does for what’s better for life itself, that is, unfolding a developmental program from conception to old age that fits the species survival.

            Our germ line is after all the last in a long cell lineage, billions of years old, the body is its carrier, mixing with a distant relative in each generation, and carrying on in another body.

            Group selection is not well regarded in evolutionary biology from what I know. But under its light many phenomena could be easily explained.

            I agree, Mark, its remarkable how much we are like even single cell organisms such as yeast. In a computer analogy, I like to think as genes as functions in a program. Calling upon each other and ‘computing’ in thousands of parallel threads. What is the main entry point? The main loop? Where are the variables? Are there any constants? Certainly you can code many different programs out of the same libraries.

    • Dr. Katcher,

      Can you give us some sort of estimate of the time frame for you to discuss your findings out in the open? Time grows increasingly short for some of us.

      • Say Michael, it grows increasingly short for me too. Right now we’re getting funding – then repeat and optimize, test on dogs, some human ‘mercy’ trials. And then hopefully, human trials – but that will take a lot of ‘tooling up’ and much depends on funding. I’m hoping new results will speed funding, so maybe two years? (I always underestimate time). To say I’m working as fast as I can would be accurate.

        • I love your approach, and your thinking. The methylation test will almost certainly be the eye-catcher when it comes to getting solid attention. Telomeres vary so much.

          If you really want to avoid Big Ph (yes please!) and get it out there more quickly once you’re sure it does good – are you considering proving “no-harm” and distributing as a nutraceutical? It could be the “aging aspirin” of the 21st century.

  5. Harold, thanks for chiming in. This is exciting news and hope that your future research will confirm your initial findings. I personally am 53 now and still in excellent shape. However this is about the time when entropy starts to kick in with more vehemence, so this news is encouraging to say the last. Please keep us all abreast on any future updates.

  6. Harold,
    thank you for your open and fascinating comment. This sounds all too good to be true. I am fascinated, very interested and sceptical at the same time. Too many time have I seen similar claims only to see the final results wither away in oblivion.

    What “time-line” are we looking at?
    Is it months, years, a decade?

    Good luck !!
    Werner

  7. This is amazing! I know in my bones that somehow, someday someone is going to discover something soon enough to make it possible for us to rejuvenate. It has left the realm of fairy tale and quackdom. People are taking it seriously. I hope this is it.

  8. Young fresh frozen plasma (yFFP) from a blood bank has been used in a randomized, double-blind placebo based 40 patient study by The Neurology Center in Houston in treating Parkinson’s disease and Multiple sclerosis. One-month results have just been made public for the PS patients and their press release states young plasma recipients “…realized dramatic improvements in critical disease-conditions such as pain, facial expression, speech, handwriting, tremors, rigidity and falling. yFFP recipients achieved improvements in 30/43 assessment categories, with yFFP outperforming the placebo in every assessment subset. Full and continuing study disease assessment and blood laboratory data is accessible online at: http://www.youngplasmastudy.com.”

  9. It is now clear that Stanford, Harvard and others are not releasing their research, despite its success, because they cannot patent a natural biologic. Rather than encourage the unfettered and relatively affordable use of blood bank plasma, they are attempting to reverse-engineer a plasma-compound they can own and control. The exciting aspect of the young plasma study is that they are completely transparent in providing the results they are realizing simply by administering plasma voluntarily donated by 18 – 25 year old individuals.

  10. “Our first pass was to try a combination of known herbal supplements that are known to bind with the targets we’d identified.”

    Can I please get a list of said herbs. While you guys work on this I love to buy some and think just maybe in 4 years I get tiniest of benefits to this works out.

    • Josh we targeted agonists of Nrf2, autophagy, mitophagy, ubiquitin proteasome system and DNA repair systems. We used proprietary synergies and conjugates to improve bioavailability. Bioavailability can not be highlighted enough: It is a problem with 90% of the herbs and vitamins we take. As someone said we make expensive urine rather than get much benefit. For example Lycopene is an incredible extract. It could probably replace statins and is also a powerful anti cancer agent. But we would need to eat 2 dozen tomatoes a day to get any benefit because so little is absorbed. One needs to conjugate it with healthy fats like ghee or olive oil or wheatgerm oil (I take the latter) for us to get decent bioavailability (I am not going into the mechanism). The herb formula too had spectacular results reversing muscle strength, memory and chronic inflammation to youthful levels although I wouldn’t expect it to be as comprehensive and permanent as the plasma fraction protocol. The formula is proprietary but will share results and key herbs via private email.

      • I think you should expedite the use of your “elixir” to pet dogs as soon as feasible (like George Church is doing). It is a brilliant idea; a stand alone business of treating peoples’ pets (for a price) and each treated animal is also both a test subject for efficacy/side effects and a poster child advertising for your treatments. How long before people would see someone’s treated 12 yr old Labrador retriever jumping around like a 2yr old dog a say “when can I get some of that stuff?” Much easier FDA approvals process for pets than people as well.

      • Hello Akshay and Harold, I am a literature researcher that is very interested in your results. If you can send some more results and info on the key herbs by email I would highly appreciate that.

        • I am pretty sure Harold is not going to share key data without locking up his patent claims first. I think we are much better off securing treatment as soon as it becomes available (somewhere on the planet).

      • Akshay cited lycopene. Gac fruit (popular in Vietnam) contains much more lycopene than tomatoes. The paper at https://www.sciencedirect.com/science/article/pii/S0308814609014356 says “Initial concentrations in the aril [gac pulp] of lycopene were from 2.378 mg/g fresh weight (FW) to 3.728 mg/g FW…Gac oil, pressed from gac aril, has similar concentrations of lycopene and beta carotene (2.436 and 2.592 mg/g, respectively).” Fresh tomatoes have only 2.5 mg to 3 mg lycopene per 100 grams; that is, 0.025 to 0.03 mg per gram. In other words, fresh tomatoes roughly one hundredth as much lycopene as fresh gac fruit.
        Does anyone know how well lycopene in orally consumed gac oil would be absorbed? There are some positive testimonials at https://onlygacfruit.com/pages/testimonials. I have no connection with that company, just interested in healthy and longevity.

      • Hi, Akshay:
        You mentioned that you take twice a week:
        Andrographolide, Pterostilbene and Resveratrol

        Can you please specify dosage?

        • Hi Zisos,
          I take 300mg andrographis with 30mg standardized andrgrapholides and 100mg root, stem, leaf plus 50mg patented pterostilbene offering higher bioavailability and 500mg transresveratrol. I need it only twice a week because I am also on rapamycin 3mg once a week and a few other powerful natural extracts. All cycled.

      • In the case of lycopene, I do not know if same in US, but in UK a product is on sale, called “Future” You, Ateron Heart. It has patented a Lycopene proven absorption of each capsule equivalent of 1kg of cooked tomatoes. It made news in all papers here, with speculation it could mean end of heart attacks.

  11. Interesting findings although independent confirmation and further studies would be required to see if the authors have missed anything. However, the basic results seem striking and begs for some insight into the mechanisms underlying the results.

  12. There is no reason why the body would stop producing it, which is why I’m very suspicious of any results that say adding something to blood works. It’s likely either something that accumulates that has to be removed, (either through phlebotomy or liver resection) or it is the result of protein mismetallation, which could, it seems, be fixed to a certain degree by restoring the iron/manganese balance in food and taking lanthanum, which seems to be necessary for excreting iron from cells.
    Also, Europium might be the correct metal for calcineurin and some other rare earths may be needed throughout the body.

    • I also think that aging is caused by toxins and not a planned cell signal. It is not possible to rejuvenate the body. The cadmium aging accelerator accumulates with age, and even if senescent cells are destroyed, cadmium will pass to other cells.
      I bought Senolytic Activator from Lifeextension, I took a double dose. And if it really killed some of the old cells, then it was totally painless. And everything remained in the old.

      • No doubt cadmium is a powerful toxin.

        However, human cells, yeast and bacteria have a highly conserved cadmium detoxification mechanism. It could very well be that cadmium accumulation in the elderly is partly due to reduced glutathione synthesis.

        You haven’t (yet) convinced me that aging is solely caused by cadmium accumulation.

        • I do not say that aging is caused only by cadmium. Learn how the accumulation of cadmium is caused. This is because cadmium is not excreted, but is deposited in metallothionein and it remains in lipofuscin plaques.

          I’m saying rejuvenation is not possible unless you find a way to eliminate cadmium.

          Do you know at all how cadmium poisoning occurs? It is manifested as a deficiency of zinc, magnesium, accompanied by inflammation. Show me an older person who does not have a “lack of magnesium, zinc” or inflammation.

          • I have had a low amount of zinc and needed extra supplement of vitamin b6 since I was 29. The condition that made that necessary was from a much earlier age, that I am not certain how far back it goes. I found this out after long frustration not getting relief from certain drugs. I am fearful of mentioning what I had though. I did receive relief and still do but sometimes get tricked by not reading labels thoroughly and missing something like copper which works against the zinc. I do not know if lack of cadmium excretion can be a factor of low zinc in my case. I am much older than back then when first started and since I got quite a bit of success self treating for something else, am interested in age extension. One thing besides copper, that has always caused me problems is manganese. For one thing has a very negative effect on my heart (palpitations and some pain). I may have a high mercury level in me. From a young age I was given mercury at the dentist to take home. I would take it as a challenge to try and pick it up. I of course did not know any better. Combine that with very high number of amalgam fillings, even now.
            For life extension and sleep I take a commercial brand of herb extracts, called Heart Health. It used to have a different name related to sleep aid and Resveratrol, unrelated to the heart but has ingredients like malatonen and resveratrol. The ingredients are: Falopia japonica to dry root powder, 40g. Extract equiv to Resveratrol, 200mg. Prunus cerasus (Tart Cherry) extract equivalent to fresh fruit 500mg.

  13. I’m not surprised to see Akshay cite the need for conjugation with oils such as olive oil in order to improve bio-availability. The Baati study that extended the lifespan of rats by 90% was done with C60 dissolved in olive oil.
    http://www.sciencedirect.com/science/article/pii/S0142961212005522
    Also, some of the products that significantly increase bioavailability of curcumin and other curcuminoids of turmeric are combined with phospholipids. One is Indena’s Meriva.
    http://www.phytosome.info
    For a while, I took a product that contained Meriva, and it helped a knee problem as long as I was taking it.
    Indena has several products in addition to Meriva that are also “Phytosome” products, including active ingredients from grapes, green tea, Boswellia, etc.
    A traditional formulation of certain “rasayanas” (Ayurveda’s rejuvenating substances such as ashwagandha) is to mix them with ghee.
    Interesting, some claims are made for a factor of 185 improvement in bioavailability for water-soluble micelle formulation of curcumin. One of them is linked below. Maybe they are all supplied by the same manufacturer.
    https://www.martindalesnutrition.com/article/185x-better-availability-curcumin/

  14. If this is based on some unpatentable natural compound, the way for you and Dr. Katcher to make money off of this is to come up with a formulation, then cut a deal with Bill Faloon at the Life Extension Foundation to market it. The LEF does respect and reward IP. The other approach is to do like Genescient and develop, manufacture, and market it as a supplement under your own brand name. I would contact Gregory Benford if you want to go this route.

    • There are two major patent claims: what has emerged from our process is something new so it would be novel but we are being told that big money can find ways around a process patent. The second one has absolutely no chance of bypass and is the difference between $100,000 for each treatment and less than $1,000 per treatment.

      • I assume you are working with Harold on this? I have filed three patents – two of them were PCT. I don’t know jack about the pharma industry but I know a thing or two about protecting IP.

        One major aspect that many patent attorneys fail to mention (as they are focused mainly on their side of the equation) is also the ‘value’ of infringement. So it’s one thing to secure the rights to ‘something’ but it’s almost equally important that you guys go out there and produce some kind of product or service.

        Consider for a moment the potential magnitude/scope of what you are working on. People would be lining up to receive a treatment or to buy the product. If big pharma can finds some chink in your armor they will grab it and ask questions later. Remember that they have literally hundreds of millions to spend in attorney fees and they would be prepared to do it as the potential market opportunity is significant to say the least.

        So yes, lawyer up, get the claims right, consider coverage where you think you’ll be able to enforce it. But also remember that having a product/service on the market is equally valuable. You do have a huge advantage in comparison with big pharma as your product is herbs based and may not require FDA approval if it can be sold as a ‘supplement’. Treatment could also be administered in this general framework at exclusive clinics. All of which can be done very quickly and efficiently.

        If your idea/invention has merit then I suggest you RUN, not walk, in order to get your patents on the books, and then start producing SOME KIND OF PRODUCT in order to establish precedence and the fact that you are actively pursuing commercialization.

  15. There’s a young plasma study taking place in Houston (www.YoungPlasmaStudy.com) that has shown some pretty impressive results so far with Parkinson’s Disease patients.

    Some very impressive results so far.

  16. Those old rats seem to be clearly diabetic with a fasting glucose around 170. I dont know maybe this is a natural consequence of ad libitum feeding in captivity.
    And they seem to be cured from their diabetes. Couldnt the same be achived with dietary restriction?

    • Very nice work Harold & Josh!
      I would for sure join a crowdfunding route!
      I’m still young but this would be great for my dad.

    • Gabor, it’s not so much the cure of their type 2 diabetes – though it it could be cured by a calorie restriction diet, it would be, but rather the coordination of muscular strength, ‘mental’ speed (maze solving), huge lowering of both inflammatory markers and blood glucose simultaneously days following the injection, and still progressing weeks after the last injection that convinces us we’ve permanently reset the ages of at least those organs/tissues directly involved (brain/neurons, glia), muscles, muscle cells have more energy available (explaining strength/endurance increases (grip strength – holding onto a bar and being pulled slowly away from it until the rat lets go, the bar attached to a meter)) and the cells are no longer refractive to insulin explains the ‘cure’ of diabetes, and perhaps disappearance of senescent cells would explain the loss of blood inflammatory markers.
      Point is – this is what we’d expect if the cells were actually rejuvenated. That the body follows might be expected. There’s a lot of very basic biology to be unlearned. More dangerous than not knowing is not knowing and thinking you do.

  17. Hi Josh:

    Thanks for maintaining this blog. As a (fairly healthy) 74 year old long interested in anti-aging I greatly appreciate your involvement and sharing progress.

    I suggest that if Akshay and Dr. Katcher have some ideas about how this community could help accelerate or promote their effort it would likely be well received.

    • We’re thinking of setting up a crowd-sourcing site – we have no expertise in this – but if anyone does, we could use some help.

        • I think that crowdfunding is a good great idea. Also, have you thought of approaching an organization like calico? They may have their own approach to anti-aging therapies, but maybe they would be open to trying something different.

          • I fear that Calico would eat them alive and you can bet that the product would not be made available at low cost for a wide cross section of society.

            Capital Cell in my opinion is their best bet:

            https://capitalcell.co.uk/

          • The problem with Calico Akshay, is that they don’t appear to be interested in translating an understanding of aging into a treatment – they are totally focussed (from what I’ve read and heard) on fundamental mechanisms, and don’t seem to have got very far down that road. If you pop up and say ‘we’ve done it!’, I expect you’d be met with condescending disbelief.

            Just my opinion, I’d love to be wrong but I’m not optimistic about anything Calico are doing.

            I’ve always hoped the solution to aging would come straight out of left field, unexpected. And you and Harold may well be fulfilling that hope. Buy don’t expect the rest of the field to share my acceptance or happiness at your success.

  18. Wow, Harold, Akshay! Just from the biomarker improvements alone your results are outrageous. Congratulations. And interesting that you used a herbal combination to test out the pathways before you made your ‘elixir’…

    Regarding the epigenetic age reversal of haematopoietic stem cell receipients, and their subsequent rapid catch-up aging – I believe this was due to host Vs graft disease.

  19. Say Michael, it grows increasingly short for me too. Right now we’re getting funding – then repeat and optimize, test on dogs, some human ‘mercy’ trials. And then hopefully, human trials – but that will take a lot of ‘tooling up’ and much depends on funding. I’m hoping new results will speed funding, so maybe two years? (I always underestimate time). To say I’m working as fast as I can would be accurate.

    • Oh, I’m certain that you are working as fast as you can. I am just incredibly frustrated with our current drug approval regime which seems *designed* to slow down the pace of medical technology development (compare and contrast the rate of medical technology growth with for instance the rate of computing technology growth – if medicine had advanced as fast has computing power over the last 40 year we’d be living centuries by now. In fact we’d have hit that singularity we all talk about). This is not because we don’t have brilliant people working in the field. It is because incumbent pharma companies have a financial interest in managing the rate of technological growth. If you’re big pharma you’re definitely not interested in having your new blockbuster drug superseded three years after introduction with something that works twice as well with half the side effects. All the big pharma companies would like to see their big banner drugs last right up to the moment the patent expires on them. They want to erect barriers to small nimble companies that might be technologically disruptive.

      The excuse we have is “well, do you want another thalidomide?”. And indeed no one wants that. But there are silent victims with the current regime – all those people that could have been helped or saved by effective drugs that are kept off the market for an unnecessary decade or so. Thalidomide kids are easy to photograph. The millions that die early deaths or have diminished quality of life due to effective drugs being held off the market are damn hard to get a picture of.

      I think it is in innovative researcher’s interest to find ways around the current drug approval process. For instance – offshore clinics that do not fall under the jurisdiction of the various national drug approval agencies, i.e. medial tourism. At first blush this seems incredibly unfair – innovative medical treatments being available to only the top few percentage points in terms of wealth. But, when the hoi polloi see the rich and famous getting *cured* and getting *younger* they will apply the necessary political pressure to roll back some of these drug approval regimes that benefit no one at this point but the drug companies.

  20. This specifically applies to hematopoietic stem cells (HSCs) which are different. Sadly, the report about that difference came out of Amy Wagers lab, published in Nature and Blood, when the first author Shane Mayack was accused of faking data and fired. The papers were retracted and we don’t know the actual results – but Shane said that HSCs didn’t change with a young environment solely on the basis of blood factors, but required the assistance of rejuvenated bone-marrow stromal cells to rejuvenate and it took considerable time. Some earlier reports showed the same thing. What the truth is, I don’t know – wish someone would find out – me perhaps. Worse came to worse we could select and amplify somatic-cell derived HSCs (that is, induced to pluripotence, and then coaxed to form HSCs, from the patient herself, sequencing those single cells to assure genomic quality. Every problem has a solution.

  21. Dear Josh&Harold et al,
    I am of the same opinion with regard to plasma as the communication mean of aging coordination at the whole organism level, and acknowledge the results seems quite impressive. Nevertheless, if true aging is occurring at a cellular level, this should have to be able to test on a simpler set up. Just take a bunch of old cells from any tissue and expose it to a continuous supply of fresh young plasma and monitor cells for a while, you should see telomere lengthening, epigenetic age reversal and many other markers of cell de-aging in vitro. To my knowledge, something as simple as this as a proof of concept has not been properly done. If so, please point me the corresponding references as I am intersted on it. The closer to this i have seen is the Nelly Olova paper on partial reprogramming and epigenetic aging showing uncoupling of epigenetic deaging from dedifferentiation (https://doi.org/10.1101/292680)

      • That’s what you’d expect – mitochondrial function being under the control of nuclear gene expression.

        And of course upregulation of mitophagy should acheive the same thing, as I’m sure you address as part of your herb mix anti aging pathways.

        • Yes Mark thanks it does. If you are interested in the process of gene expression some very intriguing papers are coming out revealing a complex and fascinating process of phase change self forming protein condensates gathering/clustering in a mesh at the correct address (super enhancers) at the right time to activate a gene. You can read here:
          https://www.linkedin.com/feed/update/urn:li:activity:6482587706659565568
          The question that remains unanswered is what decides the timing of the gathering of condensates at a particular gene activating address or methylation/repression. As we know epigenetic drift is a trend of changes in gene expression that follows a pattern for all living over their life cycle. What dictates the changes/pattern and it’s timing?

          • In my opinion it’s yet more evidence that it’s not about the genes, it’s about the signaling, that decides the state of health and aging.

            It dovetails nicely with the discussion with Adrian T above about how every lifeform on earth is calling the same ‘functions’ (genes) but can call them in any number of permutations to build the body or the lifespan that is required by that evolutionary niche.

            So now we must discover how to maintain youthful signaling, and even more importantly, how do we knock a body back into that healthy homeostasis once it has lost it?

            Another way of looking at it: what evolutionary trade-off decisions has the body made to allow youth to be lost?

          • In my opinion it’s yet more evidence that it’s not about the genes, it’s about the signaling, that decides the state of health and aging.

            It dovetails nicely with the discussion with Adrian T above about how every lifeform on earth is calling the same ‘functions’ (genes) but can call them in any number of permutations to build the body or the lifespan that is required by that evolutionary niche.

            So now we must discover how to maintain youthful signaling, and even more importantly, how do we knock a body back into that healthy homeostasis once it has lost it?

            Another way of looking at it: what evolutionary trade-off decisions has the body made to allow youth to be lost?

    • This is a very interesting paper. Of course it is hard to draw the definite conclusion (as they do) that the signaling environment has not influenced the transplanted blood DNAm age when the entire hematopoietic system has been ablated and replaced. This is different to a plasma transfusion is being added to an existing system of a given DNAm age. (note to self – probably good to remove own blood before adding younger blood)

      Also interesting that granulocyte colony stimulating factor appeared to cause some rejuvenation.

      • Hi Mark, looking at it the other way around: people with a completely ablated and replaced with a younger hematopoietic system having a long term sustained low DNAmage should have to show dramatic rejuvenation features, which are not there.
        I think a cell of a given DNAmage is locked on it and is probably paying more attention to itself and its neighbors signals than to the factors in blood (although an important part of the equation). We will probably need to add some other stuff to the plasma to get the cells more plastic (OCT4, HDACis, etc). Just a thought….

        • To be fair they didn’t look for changes in the DNAm age of surrounding tissues – for example endothelial cells, smooth muscle cells etc. There might have been an effect, though you’re right – it clearly wasn’t huge otherwise something would have been reported.

          • Do we get updates about Harolds research trough this blog, or is there a other way about being informed about the status and maybe a crowdfunding?

          • I’ll continue to tell what I know. I no longer think crowdfunding is appropriate after talking to Harold’s partner, Akshay, and realizing they already have a for-profit company set up, which owns all rights to present and future discoveries.

          • We are not a big company but a small venture started out of passion for aging science, a belief that it could be cured (only a matter of time) and a strategy to try to cure it. We managed to fund up to the proof of concept on our own and two friends. We are in the process of raising a larger round based on our trial results but till then we could use all the help we can get to accelerate next stage developments. If anyone wants to discuss supporting us you could email us at atomicblissventures at gmail dot com I am sure the same passion that got us up to this point will hopefully help us to develop a therapy/treatment at a reasonably affordable cost in the near future. One can never assume that what works like a miracle in rats will also work in the same way in humans but what gives us hope is that the fundamentals behind this discovery are highly conserved in Nature across all mammals even species.

          • Also Guillermo, another possibility is that maybe DNAm age is only a good measure of chronological age, not biological age, and therefore is not a good metric for potential rejuvenation therapies. It’s a pity they didn’t also look at telomeres, or maybe use the newer phenoAge clock.

            Akshay – are you looking to sell shares in your company, or for charitable donations?

  22. Slightly off topic comment:
    About 6 wks. ago I started Metformin, off label. On a recent blood draw, I had an issue with low platelets and low WBC. My primary sent me to a hematologist who is also an oncologist. I mentioned my taking Metformin thinking it might have affected my above condition. He said to continue the Metformin and not to worry.

    He also said that he was going to start Metformin himself for the anti-cancer benefit. Nice to know that some conventional docs are realizing the benefits of the drug. Also wondering when this drug will explode into the consciousness of the general public causing big pharma to throw a molecule or two in there and start charging an enormous price.

    • Thanks for the story. Just very recently, I’m not as enthusiastic about metformin as I have been because of unpublished data that says it might have a paradoxical effect for people who don’t have diabetes. Here is a new article about metformin interfering with exercise adaptation. https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12880
      In this season, I’m leaning toward herbal substitutes for metformin that might not have side effects.

      • Thanks Josh,
        At age 80 I did 2 miles non-stop freestyle. After that, at 84 I have tapered off aerobics and am just trying to stay active in a lot of areas especially Tai Chi.

        My main thrust has been time-restricted eating. (S. Panda author of, “The Circadian Code”, and others). It has paid some real dividends. gradual wt. loss, a better feeling of well being, and am more active. I try to eat plant-based. It is difficult to parse the effect of each effort.

        Your book was very instrumental in my quest as well as this blog though it is like drinking from a fire hydrant.

        Thanks again for that.

      • I got a significant drop in WBC (particularly neutrophils) from berberine. It also made me lose a lot of weight (AMPK activator).

        I did alot of high intensity interval training at the time, and noticed no issue with exercise performance.

        • There are any? I thought gene therapy was currently the only way to do this.

          The nearest I’ve found is ROCK inhibitors like Statins, which can cause de-differentiation to progenitor cells.

          • there are small molecule activators for OSKM, for example forskolin
            “Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds”

          • Well done!! a great service to the forum Gabor, was not aware of that. >>there are small molecule activators for OSKM, for example forskolin “Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds”<< Any thoughts on dose of for forskolin? What are other natural compounds that do similar?? If anyone is aware of. Any reason to think in terms of cycling rather than daily [as I mentioned I cycle everything 8 on-3 off but that is not optimum I know]
            I will add an NRF2 activator + I use is spermidine, worth a bit of research imo: but careful not more than every 4 days or so based on my looking into. Many positive effects besides NRF2 activation

          • I think the science for chemical iPSC induction is more estabilshed now. But I think its disfavored in the laboratory because of the low efficiency.
            For example this is a Cell Stem Cell paper
            “Chromatin accessibility dynamics during chemical induction of pluripotency”

            However the process is hard and risky. I wouldn’t try it on myself for sure.

            Seems like most anti aging medications happen to act in the cytosol mainly by altering metabolic processes and the anti aging effect is only secondary. And even achieving this is hard enough.

            Going one level deeper through the cells defense works down to the nucleus to modify the chromatin, which the Holy Grail is IMHO, is even harder and riskier.
            We only have very blunt tools and shaky, almost anecdotal science.

    • Not a bad guess, but mTOR inhibitors work more similar to stepping on the breaks on the aging program and therefore merely slow it down rather than reversing it or causing rejuvenation. The compounds used must have more dramatic reversal effects on any aging programming and mTOR inhibitors or rapamycin don’t quite fit that.

        • Do you still take Rapamycin and Metformin. What dose? I understand they are probably only hormetics but until you are successful or senolytics arrive it’s the best we have.

          • Larry,
            You are right. Till the full cure is available to humans cyclically inhibiting mTOR seems to the best strategy to slow down aging deterioration. I tried metformin in isolation because a study said it directly activated SIRT1. But the trade off was too severe for me so went back to rapamycin. I take 3mg once a week. The bulk of the benefit occurs in the 36 hours post that I take top up of Nrf2 activators which may be better way of indirectly inhibiting mTOR for 2 days and DHEA for 2 days when I do my intensive work out. So both growth and repair are important. When we age the sensor seems to go askew with increasing growth and lowering repair. Ideally we should just try to tilt it the other way. Not go to the other extreme. If we do not keep cyclical days for muscle training and growth we may also be badly affected in the long run. I have seen some anti aging enthusiasts shrivel and get hernias etc. Balance is the key. The greatest biological gift of youth is homeostasis.

          • I take Metformin because of it’s long term safety record and easy availability where I currently live. Rapamycin I do not take but it is much harder to get a hold of. If I could buy it i would look into it more to possibly take it. Rapamycin is more than just a hormetic, I think it actually slows down some of the aging programs through inhibiting mTOR and may be the most effective drug currently widely available today to slow down aging (not reverse it).

          • Thanks for that Akshay, definitely think you are right that we need periods of anabolism as well as catabolism.

            Do you also take anything to boost the NAD+/NADH ratio?

          • Mark I take andrographolide with pterostilbene and resveratrol to boost Nrf2 which upregulates NAD+ via NQO1. Sulforaphane also seems to be a great Nrf2 activator but a bioavailable form is very difficult to find. Vince Giuliano explains how that is a more sustainable way to upregulate NAD+ then NAD+ precursors. Here is the link:
            http://www.anti-agingfirewalls.com/2015/05/01/part-4-of-the-nad-world-the-nq1-gene-the-warburg-effect-sirt-1-and-inflammation-and-possible-interventions/

          • Akshay, thanks for the info. Pterostilbene and resveratrol aren’t very bioavailable in humans due to their extensive metabolism. What makes you think they will increase NRF2 in humans upon consumption? Do you have any evidene of that?

          • Olafur not on their own – that GSK lost $720 million trying to do that – but one of the secrets of pterostilbene and resveratrol and probably it’s most valuable one is their ability to synergistically multiply the bioavailability/potency of many natural extracts. So if one had to take 5x of a natural extract and 5x of pterostilbene independently to get any significant bioavailability, synergistically/together one can get similar bioavailability with 1x of each. This is a very general estimation actual amplification may vary with each combination.

          • Pterostilbene is actually pretty bioavailable (atleast compared to resveratrol). In addition to what Akshay rightly says about combinations (curcumin is my favourite pairing with resveratrol), they are also fat soluble molecules, so can be absorbed more effectively in fat, like yogurt or olive oil or butter.

          • Akshay, I haven’t seen any evidence of their synergistic bioavailability/potency, at least not in humans, but can’t say I have looked into it. My suspicion is that animal studies show synergy but metabolism is so different in humans so I wouldn’t take that as proof.

            Mark, about pterostillbene being more bioavailable than resveratrol, I wouldn’t be surprised. I am well aware of the lack of bioavailability of resveratrol and many other plant compounds but can’t say I have looked into pterostillbene. If it is much more bioavailable orally in humans than resveratrol then maybe it has more promise as an Nrf2 activator.

          • Olafur what I have shared is observations/deductions from years of research, rat model experiments and self experiments. Therefore I wouldn’t be surprised if you did not come across any human studies – even otherwise there not too many human studies that get conducted for natural extracts. One could self experiment with one week andrographolide, one week gap then one week only pterostilbene and then one week gap and then 1 week of both taken together. The significant difference would be noticeable only if you are above 55 years in age. But eventually one must only take anything that one is fully convinced of, with the type of evidence one would count acceptable.

          • Sure you could certainly self experiment but if anything is having a significant effect it’s unlikely that you will be able to tell. What effect would you expect from pterostillbene? It’s not like you can measure Nrf2 activation. In any case most interventions that work to some extent you won’t notice even if you are well above 55 years of age, unless they are effecting some parameter that you can measure accurately with a blood test.

          • You are probably not over 55. Many here who are willing tell you that if for example they stop taking rapamycin for a few doses and then when they resume again they can immediately feel the difference in multiple parameters like strength, sleep, brain clarity, stamina, etc. For me Nrf2 activation provides similar difference but not with pterostilbene alone but together with andrographolide.

        • Yes I’m well under 55. I’m 38 and pretty healthy so I generally notice nothing when I take supplements or drugs. For something powerful like rapamycin in someone over 55, yes I don’t doubt that some people notice a difference. Also some people might notice differences with some supplements particularly in combination with other supplements/drugs. I’m not discounting that and I believe you when you say you notice something positive from taking pterostilbene with andrographolide. My criticism is that even if you do notice some positive things what evidence or reasons do you have to believe that the effect you notice from taking that combination is some of the downstream effects of the benefits you’re looking for (like Nrf2 activation) rather than some unrelated effect? Unless you can somehow measure Nrf2 you can only speculate that Nrf2 activation is the mechanism behind the benefits. Of course without a way to measure it if you do feel positive benefits and have a reasonable hypothesis as to what is causing it (Nrf2 activation in this case) then I agree, it’s often good to take something anyways. If it works it works. Lots of times drugs are used for long with benefits and only much later their mechanism of action is found out. Very interesting that you do notice a difference with pterostillbene and andrographolide. Thanks for sharing. Btw how similar are those differences to those experienced in the mice in the plasma fraction experiment?

          • Can’t compare the two. Totally different mechanisms. Results though can be compared. We did see similar reversal of aging biomarkers. For example in both IL-6 levels went down to the same as young controls. Regarding andrographolide and pterostilbene both have studies from reputed labs that demonstrated their ability to upregulated Nrf2 and the mechanism or cascade by which they activated it. Their synergy to strongly activate Nrf2 at 1/5th the dose is our deduction via research and experiments and is currently proprietary but can be easily demonstrated in lab rats or mice with Nrf2 kits. Although to some that is not evidence. To me armed with third party safety data, our own safety data and the fact that it’s origin is all natural was enough to try it myself. When I felt the benefits as profoundly as when I took rapamycin my own conclusion is it may be better way to get the same benefits. My conclusion is based on study of Nrf2 pathway. But since we are yet to complete our human trials I take both (not together). Once our human trials also show the same or better benefits then I may only take the natural formula. If by then the plasma fraction cure is still not ready for humans. Once that is I may not need to take any anti aging supplement.

          • Thanks for the info. Very interesting that you felt benefits from rapamycin and also the pterostilbene/andrographolide combination. Maybe they are synergistic since the former works through inhibiting mTOR while the latter may mainly work through Nrf2 activation. Anyways best of luck with the experiments.

          • Thanks Olafur for your best wishes. Yes Nrf2 not only inhibits mTOR but also boosts NAD+ (another anti aging favorite), boosts DNA repair systems, floods our system with powerful anti oxidants (anti oxidants obtained from fruits kill one oxidant whereas Nrf2 triggered one anti oxidant kills many oxidants), it brings down chronic inflammation, it activates autophagy which naturally recycles senescent cells, it boosts ubiquitin proteasome support system which helps improve protein synthesis (reduce errors) and minimize aggregates like plaques formation, it boosts our immune system, it plays critical role in adipose tissue and protects us from obesity, it protects pancreatic cells and improves insulin sensitivity, it protects against cardiovascular disease including atherosclerosis, it detoxifies, it supports the structural and functional integrity of mitochondria, I mean I can go on and on about importance of occasional activation of Nrf2 pathway in aging. The key here is occasional. One should not keep Nrf2 constantly activated. It should be intermittently activated.

          • With all those potential benefits Nrf2 sure sounds it could be very effective. It’s been many years since I looked into it, it’s probably time for me to do it again. With respect to intermittent activation, have you looked into the optimal time period? Do you take the Nrf2 activators every other day or once a week or something like that?

          • James, thanks. My concern is that metabolism of resveratrol is very different in rodents than humans such as glucuronidation by the liver and in the small intestine during or prior to absorption such that for humans the bioavailability is no where close to 20%. Nevertheless it is interesting to see that pterostilbene is more bioavailable than resveratrol in rats. Perhaps it is also much more bioavailable in humans. I need to look into that.

          • Steve, regarding keto, I don’t think there is any evidence that a ketogenic diet will increase NAD+ levels. It’s calorie restriction that increases NAD+ regardless of whether you are mainly restricting carbs or fat or protein. If you have any evidence of ketogenic diet increasing NAD+ levels in vivo in the absence of restricting calories then please post it.

        • TY for your sharing here Akshay Curious what you may mean re >>One should not keep Nrf2 constantly activated. It should be intermittently activated.<< intermittently re that post meaning 3 days every 3 months? one week on one week off? Trying to get some rough idea of what you mean by intermittently ? Thanks

          • I think your question confirms what I suggested further below: We need a post featuring a detailed protocol of currently available non-prescription compounds.

          • sorry posted 2x as first time did not see, need to refresh. >>We need a post featuring a detailed protocol of currently available non-prescription compounds.<< GREAT IDEA!!!<< I take 7 days on 3-4 days off on everything. Except whole food supplements–relatively low potency multi, mineral and c but low potency whole food derived–gives body a break. LONG LIST OF various Nrf2 Studies on Pubmed.
            if accurate we are all taking quite a few activators.
            https://www.nrf2.com/nrf2-activating-foods-and-ingredients/

            I take Beta lapachone also sometimes on my 3-4 days off, A. is correct toxic if take too much, this one is relatively weak liquid
            Akshay, again ty, add a lot to this forum

        • what do you mean by intermittingly Akshay? 5 days in a row every 6 months, one week on, one week off? Just to get a ballpark idea of the way you are using that term. TY much, you share a lot of good info!

          • James, after the age of 50 I would think Nrf2 would need to be activated once or twice a week may be maximum thrice. As we age the frequency need not change but the dosage can be either augmented or can be synergistically made more potent.

          • Interesting discussion Akshay. Thanks for sharing your insights.

            Can you point to a paper that gives a good overview of Nrf2?

            I looked into it a while back and found some good synergies. Pterostilbene and curcumin made me feel pretty superhuman. Many other combinations did nothing for me. I do find I can feel what some substances are doing. I would be surprised of there’s anyone who wouldn’t feel both the benefits and side effects of Rapamycin. But I agree many supplements do nothing. Some of that is probably bioavailability. Some is probably a clash with diet and lifestyle. You can’t just take a supplement and expect it to fix an unhealthy lifestyle.

            Not until something like a plasma fraction cure comes along!

            I was surprised you only activate nrf2 a few times as week. Perhaps you are activating it much more powerfully than me. I generally do morning and evening 5 days a week, which I think allows for a period in the middle of the day to allow it to fall. But perhaps I’m pushing too hard on that particular button?

          • Mark, yes just as mTOR inhibition idea is to make up for the dysfunction not go overboard. In Nrf2’s aging increases repression thereby reducing activation. Opposite of mTOR. The progressive reduced action of Nrf2 leads to development of various disease conditions. But just as we discussed earlier over inhibition of mTOR leads to detrimental affects similarly over activation of Nrf2 would not just make up for increased repression but go beyond homeostatic state and lead to exhaustion important enzymes and potential for oncogenesis. This is a dichotomy. A normal Nrf2 expression as in our youth is actually cancer preventive. Mark you seem to be on the younger side of 50 so I would suggest you should activate it sparingly as the age related repression may not be so pronounced at your age. Yes I do take a powerful activating formula but only couple of times in a week.

          • Since we have a pretty experienced/knowledgable group following this thread I wanted to bring something up that has been rattling around in my brain: For the past few years I have been taking 100mg – 200mg of modafinil intermittently (e.g. once/twice a week and then nothing for three weeks) – mainly when I’m facing a heads-down hard core coding week.

            What I realized on top of the increase in mental acuity is that it also seems to kick my training sessions into overdrive. I show up and I’m practically ready to rip up the gym for two hours or so. Actually have to sort of hold me back a little in order to not get injured. Which is a great day when you’re 53 years old!

            What’s your collective thought reg. Modafinil? It’s just a smart drug – yes – plus it doesn’t work for everyone. But having great work outs can put you on the right track on a bunch of other parallels: You feel better, you sleep better, you grow muscle or are able to maintain what you have, your test levels may even be up, perhaps even better sex (wishful thinking? – I’ll ask my wife – LOL).

            Anyway, it’s something I just wanted to throw out there. For me personally it works like a charm and it seems completely non-addictive as I can pop one three days in a row and then not take any for a month or so. I think smart drugs have their place and I remember reports that it may even help stave off Alzheimer’s.

          • This is an interesting discussion that needs further clarification. There is an almost countless number of Nrf2 activators (endogenous and exogenous)

            All of us are exposed to toxins daily, which activate Nrf2 through hormesis. Exercise is also on the list.

            For now, I’ll keep exercising numerous times during the day.

          • @ Stephan

            400mg of each, in yogurt. But as suggested by Akshay, after a few days it became too much – so I’d try this with caution.

          • @Mark
            @Akshay

            Thanks for sharing your insides.

            I’m taking 1000mg Turmeric/Curcumin supplement daily for about a year. I also make my own tea from ginger and turmeric roots with a pinch of cayenne pepper. I drink every day to cups with a bit of honey and half a teaspoon 100% virgin coconut oil.

            Ever since I never had symptoms of a cold and feel very energetic. I’m a very active outdoorsman and also pump iron 5 times a week in the gym at the age of 64.

            Would you think adding 500 mg of Pterostilbene once a week will be safe?

          • Stephan you seem be doing well @64 with pumping iron 5 times a week. Do you take any hormone support? Of the 1000mg probably 3% may be bioavailable. If you boil it that is supposed to move to around 10% If you add black pepper – I don’t know about cayenne pepper synergy with curcumin – the bioavailability is supposed to double. Once a week adding pterostilbene sounds ok to me. Now let’s hear from Mark.

          • Thanks, Akshay. No, I don’t take any hormone support but living for about 20 years on a Paleo diet. The Turmeric supplement I take has black pepper added, and in addition, I open the capsule and dissolve the content in a tablespoon of Olive oil before taking it.

            I do take a few other supplements daily:
            1000mg Vitamine C
            10000 IU Vitamine D
            500mg Magnesium Oxide
            50mg Zinc
            500mg Omega-3 from Krill Oil

            I think the most important key – besides a healthy diet – is being physically active. We were meant to move.

          • You are absolutely right on the ‘being active’ part. Nature rewards active. You may want to consider Vitamin K2 Mk4/7 and copper supplements to balance out DE and zinc respectively. I am surprised that you have not needed any hormone support with the kind of rigorous exercise regimen you maintain. That’s great though.

          • Thanks for your advice, I’ll look into K2 and copper supplement. But maybe I get that through my diet already. Need to do some research on that.

            Many people are wondering about my rigorous exercise regimen at my age. I’m not a scientist or researcher, but I think it is due to my lifestyle.

            I never had a meal in a fast food restaurant nor drank I ever sugary pop. I never took any street drugs, however, occasionally enjoying some beers and Tequilas.

            I believe to have a well-balanced diet of meat (including liver and bone marrow), fish, vegetables, and fruits. I ate a lot of eggs, nuts, and seeds but don’t eat wheat/grain and dairy products (90% of the time). I supplement refined sugar with stevia.

            Also, I practice intermitted fasting and once a year I fast for a week only drinking water, tea or coffee.

            I’m fortunate to live in Canada’s Yukon Territory where we have still clean air, rivers, and lakes; plenty wilderness and wild game to hunt and fish.

          • Hi Stephan, Akshay

            Sounds like you are doing brilliantly Stephan – I think at your age the key is to just keep the physical activity going and it sounds like you are not having any problems doing so.

            I highly rate Paleo diets – in my view that is probably behind your health. As we are discussing NAD+, this level will be elevated on a keto type diet for a number of reasons, especially in the brain.

            I’m only 40 so most interventions don’t do a lot for me (ironically the older you are the easier you see the difference), but keto has been beneficial.

            A lot of the pharmacological sirtuin activators like resveratrol I think are a mild toxin – and every-time I use them I eventually have to stop. But maybe that just reflects that use should be cyclical. Or perhaps my sirtuin levels are already high.

            I like the idea of NRF2 activators but I’ve never noticed much from curcumin, sulphoraphane, ginger, rosemary, etc. I do like the idea of beta-lapachone though.

            I don’t think Vince and James have got the NAD+ argument quite right. I think direct precursors can sustainably raise NAD+, but the key is to get the balance right. I think ultimately the salvage pathway has to be balanced to sustain recycling back from Nicotinamide by keeping NAMPT high. Hence why Sinclair et al. got better results when they used a hydrogen sulphide donor in addition to NMN.

            Ultimately I think we need to hit NAD+, NAMPT and NRF2 in just the right balance. It’s tricky.

            What frustrates me is that I saw ZERO aging by 35, but by 38-39 it was noticeably kicking it. And almost nothing seems to be able to reverse it back beyond that point of deterioration.

          • The following article cites research suggesting that NR does not sustainably raise the level of NAD+ due to homeostasis, but the effect of homeostasis on NMN-induced increases is unclear. A mouse study by Dr. Sinclair showed a 500+% increase in NAD+ levels after 60 days. The article states that there is “some hope that NMN is not subject to the same limits on the long-term increase of NAD+ levels as have been found with NR.”
            https://alivebynature.com/nad-for-the-brain-nmn-for-the-body-3/
            Then there is the question of what happens to the NAD+/NADH ratio and whether, as the Vince Guiliano post that Akshay pointed to said, that ratio is more important than the absolute amount of NAD+.

          • Further down in that same article at alivebynature they added this:

            “Supplying NAD+ direct to the bloodstream bypasses the liver, temporarily enabling a greater increase in NAD+ levels.

            Any NAD+ (or NMN) in the bloodstream will get filtered out by the liver in 30-60 minutes.

            So after an initial spike in NAD+, the same limits imposed by homeostasis in the liver will likely take effect.

            This is why NAD+ clinics use slow IV drips to constantly supply NAD+ to the bloodstream rather than a single large daily injection of NAD+.

            Frequent dosages throughout the day of our NAD+ sublingual tablets provide a steady supply of NAD+ direct to the bloodstream, avoiding the limits imposed by homeostasis in the liver.”

            Do you guys buy this? I’m a bit confused as David Sinclair stated just a few days ago that he takes 1g of NMN in the morning, and probably has been for quite a while. So what’s the real story? Or is there simply no consensus on the exact mechanism yet?

          • Mark – very interesting insights about NMN. I was about to order some NMN from alivebynature but given what you said I worry that the effect would be short lived. Would you suggest the precursors instead? They sell those two but I have not looked into them.

            BTW, you’re complaining at 40? HA! When I was 45 people continuously thought I was 35. Now I’m 35 and I’m often being tagged for 45. Big difference between my body and my face however. My body has remained at very youthful levels while my very white complexion has taken some damage. Just had to laser off a few more aging spots and of course there are very noticeable crow feed around the eyes, especially when I smile. But still compared with 99% of the people my age I’m extremely pleased. I should probably do some methylation test – they are harder to get a hold of here in Spain.

          • It’s great to hear, how you are doing Stephan.

            A lot of emphasis is put on supplements, but the beauty about exercise is that the overwhelming majority of people get a positive result almost instantaneously, without potential side effects from supplements.

            Personally I’ve never noticed any significant difference in exercise capacity from taking supplements.

            However, I can assure you that I feel mentally and physically rejuvenated after a 5k run at my VO2Max.

          • @Mark
            @Akshay

            Well, somewhere I read Dr. Aubrey de Grey predicting the first human to live 1000 years is already alive and now in his/her 60ties. I hope that’s me.

            I know, just wishful thinking.

          • @ Michael

            I never said NMN was filtered out by the liver – it might well be; many supplements are. I guess it depends on exactly what the demands on NAD+ are at that moment in time.

            What seems fairly certain is that it will end up as NAM (nicotinamide) eventually, so effective cycling back via NAMPT is essential. Hence my emphasis on hydrogen sulphide donors (and exercise via AMPK) in addition to your choice of precursor (Nicotinamide, Niacin, NR, NMN, NAD+, etc.)

            The other thing to be concerned about is the consumption of NAD+ by processes other than energy production: PARP enzymes (DNA repair) and CD38 (immune system inflammation), both rise with age. So we need to address these too if we are to stop the disastrously rapid decline in NAD+ that occurs with age.

            ps – yes, I shouldn’t complain at 40, but youth is a very recent memory for me, and I’m loathe to lose it irretrievably.

          • Oh boy – I barely know you and I’m already putting words in your mouth 😉

            Some amounts of NMN being lost in the liver is actually something I read at alivebynature – but I haven’t studied this in detail.

            Per your suggestion I will start taking Niacinamide as well (as Niacin makes me flush).

          • Michael, I advice you against taking niacinamide as an NAD+ precursor. Niacinamide may actually have the opposite effects of NAD+ and reduce Sirt activity. I have seen studies on this (I don’t have the references at hand) and David Sinclair himself has also mentioned this in interviews.

          • Thanks for the pointer, Olafur – much obliged. Now just to be sure, the reduction in sirtuen activity only relates to Niacinamide or Niacin as well? FWIW – I was planning on taking sublingual NAD+ for a month and see how it goes. Niacin would only be an additional compound to (hopefully) complement the effect.Thanks in advance.

          • Regarding Keto Olafur, there is a lot of evidence that it raises NAD+. For example glycolysis in the cytoplasm turns NAD+ to NADH, obviously with low carb consumption this will be reduced so NAD+ in the cytoplasm will be higher. Secondly the way ketones burn in mitochondria is more efficient per molecule of NAD+ (the impact will mainly be in the brain, which uses ketones primarily). Lastly keto leads to improved autophagy and functional mitochondria. Having a healthy flowing electron transport chain is the number one thing you need to keep a high NAD+/NADH ratio; everything else is a proxy for healthy mitochondria IMO.

            Regarding nicotinamide inhibition of SIRTUIN 1 (and hence autophagy), this is a feedback mechanism that only occurs at high concentrations: 5mMole for robust autophagy, 20mMole for inhibited autophagy. I imagine you’d have to eat on the order of 10g + of nicotinamide to cause inhibition. But even if you did so, NAMPT will turn it back into NMN and NAD+, hence why you should also take hydrogen sulphide donors and do exercise to raise this enzyme.

          • Fascinating – thanks for that Mark. Now since I am not a biochemist I dug around and ran into a Japanese paper from 2016:

            https://www.nature.com/articles/npjamd201617

            I realize that three years back in this field is tantamount to the stone ages 😉 but it did a great job of putting some of things discussed here into context. Much of the organic chemistry is way beyond my high school chemistry pay grade, but the explanations plus the graphs are a great intro into the subject matter.

            Now Mark, I do work out religiously and even a week or two off makes me feel like I’ve aged 10 years (I’m 53 years old). I also take cold showers to induce a bit of hormesis and after about two weeks off that I don’t even enjoy warm showers anymore. You mentioned hydrogen sulphide donors in addition to exercise – could you perhaps dumb it down a little for us mortals? What compounds specifically would you recommend?

            FYI – after much deliberation I have ordered some sublingual NAD+ from alivebynature. My wife and I are both going to take them and I will report back.

            Finally, I had ordered some Berberine and started to take it for two days but had to stop today. I went to the gym and suddenly started to feel extremely weak and was worried about passing out. So I may be the exception in that it may affect my insulin levels in a way that is producing a state of hypoglycemia. I also had feeling of breathlessness at the same time which gradually went away once I got home.

            This has never happened before, and the fact that it happened right after I started to take berberine could just be coincidence. Per the process of elimination I’ve ceased taking it for now and will report back.

            My wife seems to be doing very well on it however. She always had a history of high insulin levels and doctors kept being surprised that she wasn’t diabetic for some reason. Wonderful woman but she’s easily stressed and a bit excitable. Now I don’t want to jump to conclusions but we went through a stressful patch over the past few days and she handled it uncharacteristically well. I told her to keep taking it and see how she feels.

          • Mark, yes glycolysis consumes NAD+ and converts it to NADH but so does burning of fat so lowering fat intake should also increase NAD+. Overall it’s the calorie consumption that matters not whether it’s carbs or fat. I don’t think lowering carb intake while increasing fat intake (such as by going on keto) is going to do anything significant to NAD+ levels.

            Regarding your claim that keto increases autophagy, I think the evidence points to the opposite. The main driver of increased autophagy during fasting is the brains need for glucose at all times and the necessity of the body to break down proteins with autophagy to supply that glucose. Since ketones act as an alternate fuel source for the brain, having lots of ketones in your blood actually reduces the brains need for glucose which reduces the pressure to strongly turn on autophagy to break down tissues to supply that glucose when energy intake is low. If two people fast for a full day and one of them is on a ketogenic diet and is already in ketosis at the start of the fast and the other one is on a medium or high carb diet the latter person should logically experience a sharper increase in autophagy several hours into the fast when glucose stores are low and the brain needs glucose. The body of a person that’s already in ketosis won’t be as pressured to activate autophagy during fasting since his brain can use ketones for part of the energy supply and will need less glucose than someone that isn’t in ketosis. I wish I knew of some human studies that test autophagy activation on different diets, but measuring autophagy is not easy unfortunately.

  23. Hi Mark,

    Yes, it surely could be the case that the epi age is only a correlation and not an actual cause of aging but although it can be regarded as a stochastic drift it is particularly compelling to accepting its role as a cause as epi modifications (1) occur at specific locations shared by all tissues simultaneously resembling a deterministic process (2) get erased at reprogramming and (3) are coincident with CpGs showing a daily variation due to circadian rhythms. I am more prone to think the circadian machinery is the one coopted for the aging regulation process at nuclear level and that a cell to cell communication from nearby cells contributes to the tissue clocks coordination + some high level factors involved in the whole body coordination. From an intervention point of view it is probably that a combination of drugs targeting both levels will be required and probably the duration of treatments will be also tissue specific as most of the epi marks get actually modified during cell copy.

    • Lots of methylation and demethylation is occurring, depending on where you look – Horvath has just found sites that correlate well with chronological aging across tissues. I expect the cause is metabolic (mitochondrial) activity. The rate is not the same for all tissues.

      I wouldn’t be surprised to see stem cells remain relatively unchanged due to being metabolically inactive, and that the age related changes in DNAm age may partly reflect loss of stem cells.

    • There is a new paper on researchgate
      “Screening for genes that accelerate the epigenetic ageing clock in humans reveals a role for the H3K36 methyltransferase NSD1”

      Their findin is about a rare disorder called “Sotos” where both epigenetic and biological aging is accelerated. They find that
      1. H3K36me histone methytransferase is loss of function mutated, so these histone marks have something to do with the epigenetic aging machinery
      2. Because of this loss, PRC2 binding sites that become increasingly hypermethylated during aging, in the Sotos syndrome these sites behave as other normal methylated regions, they got stochastically demethylated.

      So it seems like the hypermethylation component of the Horvath clock is not so important, it might just be a leftover from early development, the main driver of ageing is the methylation drift, the destruction of the methylation information on the DNA.

      • >>o it seems like the hypermethylation component of the Horvath clock is not so important, it might just be a leftover from early development, the main driver of ageing is the methylation drift, the destruction of the methylation information on the DNA.<<

        your thoughts or anyone's on addressing this destruction of the methylation information on the DNA.?

        why do I not truat Sinclair? Subjective, illogical, no proof; but he seems to be in it for the $$$. Just me, I do not trust his research. Lot's of ways research may be skewed btw even though the protocol looks just fine

        • In defence of Sinclair, I don’t think he is in this for the money. He just stated this in an interview:
          “Last year I signed an agreement with Harvard which mandated that any and all proceeds from Elysium Health go to directly to my lab to support the salaries of my postdocs and students. I don’t even see those funds. The writer knew that and understood that. But the story suggests that I pocket those proceeds.”
          After watching lectures about him and reading interviews it seems to me he is much more interested in advancing the science of aging than making money.

          • Excellent point!
            So when Sinclair sold resveratrol to GSK in 2008 for waaaaaaaaaaaait for it ……………………………………………………………………… $720 MILLION!!!
            he demonstrated that he is ‘much more interested in advancing the science of aging than making money’
            lololololololololololololololololololololololololol

          • Aslan. I think you are judging too quickly. I know he got a lot of money for it but that is no proof that he is in this for the money. If he was he would just take the money and retire or something, not continue pursuing aging. He claimed in a recent interview (I can’t remember which one but it’s on youtube) that he used most of the profits from the sale to GSK to invest in longevity and fund research on longevity. He claims to be funding lots of scientists out of his own pocket. And he lives quite modestly I have heard.

          • Olafur,
            You may be correct – at this point (at this stage of his life/career) having already hundreds of million$, He might now simply be trying to advance science – who can say at that level of financial riches what happens to a person’s desires & morals. The billionaires where I live seem to want even more $$.

          • Olafur,

            Regarding your comments on keto – I’ll agree evidence either way is lacking at the moment. But anecdotally from my own experience keto puts you in such a catabolic state (far more than either Rapamycin or intermittent fasting, both of which I have extensive experience of), that I’m confident autophagy is markedly upregulated.

            I’d go as far as saying you’re wrong about the number of calories being what matters, I’d say that the burning of fat is the important part. And that is common to keto and CR. But we’ll see what the science says over the next few years.

            In the meantime, this is quite interesting:

            https://www.physiology.org/doi/full/10.1152/ajpendo.00717.2006

          • Mark, yes evidence is certainly lacking on how strongly autophagy is activated on different dietary conditions. It could even be the case that basal autophagy is a bit higher while in ketosis but fasting-induced autophagy stimulation is lower, it’s hard to say. In any case whether the overall effect of keto on autophagy or NAD+ levels is positive or negative will be somewhat individual. I agree that certainly burning of fat is important (if you’re talking about the fat on your body) to reach and maintain a lower body fat percentage but keto is not necessarily better for this. It will depend on the individual. For you, yes perhaps keto works very well for you to lose fat, I don’t doubt that if you say so. For other people it’s not so effective. Take me f.ex. I tend to do great on high carb diets and I can more easily lose weight lowering my fat intake than my carb intake. That said I am fully aware of the fact that I tolerate carbs very well compared to most people and easily maintain a very low body fat (visible sixpack) on a high carb diet, while many others do much better on lower carb intake. So again it’s very individual. Losing weight and having a low body fat percentage should help activate autophagy and fortunately people can try different diets to see what works best for them.

        • my take is that the “proper” methylation state is estabilished during embryogenesis by an early development progman and after this development program run its course there is nothing that could reset the methylation status. probably there are lots of automatic feedback processes that keep the methylation state largely in shape, but there is no template. if a protein degrades there is always a template for a new protein in the DNA. but no such template for the chromatin state.

      • Actually what I’d like to see is an “adult” aging clock from ages 20-80. So the impact of development processes could be filtered out.

      • I’m sure I read a paper once showing human DNA in a mouse cell epigenetically aged at a mouse rate (much faster than normally). Assuming I didn’t dream it (entirely possible!) then it would support a ROS source for loss of methylation.

      • Seems like I misunderstood the paper at the first read. Sotos syndrome epigenetic ageing is similar to control there is both hypo and hypermethylation involved in control and Sotos.
        What confused me is that they compared control vs Sotos and control vs aged differentially methylated positions. Sotos syndrome vs control is mostly hypomethylated, but during ageing Sotos syndrome clock sites get either hypo or hypermethylated just like controls.

  24. Primary doc prescribed it. Told her about a distant relative that had diabetes.

    I will certainly investigate Josh’s links as a possible substitute. I was originally motivated by the TAME, anti-aging study that had non-diabetics as part of the cohort.

  25. Not all successes in a rat laboratory model may translate to humans. Harold and I have had two trials with different strategies both showing key bio markers of aging reversed in old rats. On the first one a natural extracts protocol we are hoping to go into human trials soon. 2nd with plasma fraction as shared in this post will eventually be tested in humans. So it is quite encouraging to find another anti aging therapy senolytics translate to humans from mice models. I don’t know if this has been shared here:
    http://dx.doi.org/10.1016/j.ebiom.2018.12.052
    Human trial success is exhilarating 😊

  26. So like many following this thread I am not a biochemist by trade. I personally happen to be an engineer so I don’t shy away from reading scientific papers here and there. But clearly much of what’s being discussed here is way over my head, despite the fact that I have been following gerontology research (as a layman) for over 20 years.

    Until Harold and Akshay are able to launch human trials we are all relegated to maintaining our respective health/youth by resorting to promising and relatively easily available senolytics. For example I have been taking a large dose of quercetin once per month but I’m unsure if it has been doing much for me as I’m ‘merely’ 53 years old (cough cough). Incidentally I just ordered berberine HCL which was mentioned in this thread as well.

    IMO it would make sense to produce a list of top 3 easily available compounds for ‘the rest of us’, allowing us to bridge the gap until (hopefully) Akshay and Harold are ready to launch human trails. The list should also include a respective regime as it appears that e.g. rapamycin should not be taken on a constant basis.

    Many thanks for any pointers/insights in advance.

    • Have you read Dr. Sandra Kaufmann’s book, “The Kaufmann Protocol?” She started out as a pediatric anesthesiologist, but got interested in aging. She read a large number of papers for her own benefit but subsequently decided to write a book about what she learned. She recommends taking supplements to address each of several areas: life span regulators (sirtuins and others), mediator genes, effectors (DNA repair proteins and things that cause production of endogenous antioxidants like SOD and catalase), housekeeping genes (“garbage disposal”), mitochondrial function genes, and cellular senescence genes (apoptosis, etc.). She has a list of about 20 supplements total, but you can select a subset so that all categories are addressed (if you are so inclined).

      • Some suggestions seem counter to others? for example anti-oxidents will hinder autophagy. Everything we take I think has unintended consequences and sometimes couter each other. LEF is a prime example with their popular lef mix. Also supplement research is so often skewed, again LEF a prime example I think “cherry pick” research to sell supplements, and one would end up with “unintended consequences” I think. I suggest to friends that supplement co.’s are certainly not as bad as pharm’s, but they are approaching and one needs to be cautious.

        • Yes. I don’t know enough to know whether Dr. Kaufmann’s suggestions are all good or all compatible. Akshay’s comment indicate that what is best is (1) homeostasis and that (2) certain processes be alternated.

  27. New original researh on in vivo OSKM reprogramming.
    https://reader.elsevier.com/reader/sd/pii/S1525001618305033?token=D598DFFDF63912CBF8A30325F0A2F1CCA6358163DD8995833908D5B53E5F7C8E56DB739D8251DCCD30505616855615E9

    Sounds really elegant and simple, just one injection of plasid OSKM into muscle helps regeneration of injury. Activity of transfected genes dereases rapidly after day 2

    This is third paper about OSKM induced in vivo regeneration since the first Ocampo experiment.
    Why aren’t more research teas picking up this topic I dont understand

    • Perhaps they are, but they are all keeping quiet for now – I believe Sinclair said in his recent Joe Rogan interview that his Harvard lab was starting a human trial using OSKM for macular degeneration (in 2020?)

      It seems the key to triggering OSKM is old tissue without oncogenesis is intermittent treatment. What we really need is a body wide distribution system but why oh why is gene therapy still SO expensive.

  28. After watching David Sinclair’s recent interview I am eager to give either NMN or NAD+ a shot for a month or two, just to see what happens. In terms of source I settled on alivebynature – has anyone used their products and would you recommend sublingual NMN or NAD+? The stuff ain’t cheap so any pointers would be appreciated. Thanks in advance!

    • A friend of mine thinks highly of alivebynature.com and says that the sublingual NAD+ gives him great temporary results. He uses it four or five times a day. They were out of NMN for a while, and he will try that next in addition. NMN would have a longer-term effect, although the research that Akshay has cited suggests that there may be feedback mechanisms that would reduce its effect over time over time also.

        • You’re welcome. I recommend you read the entire article at https://alivebynature.com/nad-for-the-brain-nmn-for-the-body-3/ to get a feel for the differences in the effects of NAD+, NR, and NMN. Then I suggest that you read a couple dozen (or more) reviews of Niagen (a leading NR product) and maybe an NMN product at amazon.com. There are many highly positive, some negative, and some “no effect” reviews of Niagen there. I think it illustrates that there is a lot of individual variation in whether and how much of a substance is good for each person. I wonder if some of the negative effects would have been positive if a smaller dose had been consumed or if NMN had been used instead of NR.

          • Ha – I wish I had time to read all those papers as I’m already working 16 hour days. Was hoping I cut take a shortcut by asking here but I guess it really depends on the individual. That said, not being a biochemist and all, I would assume that small doses of NMN spread throughout the day would most likely be the better approach. Well, I’ll try that and report back.

  29. Crowdfunding might not work if you can’t show absolute proof that the treatment actually does have all the effects you claim. One way of getting recognition and attention would be self-experimenting. I’m sure if you could demonstrate these amazing rejuvenating effects on yourself, you wouldn’t have a problem getting all the funding you need.

  30. The authors Kathyln Gan and Thomas Sudhof write: ‘We asked whether young blood is enriched in factors that act directly on neurons to promote synapse formation.

    ‘We show that serum from young but not old mice indeed directly boosts synapse formation in cultured neurons, and identify two factors, thrombospondin-4 and SPARCL1, that are enriched in young blood and mediate these effects.

    ‘Thus, our experiments show that young blood is enriched in multiple factors that directly promote synaptic connectivity between neurons.’
    https://www.pnas.org/content/early/2019/05/29/1902672116

  31. Anything new about this experiment? Did you manage to get the founds to move forward?
    I’m looking forward to earing some news about it.

    • Yea we did get funds to complete our next trial on 96 rats to replicate results and to determine optimum dose and frequency. The trial is under way. After this we are planning for old dog trials in USA with a highly reputed scientist and simultaneously begin process to raise a larger round of funding to continue progress towards regulatory approval, human trials and hopefully making elixir commercially available. In meantime we are in process to launch a transdermal patch of one of the most powerful anti aging molecules which goes down with age. Human trial is expected to start this month including our co-founder Harold. Josh will be the first to get a box to try and share his evaluation with his blog readers. We are trying our best to make it reasonably priced. But it should make a significant uptick in quality of life of aging.

      • I’m officially volunteering for the trial – free or pay2play – please send me an email once you’re looking for new test subjects.

        • Patricio Yes we did get funds to complete our next trial on 96 rats to replicate results and to determine optimum dose and frequency. The trial is under way. After this we are planning for old dog trials in USA with a highly reputed scientist and simultaneously begin process to raise a larger round of funding to continue progress towards regulatory approval, human trials and hopefully making elixir commercially available. In meantime we are in process to launch a transdermal patch of one of the most powerful anti aging molecules which goes down with age. Human trial is expected to start this month including our co-founder Harold. Josh will be the first to get a box to try and share his evaluation with his blog readers. We are trying our best to make it reasonably priced. But it should make a significant uptick in quality of life of aging.

          • Thanks for the update. It sounds very promising!

            Like Stephan, I would like to know what are the requierements to get a box.

          • How quickly to you think that you can get this to market and when will you be able to discuss exactly what is in the product?

          • After our human trials confirm dermal permeation and rise to youthful levels through our patch. When Harold applied the goop in our lab on his skin his liver spots went away and he was carrying loads and jumping about like a young man his gait and walk improved so he is sooo excited right now he is pushing us to move faster 🙂 probably too hard. We have already filed for PCT patent which covers 152 countries but would like Josh to reveal it here on his blog when first lot for soft launch is ready.

          • Forgive me if this has already been discussed, but I take it whatever is in this transdermal patch can be classified as a supplement does not require an arduous FDA review and approval (fingers crossed)?

          • Excellent. If you need additional test subjects I’d be interested and more than happy to pay for product.

            I look forward to when you have all your IP protected and you can talk about the contents and MOA in some detail.

          • Hi:

            I am volunteering as well. If you want to determine the effect on a fairly healthy 74 year old. The projected cost sounds very reasonable.

            Ed Quinn

          • Akshay – regarding the PCT: It’s not really a patent – it’s a patent cooperation treaty. I’m glad you filed for it, but once it’s approved you will still have to file the actual patents in the respective countries in which you plan to seek protection. Which is expensive as hell but the PCT buys you a few years worth during which you can do it. The bottom line is that you will have to generate income in the interim so that you can afford to do filings in the countries you consider worthwhile.

          • Thanks Akshay, that sounds very reasonable, count on me to be an early self experimenter.

          • Hi Ashkay and Harold,
            If you are looking for volunteers, I am a former solo OBGYN who killed my brain with lack of sleep. I developed an REM sleep disorder and aged quickly. I now practice anti-aging medicine. I recently tested my Teloyears at 57 and it said I was 64 or older. I volunteer to be a participant.

    • Hm. My comment was intended as reply to Christopher Riegel’s comment, however apparently it ended up as standalone comment. I apologise, however don’t see how that can be undone

    • Truly respect Vince and James. I love their meticulous detective work at the molecular level with regards to aging. A big fan. There are many similarities with our first natural extract trial. We both have taken steps to improve bioavailability the major stumbling block that dilutes almost all benefits of herbal and natural extracts. What I also liked to see is that the herbs used are Ayurvedic from India 🙂
      They have focused on the one common thread that binds almost all the age related pathologies: chronic inflammation. Thereby transmitting benefits for aging itself. Our first trial focused on activating our repair pathways and old treated rat’s age related markers including Il-6 and Nfkb reversed back to levels of young control. So the liposomal 4 herbs sold by Vince should be purchased by all as it will help slow down aging pathologies but if our second trial of elixir translates to humans it should make Vince a teenager again biologically.

  32. I assume ” his liver spots went away ” implies his proteasome system was stimulated to disposed of the lipofuscin that causes “liver spots” and probably disposed of lots of other accumulated protein junk.

  33. Not to rain on the parade, but once you solve the problem of aging, you need to then figure out how to regenerate all of the neuronal losses that accumulate in the human brain, starting at age two and moving progressively until old age. One source I read suggests we lose about 1/3rd or our brain mass by the time we are 80, and those are neurons in places that cannot be regenerated. So we risk creating a zombie army of 110 year old people with the brains of morons because we never brought back their lost neurons nor did we stop the ongoing losses after they became “young” again.

    From this source:
    http://chronopause.com/chronopause.com/index.php/2011/05/30/going-going-gone/index.html

    “Cerebral atrophy is a big problem in aging, and it turns out the process begins not in middle age, but at approximately 2 years of age – at least for the neurons that comprise the gray matter of the cerebral cortex.23 Brain cell loss and degeneration become morphologically apparent in the brain’s white matter by the time we are in our early 20’s, although there is evidence that more subtle changes have been afoot for much longer.24 Losses in gray matter volume proceed approximately linearly with age in normal aging, and the average gray matter volume decreases from ~390 mL at age 22, to ~300 ml at age 82.25 Total loss in brain mass between age 20 and age 80 is, on average, ~450 g, or roughly 1/3rd of our youthful brain volume. If you are not on the metric system, all you need to know is that an average human brain weighs ~3 pounds when you are age 20, and by the time you are 80, your brain will weigh a pound less. And that is absent disease – if you have Alzheimer’s, hypertension, or atherosclerosis (cardiovascular disease) your losses will be greater – a lot greater.26”

      • Akshay, that would be most likely regeneration in the hippocampus, which is one of the few areas of animal brains that can regenerate on its own anyway. It is important to record that, but I do not think that is really an answer to my point.

        What I am trying to call out is the atrophy of many areas of the cerebral cortex – where our most critical thinking functions reside – and these are neurons that probably require some kind of stem cell strategy to regenerate.

        P.S. Is there a website for your project? What is the best way to reach you?

        • There is actually some regeneration of brain cells, very limited although. The fact is that we still don’t know which would be the effect on it of a rejuvenation treatment, if we find one.
          However, intellectual capacity is not just a matter of number of neurons, but of connections. The best example are the babies: they lose a significant number of neurons during the first years and yet develop their intelligence as ever.

        • I would expect our technology to holistically make the brain young again. But we will have to find out in our future trials. There is link to the results of our previous trial on this post. You can reach me by email atomicblissventures at gmail dot com

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