Follow-up on Telomeres: Genetic Studies vs Straight Epidemiology

My August post on this subject stretched my readers’ patience with technical detail. On the other hand, that column has generated a larger volume of discussion than any other in the history of this blog. For readers who are put off by numbers, I promise to get back to a juicier topic next week. But today, here’s another one for the geeks…

While I was at the National Biological Institute in Beijing this past July, I taught a seminar to biology grad students which I called “Intuitive Statistics”. I asked them to put aside the powerful software that would calculate all manner of statistical indicators automatically, and instead to play with numbers in Excel, where they could see what they were doing, monitor each step, and think about why the results came out the way they did.

Already in 1954, Darrell Huff titled his all-time best-selling text, How to Lie with Statistics. Today’s menu-driven statistical software tempts the professional statistician to deceive himself first, others incidentally. The guts of the calculation are performed automatically. It’s so easy to obtain right answers to wrong questions. The professional division of labor between biologists and their statistical consultants adds abundant opportunity for miscommunication, and the spreading of responsibility among a large team of authors leads to the unintended consequence that no one feels the burden of personal responsibility that the reported results make sense.

The first principle is that you must not fool yourself — and you are the easiest person to fool.
— Richard Feynman

I wanted the students to begin to develop a feel for numbers that would inoculate them against the embarrassment of deep forays into their lab data that were fundamentally misguided. I knew that they would be working with professional statisticians, and I wanted them to be able to do back-of-the-envelope calculations that would tell them when the advice they were getting was outside the range of the plausible. Where the detailed answer differs from the back-of-the-envelope calculation, it’s important to understand the difference before assuming that the more sophisticated calculation is correct.

Here’s one of the exercises we did:

A is positively correlated with B. B is positively correlated with C. What do you expect about the relationship between A and C?

Of course, our first expectation is that A is likely to be positively correlated with C. Can you prove this? Can you think of a counter-example that disproves it? The answer, as it turns out, is that our expectation is only valid if the relationships (A,B) and (B,C) are quite strong. In that case, we are justified in assuming that (A,C) are likely to be a positive correlation. But it is not hard to come up with examples where the opposite is true. The correlations (A,B) and (B,C) can be highly significant, though less than 0.5, and (A,C) can be negatively correlated.

I asked the students to construct an example with made-up data. There are also plenty of real life examples. My favorite has been salt: Salt consumption is positively correlated with high blood pressure. High blood pressure is positively correlated with cardiovascular risk. But salt consumption is negatively correlated with CV risk.  Yes, eating more salt may raise your blood pressure and also decrease your chance of having a heart attack. [Link to the course web page]

What this has to do with telomeres

Longer telomeres are positively correlated with certain genetic variants (SNPs). The SNPs are positively correlated with higher risk of cancer. A series of genetic studies [refrefref] claims, on this basis, that long telomeres pose a risk of cancer.

Advocates of this kind of study (called GWAS), say that it avoids mixup between cause and effect, because your genome is always a cause, never an effect. But the hitch in this reasoning is that we have to accept an extra level of indirection, so we’re really back where we started. What I mean is this: The authors are trying to establish that long telomeres can cause cancer. Their data shows that certain SNPs (genes) are correlated with long telomeres, and the same SNPs are correlated with cancer. So they conclude that

SNP long telomeres cancer

But they cannot exclude the possibility that

SNP long telomeres AND

SNP cancer (directly, bypassing the telomere)

This is especially problematic because the correlations are quite low – under 10% for each of the SNPs separately. The SNPs cause very small differences in telomere length, and the statisticians find very small differences in cancer risk. Then the software works automatically to “standardize” the result, and report what the cancer risk would have been if there had been a large difference in telomere length. For esoteric reasons of mathematics, the risk estimate is extrapolated exponentially. The result ends up looking quite scary. 5 times the risk of brain cancer and 3 times the risk of lung cancer for people whose telomere length is in the top 16 (1 sigma)%. The 2% with the longest telomeres (2 sigma) would be projected to have 10 times elevated rates of lung cancer and 28 times elevated risk of brain cancer.

Such high levels of risk for long telomeres have not been observed in previous studies that look directly (not through genetic intermediates) for correlations between disease and telomere length. What these studies have tended to show is small increases in some cancers, decreases in others connected to telomere length. If people in the top 2% of telomere length really had 28 times the risk of getting brain cancer, then more than half the people with brain cancer would have extra-long telomeres and everyone with brain cancer would have longer-than-average telomeres. It is difficult to imagine that such a huge effect could have been missed.

Phillip Haycock, first author of the large GWAS study I described last month, has been gracious enough to write to me generously and to comment directly on this blog page. Below, I respond to some of his comments (his comments in purple).

In observational studies almost everything is correlated with everything, making judgements about causality basically impossible. For example, observational studies tend to find that telomere length is associated with everything-under-the-sun (from meditation to stroke).

The way I think of it, the correlation motivates us to look for a plausible causal mechanism, and some are much easier to imagine than others. I don’t think anyone has proposed a theory that telomerase makes people more likely to take up a mediation practice. Common sense tells us the causal order is that meditation promotes release of telomerase, not vice versa. In the other direction, when we find that short telomeres now are predictive of disease several years down the road, we don’t argue that the future disease has reached back in time to cause telomere shortening.

So there are two possibilities: A) Short average telomere length usually means a high number of cells with critically short telomeres. These cells become senescent, and spew out inflammatory cytokines. The resultant inflammation is already known to be a cause of cancer, AD, and cardiovascular disease. B) The body has suffered infections and toxins in the past that have prompted extra cell divisions, shortening telomeres. The same infections and toxins have raised the risk of cancer, AD and CV disease by a mechanism that has nothing to do with telomeres.

Clearly, the presumption is in favor of (A), that short telomeres contribute to the diseases of old age. All the steps are filled in and previously established. This doesn’t disprove (B), but it establishes the burden of proof. For those who want to argue in favor of (B), the next logical step is to do a prospective study including as independent variables both telomere length and the infections, toxins, pollution, smoking, etc that could cause both telomere shortening and disease risk. This is exactly what was done in the Rode study two years ago, and they found that short telomeres were still correlated with cancer and (especially) CV disease even when correcting for history of infections and smoking. In fact, the correlations with infections and smoking were far weaker than the correlations with telomere length. At this point, (A) looks very strong.

In contrast, genetic variants do not generally correlate with classic environmental and lifestyle factors (predicted in theory by Mendel’s laws and observed in practice).

Let’s be specific here. The primary finding of GWAS studies like Haycock’s is that certain genetic variants (SNPs) are associated with slightly higher risk of cancer. The interpretation which Haycock and other authors offer is that the effect is indirect, mediated entirely by the effect of the SNP on telomere length

SNP long telomeres  cancer

I note that

1) In contrast to (A) above, there is no plausible mechanism offered. The mechanism is never spelled out, but here is what I think is the implicit hypothesis: A pre-cancer cell is replicating and mutating. Because its telomeres are slightly longer than others, it has more time to mutate before it runs out of telomere and dies of cell senescence. Therefore the pre-cancer with long telomeres has a higher probability of neoplastic conversion than a cell line with shorter telomeres.

I think the reason that this hypothesis remains implicit and is not spelled out (let alone tested with computational models) is that it doesn’t make sense quantitatively. The difference in telomere length from the most powerful of these SNPs is a fraction of 1%. This corresponds on average to much less than one cell division. It’s hard to imagine this having a detectable effect on cancer risk.

2) The correlation between each of these SNPs and telomere length is very low, accounting typically for less than ½% of the variance in telomere length. SNPs generally have more than one effect. So it is easy to imagine that some of the SNPs have a direct effect on cancer risk.

3) The direct effect doesn’t have to be very large. All of the observed increases in cancer risk associated with the SNPs are under 25%. Odds ratios less than 1.25 are generally discounted in epidemiology, and for good reason.

4) Another plausible explanation for the observed correlation is that SNPs are not randomly distributed through the population, but are significantly correlated with many other genetic, geographic and cultural variants. Let’s spell out the premise of “Mendelian randomization”: Literally, it relies on the assumption that nothing that could be associated with cancer risk is at all correlated with the “telomere SNP.” Of course, this is very far from being true. As Haycock says – everything is correlated.

This kind of thing is a hazard in all forms of epidemiology; but what makes it more treacherous in this case is that the effect you’re looking at is so small. OR<1.25. This can be caused by literally thousands of different associations unrelated to telomeres. For example, these SNPs may be associated with more people from cultures that have higher rates of smoking; more people of African descent; more people who come from Northern climates… Haycock doesn’t control for any of these possibilities, and, of course, neither do any of the other authors of GWAS studies. Controlling for other variables is supposed to be unnecessary because of “Mendelian randomization”. But in reality, Mendelian randomization is far from complete.

Observational studies of directly measured telomere length provide opposite conclusion.

Our findings are generally in strong agreement with prospectively designed observational studies (where telomere length is measured before cancer diagnosis). The apparent conflict you cite is almost entirely due to the retrospective studies, where telomere length is measured after cancer diagnosis, and which generally do find that shorter telomeres increase cancer risk. In my opinion this is due to reverse causation bias…

The only observational study that I referenced was Rode, because it’s the only one I have read carefully, and because it is the largest (65,000 people), it uses a homogeneous population, and (crucially) telomere length is measured before onset of disease.

Contrary to your claim, our findings are in strong agreement with the findings from these studies. The studies are large with samples sizes ranging from 47,000 to 96,000. The main studies are:
“…Short telomere length is…not [associated] with cancer risk”

Short telomeres are associated with older ages. In any study that includes a range of ages, there is a choice of ways to tease apart the effect of age. Age always wins, but some statistical methods will make it look like age is the whole story, while others will say that short telomeres are a risk independent of age.

This study found a strong correlation between short telomeres and incidence of cancer, also of short telomeres and risk of death from cancer. After correcting for age, the association with cancer incidence disappeared, but the association with death from cancer remained strong. I can’t see how this is “in strong agreement” with your claim that short telomeres protect against both cancer incidence and mortality.
“…genetically determined short telomeres were associated with low cancer mortality…”

This is the Rode study, about which I have written extensively. A small part of the Rode study used GWAS methodology, and its conclusions were, unsurprisingly, more similar to other GWAS studies than to conclusions in the main section of the same paper.

Results are due to direct effect of SNPs on cancer

This possibility would be a violation of assumption 3 above – that the SNPs affect cancer exclusively via their effect on telomere length. Horizontal pleiotropy is a well known genetic phenomenon that could induce such direct associations between SNPs and cancer that bypass telomere length. This is the most important potential limitation of Mendelian randomization studies. We observed some evidence for this in our results and we admit in the discussion that we cannot entirely exclude this possibility.

Remember that all it takes is a very small direct effect to mimic the a very large indirect effect.

“The new studies require very large implicit extrapolation that is not necessary in the old studies. The 50 to 1 extrapolation is very speculative, and it magnifies the noise along with the signal.”  We standardise the results to reflect a 1-SD (standard deviation) change in telomere length and therefore you are correct that we are extrapolating beyond the observed effect sizes of the SNPs. However, the extrapolation you describe is more like a 7 to 1 than 50 to 1 extrapolation because the average effect size of the SNPs is 0.13 SD units per copy of the telomere length raising allele.

Thanks for this information! I didn’t have the number 0.13 when I was writing the column last month, and in fact I assumed 0.05. Working backwards from reported odds ratio of 5.27 for brain cancer, I said they must have started with 1.08; working backwards from reported odds ratio of 3.19 for lung cancer, I said they must have started with 1.06. These numbers should be corrected to 1.24 and 1.16, respectively.

These numbers are still very low. Epidemiology is well-known to be full of uncertainties, and an odds ratio of 1.24 is just near the lower edge of what might be considered actionable. For the genetic telomere studies, however, it is the highest risk ratio they observed (reported as 5.27 times extra risk for brain cancer).

Question for Dr Haycock: Is 0.13 sigma the average increase (or decrease) in telomere length for subjects in your study? How was the 0.13 computed? Is it consistent with Table 1 in your paper, in which the highest percent of variance in telomere length explained by any one SNP was less than 0.5% ?

You write about GWAS and Mendelian randomization as if they are the same techniques. They are actually quite distinct methodologies and analytical approaches. In GWAS we measure the association between genetic variants and human traits across 100s of thousands to millions of loci across the genome (focus is gene-trait association). Mendelian randomization is the use of genetic variants as instrumental variables to appraise causality in hypothesized exposure-disease associations (i.e. the focus is the exposure-disease association).

Thank you for the correction. I gather that, though GWAS studies rely upon Mendelian randomization, the term “Mendelian Randomization Study” is reserved for a different animal.

“Another possibility is that one or more of the SNPs happen to be more common in a segment of the population that is prone to cancer, for whatever reason.” The problem you are referring to is known as confounding by population stratification – the tendency of cases and controls to have slightly different genetic ancestries and which can introduce confounding into genetic association studies. This issue is taken very seriously by genome-wide association studies. We did our best to take this into account. For example, our analyses were either adjusted for principal component scores of genome-wide genetic variation or we found little evidence for population stratification in diagnostic plots (these are standard techniques in the field). However, I agree and acknowledge in the paper that we can’t entirely rule out this possibility. More details in the discussion section of the paper.


[Concerning tradeoff between benefit for heart disease and liability for cancer]: We don’t know what the net benefits are at the population level and can’t infer that from our study. This requires detailed statistical modelling of absolute as well as relative risks.

This is a computation that I did myself, very approximately, combining risk ratios from the Haycock study with data on death rates from each of the cancers, and from heart disease. The answer that I got was that in the Haycock study, the two effects approximately cancel each other out, but in the epidemiological studies there is a large net benefit from longer telomeres. I didn’t think it worthwhile to do the computation more precisely because the data it relied on was highly uncertain.

Evolutionary tradeoff
There’s an interesting literature about potential evolutionary tradeoffs in cancer and vascular disease risk and the impact of body size and telomere length. Cancer incidence doesn’t seem to increase with increasing mammal body size (about same rates in mice and humans, known as Peto’s paradox). See this interesting review on “Telomere Length and the Cancer–Atherosclerosis Trade-Off”:

This study, published just this last summer, claims that, in humans, telomerase levels have evolved to be low and telomeres short, creating an optimal compromise between deaths from cancer and deaths from CV disease.

As you have guessed, I’m skeptical. I have staked my career on the thesis that the evolutionary theory of aging on which this paper is based is wrong. However, the paper cites several references on telomere length and cancer which I will read with an open mind.

[Savage, 2013; Anic, 2013; Nan, 2011; Machiela, 2014; Seow, 2014; Sanchez-Esperidion, 2014; Pellatt, 2013; Qu, 2013; Lynch, 2013; Julin, 2015]

How I see it: Aging is an evolved adaptation. Telomeres are short on purpose, as a clock that regulates lifespan.

258 thoughts on “Follow-up on Telomeres: Genetic Studies vs Straight Epidemiology

  1. Thank you for this follow up Josh. As you will have seen from the comments following your last post, this study has given many of us headaches!

    I am convinced now that the SNPs that give rise to slightly longer telomeres, also make it easier for cancer cells to activate telomerase when they reach the crisis stage of very short telomeres. Not all cancers do this the same way, so if we can show one of more of these SNPs is near a HTERT promoter region used by brain cancer to activate telomerase for example, then we can also explain why brain cancer is more likely (If only by a small amount) with these SNPs. The long telomeres are a red herring.

    Thanks again for a very interesting series of posts.

    • Incidentally Josh, do you have the information from Philip Haycock on the location of the relevant SNPs reviewed in his paper? The paper is firewalled unfortunately.

        • Josh
          I think you may find this clinical observation interesting. I talk to several hundred patients a week and often get on the topic of anti-aging. It may surprise you to know that the vast majority of people have reached an acceptance of both aging and death as ” natural” and have no interest in anti-aging interventions. In fact , it seems to present a type of cognitive dissonance to them and they are very uncomfortable with it even to the point of rebelling against such a notion.
          Recent polling data also supports this as the vast majority of people do not want to live past 80, even in good health. It seems to be a type of brain -programmed acceptance of our mortality as good and natural, and anti-aging is weird and even in a sense wrong.
          Those of us on this site yearning for immortality, or some semblance of such are outliers it would seem. Was wondering if you have any thoughts on that?

          • I find the same thing to be true among my friends. I remember, as a small kid in grade school, learning about Ponce de León’s search for the Fountain of Youth, and thinking “How foolish”. Can’t shake that ingrained feeling, and perhaps most other people cannot as well. Therefore, I have chosen to avoid discussion about the subject with my friends, particularly my peers, to avoid coming across as foolish to them. This is also the reason why I am posting here with only my first name, though I don’t mind if any of you guys figure out who I am.

          • Those people havent though it over. Most people live in the state of subjective immortality meaning they are not consciously aware of their own death. So what they say is what they expect of others of what they think others expect from them.
            Also most people think life extension means adding very bad quality years.
            What I really dont understand why really rich and clever people, like Bill Gates, Elon Musj, Warren Buffet and the likes dont invest more money into life extension or rejuvenation.

          • Agreed. But what I’m really wondering is whether this acceptance of aging and death is an evolutionary adaptive mechanism so that we won’t try too hard to defeat them, thus ensuring the greater survival of the species . In other words we are programmed to accept Josh’s program!

          • This has always been a source of distress to me. Why does almost everyone I know think so differently to me on aging? I think it is awful, they are fine with it – although they are generally not old enough for it to have really started to bite them yet.

            I believe you are wrong however Paul thinking people would not welcome some additional life they knew it was in good health. With modest increases in lifespan I think it is just a framing problem. However the idea that some people may become youthful again whilst others die strikes most as completely unfair, as it is. We are in fact approaching the most unfair time in the entire history of human existence: eternal life vs eternal death. Faced with this many would prefer us all to die of horrible age related diseases.

  2. > because your genome is always a cause, never an effect.

    Which is ALSO wrong. Genome EXPRESSION is always a cause and, as we are well aware around here, this can be fed back through myriad (epi)mechanisms.

    > But they cannot exclude the possibility that

    For instance, that people are IMMUNE to cancer… as long as they’re DEAD. ; -) Longer telomeres lend you longer life and I bet it’s not hard even to maintain the exponential increased correlation, after say, 123 years old? hahaha!

    My conclusion is that humans cannot resist the conflict of interest between their self image and everything they attach it to: political party, religion, soccer team, statistical model AND/OR are dumm. And, therefore, deserve to be.. spared of cancer.. A S A P.

  3. Hi Josh,
    The key issue here is your particular view of evolution. The conventional view is purpose of evolution is to increase frequency of particular genes by promoting survival and life. Sometimes there is what the Intelligence community calls “blow back” or unintended negative consequences.
    In evolution, traits that promote aging are viewed as example of pleiotropy, in which trait meant to promote development and good health in young animal has unintended consequence that it promotes aging in old animals.
    Your major view is evolution wants to kill you. That evolution intentionally evolves traits that will make sure you die.
    Since you seem to be worried that without evolving these traits animals might live forever, here is another theory which as a trained physicist you can understand very well. the Law of Entropy. The general law that things go from order to disorder.
    The universal law of entropy insures death. Predators and external factors insure death. That animals might live too long was never a problem evolution worried about.
    The reason evolution gave humans short telemeres, might be unclear; but the reason was not to make sure we all die.

      • Hi Josh,
        Thanks for your explanation.
        My point was that one’s conception of how evolution works is very closely intertwined with one’s conception of how aging works. Therefore, if somebody has a fundamentally different core view of how evolution works; they will also have a fundamentally different core view of how aging works. You can look at the same numbers; but they will not add up to the same answer.

      • Hi Josh,
        I took second look at your theory and think it was very good theory prior to 2006. At that time the accumulation of cellular damage and ROS were dominant theories and both were extremely inadequate. You correctly point out a need for aging so a theory of programmed aging made sense. Although most animals in the wild might died early, without aging, a very good animal had the theoretical potential to maintain control indefinitely. So we both agree, aging was essential for life to progress.
        The discovery of TOR and the Blagosklonny theory of aging published in 2006 changed everything. Suddenly there was a theory that explained aging and fit with accepted theories of evolution. TOR was the program which drove growth and development in all living things and when growth and development stopped, hyperactive TOR drove aging.It was a quasi-program, just one step away from programmed aging.
        Furthermore, it could be demonstrated that aging in every animal could be slowed by lowering TOR.
        TOR did not need to kill, but the adverse changes due to TOR including the accumulation of senescent cells would make the animal slower and weaker and no longer fit to survive among younger stronger animals.

        So I think we can both agree about one thing, the Josh Mitteldorf theory and the Blagosklonny theory of aging, one aging being programmed, the other not programmed are mutually incompatible.

    • Hi Alan,

      You make good points but technically, it is only when a system is CLOSED (do not receive energy from outside) that its entropy must increase with time (order to disorder). However, since living creatures do receive energy from outside (through eating), they could be, in theory, capable to control their entropy using the energy they receive.

      However, because we are far of being perfect machines, we do not control well our entropy with time and we can certainly see that through multiple effects of aging. However, this is not strictly a law of physics that we must age.

      • Hi Aldebaran,
        I was not using Law of Entrophy as how would be used by engineer talking about thermodynamics. I was using term as used in Theoretical Physics. In Theoretical Physics it is general concept that things go from order to disorder. As this applies to living things, we all have very complex systems that must be maintained in perfect condition, everything must function perfectly. As the programs become old, things change, things start to go wrong. Just like strong tendency for things to break in car, tendency for things to go wrong with living things. As things go wrong on molecular level, the system tends to break down. This break down in control and order then becomes disease and downward spiral. That is what I meant by general law of entrophy, order to disorder, favors death. Natural for us to break down and unnatural to continue in perfect order needed for life. We do not need an elaborate program to kill us, the Law of Entropy will do it just fine.

        • Hi Alan,

          I think I understand your point and I agree. The entropy naturally increases in every systems (order->disorder) so it is certainly difficult to control it, particularly in complicated systems such as living organism.

          Thus it seems to me that it would have been very complicated for evolution to come up with non-aging living systems (at least for higher organisms such as mammals) and there was probably little evolutionary pressure to do that anyway.

          However, as far as I know, there exist simpler organisms (hydra) that might not age. It is not straightforward to me why evolution have created them in this way. Would hydra be extinct if they were aging?

          • It is worth examining the evolutionary pressures on telomeres in more detail to understand why we’ve ended up with relatively short telomeres.

            Given that long telomeres are protective against a range of diseases including CVD and cancer, why would evolution not just give us all long telomeres? I think the simple answer is that the only way it could is by mutations that made it easier for cells to activate telomerase (for this is the critical step in the process of extending telomeres). And unfortunately a genetic change here also makes it easier for cancerous cells to activate telomerase too.

            There is evidence for this argument in the fact that larger mammals with more cells have more controls on the expression of telomerase.

            I think the above explanation precludes using the evolution of short telomeres as an argument for programmed aging (not commenting on whether aging is programmed or not)

          • Hi Aldebaran,
            Your question about Hydra is very good question. Blagosklonny theory of aging first presented 2006 is that aging starts when growth stops. Hydra never stop growing and hydra never start aging. Lobsters also never stop growing and never start aging. The problem for lobster is the bigger they get, the harder to change their shell. My idea of Entropy is that living things needs to work very hard to stay alive and to stay healthy.The idea is if things go a little wrong, the law of entropy will finish you off. Blagosklonny theory is TOR is driving growth and development and when growth and development stops, TOR is at too high a level and is diving aging. So Blagosklonny has main theory of aging which I believe. The law of Entropy, that things go from order to disorder, is just an explanation of common saying, “shit happens”, the general understanding that things have a tendency to go bad.

          • Hi Alan,

            Thanks. It makes perfect sense!
            I definitely need to read more about the Blagosklonny theory of aging.

        • To a physicist, all of life is an end run around the Second Law of Thermodynamics. Only living things can perform the trick of building up order within themselves by taking in free energy and dumping their entropy in the environment. From a thermodynamic perspective, this is what makes life, life.

          • Hi Josh have you heard of Jeremy England and his idea that life is emergent from the laws of physics?

            He has postulated that atoms with an external energy source like the sun, in a heat bath like the ocean, can organize themselves to dissipate ever more energy and therefore acquire the physical attributes of life.

            There are a couple of good scientific American articles on the subject but I can’t get your spambot to let me link to them right now.

            I think Jeremy England isn’t familiar with biology, and he’s barking up the wrong tree. I think we will discover over the coming decades that life is a fundamental part of physics, rather than the other way around.
            – Josh

  4. Wow Josh that was a great post and critique and much appreciated by all of us who have been struggling with this for weeks now. Your post is long so:
    ” A is positively correlated with B. B is positively correlated with C.” It can be a positive or negative correlation, or it can even be absurd.
    Children drowning is associated with pools. Pools are associated with children eating ice cream.
    ” SNP = long telomeres AND
    SNP= cancer ( bypassing the long telomeres)”
    Mark has surmised this and even given a mechanism for such.
    ” The result ends up looking quite scary. The 2% with the longest telomeres would be projected to have 10 times the elevated rates of lung cancer and 28 times elevated risk of brain cancer.” This type of extraordinary risk from long telomeres certainly seems to fly in the face of all of the available evidence to date. But even so , this reporting of relative risk should stop since it serves no purpose other than sensationalism. Both brain and lung cancer ( in non- smokers) are very rare and when you factor in margin of errors, the increased absolute risk is miniscule.
    ” If people in the top 2% of telomere length really had 28 times the risk …… everyone with brain cancer would have longer than average telomeres”
    There would then be no greater carcinogen for any single cancer than long telomeres. HaHa.
    ” So there are 2 possibilities. A) Short AVERAGE telomere length usually means a high number of cells with critically short telomeres”
    I’ve been beating this drum ad nauseum and the need to evaluate telomere distributions instead of averages. There is almost certainly a group with high average length with a high proportion of very shorts as well.
    Finally, there is really no plausible mechanism for long or very long telomeres, whether acquired or genetic, causing cancer. That one extra cell division isn’t going to cut it.
    You quoted from the Rode Study but the Willeit study was also well done and measured telomeres BEFORE a 15 year follow-up and was peer reviewed by JAMA.
    Again Josh thanks for the many cogent clarifications for us neophytes.

  5. I can’t see telomere as a clock regulating aging – just a protective part of our biology. Shortening is just a result of lack of replenishment caused by aging. If there is a central clock for aging it can be expected more at a source like our DNA, epigenome or the brain.

    • What do you make of telomere shortening in one-celled protists? Cancer, of course, is not an issue. The only conceivable function is replicative senescence, enforcing the imperative to share genes. William Clark wrote about this 20 years ago in A Means to an End.

      • So all of us have different view points based on our individual trajectory in aging research. In my mind I am clear that telomere is not a meter as there are various inconsistencies even amongst mammals. Mice have long telomeres but short lives. Its primary function is as a cap as protection. Our hair turns grey but we don’t age because they turn grey it’s the other way round. And when melanin (if I remember correctly) is replenished it turns back to original color. We have seen telomeres do the same. So if we can reverse our body back to youthful homeostasis than telomeres and many other symptoms of Aging would also reverse back to their prime levels. In mice when we mitigate major aging symptoms like telomere shortening or senescence clearance it has shown some lifespan expansion because that portion of the damage has been reversed. When we cure aging itself the lifespan expansion can be in multiples.

  6. Even if there were an “optimum” telomere length in young humans, that doesn’t mean it won’t increase healthspan to lengthen them in old people (especially the critically short ones).

    Thanks for these posts, BTW. Maybe in 50 years the programmed aging theory will be mentioned in Biology departments 😉

    • @ Bill Walker –

      There are recent studies that indicates a strong programmed aging vector.

      Such as this one:
      “A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia”

      Or if you look at the work of Vladimir Titorenko @ Concordia University in Montreal:

      “Empirical verification of evolutionary theories of aging”

      • Thank you, Adrian Crisan! I love “A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia” in particular. Here’s a recent paper that I am hoping will set the record straight on the genetics of major depression. Here, “adult onset” cases of major depressive disorder (MDD) fit in fairly well with that Transcriptome Trajectory Turning Points window of 26 to 40 years:

        Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

        “Unexpectedly, the strongest associations we observed were with the oldest half of MDD cases, where previous analyses have focused on early-onset MDD, supported by studies of the genetic epidemiology of MDD. We emphasize that here ‘late’-onset MDD was at still a relatively young age (median onset of MDD was at age 27 years with 98% of our sample having onset before 60 years) rather than onset in old age.”

          • Paul we have read here in some comments of their interest in trying rapamycin but concern about suppressing the immune system. LDN is noted by Dr. Behari to rapidly restore the immune system. So may be you could investigate if for those who want to try higher doses can benefit by taking LDN during the intermittent period.

          • Hi Akshay
            As I’m sure you know, daily rapamycin for renal transplant patients is a potent immuno -suppressant , and would be dangerous indeed. However, at once a week dosing from 2-6 mg’s, you dose the drug at virtually a zero trough level, and it is then an actual ( 20%) immuno stimulant , as proven by an actual human study on old people.
            This was indeed predicted to occur by Blagosklonny.
            As you also are aware, LDN is an immunomodulator due to the increase in natural endorphin levels, which are the most potent immunomodulators in the body, but no known effect on mTOR.
            But since I know that you already know all of that, I’m too dense to fully understand what it is that you wish me to ask them?

          • So it would seem that their feeling is that it may not be a good idea to use LDN if you are actually trying to immunosuppress. But it ‘s fine otherwise ( such as weekly use of rapamycin) where immunosuppression is not the goal.
            Not many doctors know much about rapa for anti-aging it would seem

          • I’m leaning towards this now:
            Sunday 2mg rapamycin with nothing else
            Tuesday, Thursday, and Saturday LDN 2-3mg’s
            but I’m not certain

          • From the findings of Dr. Behari himself which he shared in his published interviews. He kept records of LDN therapy on thousands of his patients. Since he is no more I don’t know who has inherited that data as that would be the Bible of LDN.

          • Wow. That’s great to know.
            Two oncologists speaking today and I’ll get their input.
            Doesn’ t it only stand to reason that a preventative dose would be lower and less frequent ? Maybe 3.5mg three times a week is enough?

  7. Do we know if the correlation SNP ->telomere lenth is independent of age?

    For example, if people of 20 years old with SNP1 have on average 1% longer telomeres than people of 20 years old with SNP2, do we expect people of 40 or 80 year old with SNP1 to have on average also 1% longer telomeres than people with SNP2 of the same age? I would expect so but I have not seen that written anywhere

  8. Perhaps the same SNP’s that correlate with longer telomeres also make it more probable that a cancerous cell will hijack the mechanism that allows it to express telomerase and immortalize itself.

    So it would not be average telomere length by itself, but the means by which it is achieved. Although this could still be an indictment of telomere lengthening therapies.

    If telomere length was directly correlated with cancer rates we would see higher prevalence in young age, but it is the exact opposite. So there clearly must be other mechanism at play

    • These SNPs lead to longer telomeres because they either upregulate telomerase production through either the protein or the RNA template construction, reduce some other genetic regulation on telomerase production, or help in some way with integrating the telomerase into the telomeres. It is very complicated and I am in the process of looking into all the relevant genes.

      But what is highly instructive is that the changes these SNPs cause are exactly what is required by cancer to immortalize themselves. I have seen paper after paper to that effect. It is beyond doubt.

      Cancer still needs to go through the crisis stage by which it escapes senescence, via very short telomeres, therefore long telomeres are preventative of cancer. It is just that the SNPs that allow longer telomeres also mean that once any of them do get short (through damage and aging), you are more likely to get cancer. I am of course generalizing here, some cancers need telomerase more than others, so not all cancers are enhanced by these SNPs (its worse in slow growing tissues because they need telomerase more).

      The conclusion is rather funny, really. The longer your telomeres are through genetics, the more you need to keep them from shortening.

      • This analysis is a good one and ties some things together.
        I’m right in that it is indeed the very short ones that lead to the final malignant transformation process and not the long ones. But I am wrong in not acknowledging some risk due to genetically long ones.
        Haycock is right regarding genetically average mean lengths being a risk, but wrong in his conclusion that longs give cancer.
        It also explains that you are better off overall to have long telomeres as long as you prevent critical shorts down the line.
        The body attempts to escape cancer not by the widely accepted method of telomere shortening but by the selective action of telomerase on the critically short ones
        In the future we need to know the distributions throughout time starting at birth.

        • Like so many things in the body this adaptation is a two-edged sword. The body needs to shorten telomeres with divisions otherwise cancer would be rampant (any oncogenic cell would immediately be able to express telomerase), but in doing so it creates the conditions (crisis due to telomere loss) to allow cancer to escape the trap anyway.

          Ideally the body would create long enough telomeres at birth that we would never suffer from replicative senescence in any tissue even in a very long life, but as Haycock has shown that involves mutations that cancer can also use.

          Imagine the scenario where you genetically had inherited telomeres many multiples of the length humans have now – even if none of your tissues ever suffered from replicate senescence, an infection or other damage could still shorten some telomeres sufficiently for cancer to take advantage of the genes that gave you the long telomeres in the first place (There might also be other reasons why we evolution doesn’t favour super long telomeres).

          Interestingly, the reason cancer needs short telomeres to evolve mutations to boost telomerase is because the shortening of telomeres removes the looping part of the telomere tail from associating with the DNA stand near HTERT on chromosome 5. This is a necessary (but not sufficient) condition to activate telomerase in somatic cells.

          The details are given in this excellent paper from Shay & Wright in 2016

          “Regulation of the Human Telomerase Gene TERT by Telomere Position Effect – Over long Distances (TPE-OLD): Implications for Aging and Cancer”

          • That seems like a simple negative feedback control loop.Longer telomeres project silencing into the subtelomeric regions, so when telomeres shorten, the repressed region inwards shortens too. Thus telomerase can get expressed elongating telomeres and automatically shutting itself down when the job is done.

          • Also explains why mouse has long telomeres. They have their mTERT in the middle of the chromosome, so it is not regulated by TPE-OLD, but normal developmental processes. It also explains why it takes several cell doublings in mouse to reach final telomere length in iPSC cells as opposed to human cells.

          • Spot on GaborB, I thought the exact thing about mice telomeres, the promoter region cannot be inhibited by even by very long telomeres.

            It would be good if human cells did express telomerase when their telomeres got too short, but there seem to be other layers of control as well to prevent this, presumably to keep cancer at bay. We are back to the trade off between cancer and aging.

          • Hi Mark,

            I think that other mechanism is mostly the development program of the body.

            I think you are very possibly right about the effect of SNPs. Even without reading the papers on those SNPs that makes a lot of sense. We know that telomerase supports cancer growth and not only because of the telomere protecting effect but other unknown processes. So telomerase must be suppressed most of the time. If the other inhibitors of telomerase are somehow removed from the cell its onlyTPE-OLD protecting the cell from cancer.
            I speculate that overexressing only the telomere elongating domain could be a safer way. I should review the hTERT overexpression studies what they really overexpressed, the whole gene or the catalytic subdomain only…

      • Hi Mark,

        If a given SNP1 lead to longer telomere than SNP2 because of telomerase activation, I would expect the difference in telomere length between SNP1 and SNP2 to increase with age (since telomerase activation should act during all life).

        On the other hand, if the relative telomere length between people with SNP1 vs people with SNP2 does not change with age, it would suggest to me that telomere length difference is not the result of telomerase activation.

        My point is that this might be a testable hypothese.

        Would you agree with that?

        • It is an interesting idea, but although it is testable in theory it might be hard to do in practice.

          The answer to this might be in the Haycock paper, as I believe they corrected for age reduction in telomere length. If they did this using a constant (reduction per year) then you would expect greater scatter with age and this might indicate telomerase is more active in some people than others. The greater scatter with age might also be due to a longer time period during which different levels of stress or infections took their toll however, so you’d need to correct for that somehow.

          You could also just take blood samples from different people and detect telomerase activity, assuming low levels in somatic tissues would be measurable and the even small differences between people.

          Based on what I’ve read in the Shay paper I quoted above I’m leaning towards the SNPs in question contributing to a telomere length you are born with, but not playing an active role in maintaining or extending telomeres during your life (other than in senescent or near senescent cells that have the telomere tail separated from HTERT and perhaps in some stem cells?)

          What do you think?

          • Yes, maybe the answer is already in Haycock paper or others.

            Otherwise, I like the idea of taking blood sample on people to measure telomerase activation, SNP, telomere length, telomere distribution, and so on, and infer various correlations with age.

            Maybe existing databases already contain enough information to answer these questions but I have not found any paper about that yet.

            I have not read the Shay paper yet. Will try to spend time on it. Thanks for the reference.

          • Excellent basic telomere science Gabor and Mark, but now can we bring this back to a practical clinical application and get both of your inputs.
            The only examples of telomere evaluations are my father and myself done several years ago at Harvard by the Church group. So here goes. According to them the average person starts at about 10,000 base pairs and loses 70 per year or 700 per decade of life. At birth the percent of very shorts can be zero.
            So measured at 58 my total base pair number was down to 8316 representing a total attrition of 1632 over 58 years. The average attrition over that period would be 4060.
            My percent of very shorts was 10.5% ( defined as under 3Kb) and my percent of shorts was 8%. The average percent of very shorts at 58 is about 20 to 25 %.

            My father at 92 was close to 9000 base pairs representing an attrition of 1000 over 92 years. The average attrition would be 6440. Percent of very shorts 12.5%, or about 1000 in absolute terms I suppose. The average percent of very shorts at his age would be 35%.

            Of interest , he developed a great deal of stress at 93, then a chronic inflammatory illness ( psoriasis) at 93 1/2 and died of an unknown cancer type at 95.

            Several things come to mind. It is possible to maintain an incredible telomere length over many years with lifestyle only. It is also possible to keep the critically shorts at bay for many years.
            What we don’t know is how many critically shorts is acceptable. Perhaps his should have been measured at birth and when maybe he hit say 5% ( at perhaps 50 ) a telomerase activator should be added? Does TOR inhibition play a role in telomere length , he practiced calorie restriction, and should rapamycin be added at some point? What about anti- inflammatory drugs?
            I wonder if telomeres are sensitive to both good and bad environmental factors to a very large and labile degree and the distribution can change rapidly?
            Do we need a detailed analysis of all organ tissues?
            There are many practical questions that need to be answered.

          • Hi Paul,”
            Connection between rapamycin and telemeres very interesting.
            First, everybody should read “The Telomere Effect” by Elizabeth Blackburn. As you pointed out, she won Nobel Prize for telomere work.
            Most of book is about how to keep healthy telomeres by natural means.
            Interesting thing is natural means to keep telomeres healthy reads like natural things would do to keep mTOR low. Examples are avoid red meat, (red meat raises TOR), physical activity and avoid insulin resistance, (things that lower mTOR), avoid stress (stress increases stress hormones which increase mTOR).

            However, in cancer, rapamycin stops cancer from growing by BLOCKING production of telomerase. Based upon these studies all the usual rapamycin bashers will claim that should not take rapamycin as blocks production telomerase etc.
            Now recall my previous post that cancer is normal tissue growth from pre-cambian period, 600 million years ago.
            At that time I suggest it was job of rapamycin to promote production of telomerase so tissues could have unlimited growth. So that is what happens in cancer, mTOR promotes telomerase and rapamycin stops cancer growth by blocking mTOR and lowering telomerase. But cancer growth is not normal tissue growth.
            Fast forward 600 million years.
            “Telomerase and mTOR in the brain: the mitocondria connection, 2017,Miwa.
            “We have recently published that TERT protein accumulated in mitochondria from brain tissue of mice that had undergone short-term dietary restriction and rapamycin treatment.”
            Rapamycin having opposite effect in non-cancer brain mitochondria than in cancer.
            My suggestion: when living things went from cancerous-like growth to more organized growth similar to growth see today in normal tissues, TOR switched sides. TOR began developing a blocking protein to limit activity of telomerase.

            So in normal tissue, like mitochondria in mouse brain, blocking mTOR with CR or rapamycin increases telomerase activity and TERT.

            Bottom line: Studies about what rapamycin does in cancer tissue doesn’t say what it does in normal healthy tissue. (Of course, dose with rapamycin also changes everything.

            So my opinion, healthy levels of rapamycin promote longer healthy telomeres.

          • Hi Alan
            Always wondered about the effect of rapamycin on telomerase, thanks for the clarification, and what you say rings true to me. Rapamycin is remarkable and I’m grateful that you had the chutzpah to self- experiment 2 years ago.

          • hi Alan
            Did you see this one:
            Pub Med 28514891 AK Singh et al Rejuvenation Res 2017 Sep 14
            ” the cotreatment with rapamycin and metformin showed a significant augmented effect compared with individual drug interventions on reversal of age dependent biomarkers of oxidative stress”

          • Hi Paul, Alan

            I think there is no conflict between using rapamycin and maintaining telomere length – rapamycin just blocks protein synthesis so cells can’t divide, and although this would also block telomerase production, as most cells don’t produce this anyway the overall effect is to preserve telomere length through slower proliferation. Lower MTOR also lowers ROS, so telomere attrition is reduced that way too.

            I’ve also read the paper Alan references and it seems under conditions of stress TERT can locate to mitochondria for protection purposes. This is a check against apoptosis. I am not sure of the details but I expect telomere loss reduces this ability. The version of HTERT might be different to that used to extend telomeres.

            Paul, the results from yourself and your father are amazing, and almost beyond belief. Yes CR, exercise etc will help, but not that much! I expect the limitation is only measuring telomere length in the immune system. I am not sure, though.

          • Hi Mark
            Well, the molecular biology group was so astounded at his result that they ran the test 3 separate times for verification, and when the Church group at Harvard calls you in to study you , then you know that you’re a rare bird. Now understand, he was fanatical to the extreme. He was the first person perhaps to engage in CR, this was 35 years ago, and maintained a body weight of 120 lbs. at 5 foot 10. He had a resting heart rate in the 30’s and body temp of only 94 degrees. He was hospitalized one time, for a kidney stone, and when I went to visit him he was running sprints in the parking lot in his gown.
            The Harvard group at that time used saliva rather than blood.
            CR mimicked much of the effect of rapamycin I believe, but it would have been better ultimately to do both.
            I use him as an example of what the body is Capable of doing, albeit under extreme circumstances, at least until about 90, with no outside intervention. I’m also wondering if telomerase activation therapy should start when you are still at Zero critically shorts.
            It also proved to me the damning effects of chronic inflammation and stress, even on him.

          • Another thing is that if the measurment was done with PBCs then these cells are derived from HSCs and it is well known that telomerase is expressed in HSCs.

          • Hi Gabor
            I double checked and they do state an attrition rate of 70 base pairs per year. By they I mean Preston Estep And George Church ( founder of the human genome project) at HMS. Their credentials are impeccable but I don’t know from where they got that number.
            The study you referenced was very interesting in that they showed almost identical telomere lengths in four separate tissue groups, including blood, which was surprising to me. They also found that most telomere shortening occurred in the first 2 decades.

          • Hi Paul,

            another study referring other studies as leucocyte telomere shortening rate consensus is between 20-40 bp/year
            The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men
            Elissa S. Epel,1 Sharon Stein Merkin,2 Richard Cawthon,3 Elizabeth H. Blackburn,4 Nancy E. Adler,1 Mark J. Pletcher,5 and Teresa E. Seeman2

          • Hi Paul,

            First, congratulation for your telomere length! Whatever you do in term of healthy life style seems to work. I wish I could know the important factors.

            I am truly impressed by what your father has accomplished with CR..In particular, if my math are correct, he has started CR even BEFORE Walford et al. showed that CR prolongs mice life span when started in middle life. This was a milestone experiment . I thought Walford was the first to adopt CR (based on his own experiments with mice) but it seems that your father started even before him! Given what we know now about CR (reduces mtROSp, inhibit mTOR), I see your father was a true pioneer. Plus, he must have had an incredible will.

          • All of the above! Thanks Aldebaran. But here’s what still got him :

            Stress/depression—— breakdown of immunity——- chronic inflammation/ psoriasis——–cancer——– death. ( at 95)

            Among MANY things we must deal with, chronic inflammation must be inhibited.

          • Hi Paul,
            Remarkable how your father preserved telomere length, very inspiring.
            I have different causation.
            Prostate cancer is start.
            Early asymptomatic prostate cancer causes paraneoplastic syndrome with altered immune system.
            Paraneoplastic syndrome most frequently presents with Shingles few years before diagnosis of cancer. Here presentation of psoriasis was a bit unusual. However, since first presentation at age 90 without some change in immune system, seems very unusual, this consistent with paraneoplastic syndrome.
            However, next part of your analysis in which stress results in changes in capacity to control prostate cancer and clinical presentation of cancer and cancer death all seem likely.

          • Hi Alan
            Paraneoplastic syndrome is a very good possibility in this setting and could well be the case.

        • they might have gotten their 70bp estimate from this 1998 paper

          very interesting that there is a plateau between age 5-25 of maintained telomere length
          i am getting sick of all the papers publishing relative risk of cancer, cvd, etc derived from telomere length while the basic science of baseline telomere attrition across tissue types is far from settled. i guess that is because thats what you get grant for. curing cancer. yeah garbage in garbage out.

          • They claim on their report that they compared our results with literally thousands of others that they have access to in their database. It’s probably true considering who they are.

          • I guess the period of fastest growth is before the age of 5? Fig3 is a nice curve. I would also expect greater attrition towards the end of life but they don’t show that.

  9. Getting practical:
    Reducing MTor and increasing AMPK and eliminating senescent cells are our best hope right now to increase our healthspan and lifespan by 10-15%. But despite the optimal combination of diet, exercise, rapamycin, metformin, and senolytics…..
    when that hayflick limit is reached, our telomeres are finished, and so are we.
    So practically speaking, we HAVE will have to extend our telomeres to make any substantial gains in longevity. So even if telomerase, or long telomeres, increase our risk of cancer, we must accept that, and solve the cancer problem by other mechanisms. We have many partially successful anti-cancer methods now and I believe the day is coming when cancer will be effectively cured. When that day comes, give me telomerase!

  10. Sp what if it is not really the length of telomere that matters but the epigenetic state of telomeres?
    Telomeres are supposed to be heterochromatin, densly packed, with H3K9 methylated histones. It may influence proper segregation of chromosomes as stated in this paper
    Heterochromatin revisited

    Both centromeres and telomeres are supposed to be properly methylated in yeast for reproduction.

    • The epigenetic state around the HTERT gene definitely affects production of the protein. The same is probably true of all the other important genes like TERC (the RNA part). Perhaps the same also applies to the telomere itself, in that it needs to be in a certain configuration to have extra length added. All very complicated and no one has yet elucidates the whole process but I expect it is all regulated in somatic cells and part of the intentional inhibition of telomerase production.

    • Thanks Paul, I’ve dropped you a message. Amazing what your father achieved. Very important to understand what eventually got him. One thing we have not yet discussed is the link between telomerase and NF-kB. Many papers discuss this, but no one seems to have got to the root of what is going on.

      • Hi Mark
        You brought up my favorite subject NF-Kb which is believed to be the master activator of inflammation. During inflammation the combination of toll like receptors and macrophages lead to the production of NF-Kb and through a signalling pathway allows it to enter the cell nucleus activating genes to transcribe inflammatory proteins like cytokines, prostaglandins, COX, and even the generation of ROS. And in old age the production of NF-Kb ( a motif actually) is constantly in the ” on ” position leading to a chronic state of inflammation and damage. Only 15 % of cells of a centenarian are senescent but 100 % exhibit inflammation.
        But here’s the rub, Shortened telomeres associated with DNA damage can trigger a cascade leading through NF-Kb to IL6 to NK cell recruitment to senescent cell clearance! So we need to be careful once again in how much and how often we inhibit it.
        Amazingly, Low dose naltrexone inhibits TLR’s for only several hours allowing NF-Kb to take a significant but transient hit. That is one reason why it is good for cancer as auto-immune diseases, and sorry for being so long winded about this.
        But also check out parthenolides such as feverfew which can inhibit NF-Kb ( as can curcumin).
        This topic could easily be an entire post.

          • Thanks Akshay
            On your very excellent blog where you discuss supplements and cancer prevention ( better than anyone) you also mention anti-inflammatory mechanisms. Which substances do you feel are the most potent at reducing inflammation?

          • Thank you Paul always very kind. Nature has gifted us many potent anti inflammatories. I have now a list of 37. All of them also have many other powerful benefits. I am listing below a few of my favorites:
            Lutein (one my favs)
            White Willow Bark
            GSK (can reset genes in elderly)
            Andrographolide (my super favorite right now)

          • As usual you are a font of information and I’m certain that you have done your homework on each of those supplements. I now have alot of researching to do.
            I’m not at all familiar with GSK or Lunasin. Is Andrographis the same as Andrographolide? I’m curious as to why you left out glucosamine and boswellia?

          • Paul, I take glucosamine once in a while but more for joints tissue along with Chondroitin. Boswellia is not for everyone as it can cause gastrointestinal discomfort even ulcer to some.
            Yes Andrographis Paniculata is the plant name.
            I am excited about GHK here are some of my notes on it:
            During aging there is an increase in the activity of inflammatory, cancer promoting, and tissue destructive genes plus a decrease in the activity of regenerative and reparative genes [1].

            The most exciting discovery of the past decades is that these changes in gene activity can be reversed, often by quite simple and natural molecules [2]. Recent discoveries on the actions of the human tripeptide GHK (glycyl-L-histidyl-L-lysine) to reset gene expression of human cells to a more healthy state may open a door to the therapeutic resetting of genes in the elderly. 

            this simple molecule improves wound healing and tissue regeneration (skin, hair follicles, bones, stomach, intestinal linings, and liver), increases collagen and glycosaminoglycans, stimulates synthesis of decorin, increases angiogenesis, and nerve outgrowth; possesses antioxidant and anti-inflammatory effects, and increases cellular stemness and the secretion of trophic factors by mesenchymal stem cells
            GHK’s actions on gene expression were determined by the Broad Institute and, using their data, we determined that GHK increased or decreased gene expression (UP or DOWN more than 50%) in 32.1% of the human genes 
            The Suppression of Fibrinogen Synthesis
            Activation of the Ubiquitin/Proteasome System (UPS)
            Activation of DNA Repair Genes.
            Antioxidant Genes
            Suppression of Insulin and Insulin-Like Genes.
            Tissue Repair by TGF Superfamily.
            Cancer Controlling Genes.
            When GHK is administered internally to an animal, it induces actions throughout the body.

        • I’ve been on the lookout for something I can to really knock down inflammation. Never been overly impressed with curcumin and the like, and don’t really want to regularly take NSAIDS. Maybe one of the other substances suggested here is the answer.

          I get the impression that with aging MTOR and mtROS pushes inflammation up, this speeds up telomere attrition, which also feeds back to a greater inflammatory response and higher MTOR. Any of these processes can start off the downward spiral in the others.

          Hard to see what else your Dad could have done Paul, other than maybe rapamycin. Really we need a way not just to slow things down or block key pathways like NF-kB and MTOR but turn the clock back. I think that is the only way most of us will start living over 100.

          • Curcumin works for me. This is how I take it. Every morning on empty stomach I take about 10 tablespoons of aloe Vera pulp with equal amount of water on it I drop 1 full teaspoon of cow ghee (a type of clarified butter one can get at Indian grocery store) on it I drop two drops of G2 gold which comes with a dropper. It contains all 3 curcuminoids enhanced by piperine also turmerone enhanced – quite inexpensive I must add. I mix this and gulp down and wait for 10 mins before having any breakfast. There are many natural molecules and compounds with studies demonstrating their potent anti-inflammatory actions including the molecular basis of its actions. I am sure you will succeed in taming inflammation through natural interventions. All the best.

          • Akshay
            You are the KING of supplements .
            I assume that you take milk thistle along with this concoction.
            Can’t seem to find GHK anywhere, where do you get it?
            It’s funny that you mention Vince in one of your replies. He’s about 90 now and he claims that up until now he has only used supplements for anti-aging effects but that now he has started using some drugs , but he doesn’t say which and they never respond in their comments section.
            He also recently gave a presentation where he stated that his level of inflammation is literally zero and that , ” I ‘m not going to get cancer, I can tell you that, I’m not sure what’s going to get me but it won’t be that!”

          • Yeah. Ditto Jim Watson MD. They are going to soon give their list of anti -inflammatories. Maybe I’ll be able to actually understand what they’re talking about for once.

          • Paul you are right milk thistle and syllibin have very low absorption so I pair it a patented supplement called DIM-plus which contains phosphatudylcholine which enhances milk thistle absorption. GHK is one of the many powerful anti aging supplements my venture has identified. After successful validation on safety, bioavailability, dosage and efficacy in our clinical data from trials held at highest standards we hope to license out manufacturing and distribution which is when they would be available individually and as a protocol to all of us.

          • Hi Mark
            So when all is said and done where are we at this point?
            I guess start with healthy life style , combined with either CR, or easier to do , fasting.
            This alone may well get you close to 100 .
            Next slow it all down with weekly rapamycin.
            Bring down insulin and IGF and ramp up AMPK with metformin/berberine.
            Dampen chronic inflammation with multiple supplements ( Akshay knows this stuff).
            Keep up NAD levels to some degree at least with supplements. I only use NR twice a week.
            I personally would use low dose naltrexone as an immune modulator and TLR blocker. I’m also very impressed with the decrease in overall mortality and life extension of Glucosamine.
            Finally, I guess very much look at family history, and see which of the age-related diseases is of most concern. Like Blagosklonny says, we die of age-related diseases, not of aging per se, so fighting one is fighting the other. In my family it’s mainly cancer, so I am careful to take special aim at that.
            I fully agree that none of these measures will turn back the clock. I feel like prolonging our life to maybe even 140 is within our grasp, but true immortality is very far away still.

          • Yes that one and more Aldebaran:
            2010 Amer Soc of Nutrition Total mortality risk in relation to use of less common dietary substances. They found a very impressive hazard ratio of .83 for all cause mortality risk. Then a follow up
            2012 Use of glucosamine and chondroitin in relation to mortality. Revealed a HR of .82 so that you would have an 18 % less risk of dying from all causes.
            2007 Gluc inhibits prolif of human cancer cells by inhib of p70s6k. Also added to mTOR inhibition of rapamycin.

          • Hi Aldebaran,

            Great post on Glucosamine. Excellent paper with 2 human studies. Very impressive.

          • I believe Glucosamine works by mimicking a ketogenic diet – as it competes with glucose in the electron transport chain in mitochondria. This actually causes a rise in mtROS with a following rise in NF2 antioxidant response. It is a hormetic substance that harms you but leaves you better off than you started by the body’s adaptation.

            I would be cautious using Glucosamine as well as something like Berberine or Metformin as they inhibit the electron transport chain in a different way, and you probably don’t want to do both!

            On Vince – I think he uses a liposomal concoction including curcumin and resveratrol. I believe I’ve seen him posting on Longecity on the rapamycin threads, so I believe that is the drug he has now started.

            Incidentally don’t take rapamycin on the same day as curcumin, as curcumin ups the enzyme CYP3A4, which degrades rapamycin.

          • Hi Mark
            Great bits of information. I’ll now stop curcumin on my rapamycin day; wasn’t aware of the enzyme effect. Also didn’t know about the electron transport inhibition of both berberine and glucosamine. Hate to stop one but may have to do so.
            Vince and Jim are excellent theorists but I wish they’d give more practical advice, especially since Vince got his inflammation down to zero ( I guess by highly sensitive CRP). I suspect that you are right and he’s now on rapamycin, but does it help if you wait til 90?

          • hi Mark
            You’re absolutely right about the enzyme effect with rapamycin, and I have been taking curcumin with it like a total dumb ass. Since rapamycin has a long half life maybe skip the curcumin for 2-3 days.

          • Hi Paul,

            Well Alan started rapamycin at a relatively late stage of aging and seems to have got great results!

            I had the good fortune to be able to take it from the beginning of middle age, so I am hoping to preserve rather than restore youthful function.

            My objection to taking Glucosamine + Berberine or Metformin is only theoretical, you may be able to do it, but I’m only advising caution because they are both making it harder to get energy from you food in a way that could be additive or synergistic, and that might not be good for you. If you have been doing both with no ill effects, then fine.

            Incidentally, I found weekly rapamycin + daily berberine too much, I just felt too run down (on top of weekly NAD+ boosting efforts too). Since I dropped berberine I feel much better.

          • hi Mark
            I appreciate any bits of advice. I was very fatigued on metformin and had to stop it, berberine is better but only at 500mg’s, 1000 is too much for me. I’m trying to get my fasting insulin under 4 and bring down IGF levels as well.
            I’m going to be more careful with the glucosamine.
            I also only jack up NAD once a week.
            I’ll email the authors about the spleen and C60. They didn’t state but insinuated that they thought the rats would have gone on indefinitely with the stuff.

          • My friend’s grandmother just celebrated her 100th birthday. She lives in China, a Buddhist and vegan. Her diet is very simple and repetitive. Breakfast: half serving of rice with some pickled vegetables (in the Brassica family), lunch & super: one serving rice with fresh vegetables with or without tofu. Never any supplements. All day long, she sits with a Buddhist prayer beads going through mantras. There are many old ladies like that who live over 90 to 105. My own grandmother lived to 92 with exactly the same lifestyle. Basically by taking care of stress through not thinking (repeating mantras) and CR (from my calculation, their daily calorie never exceeds 700, protein maximum 15g), they are able to live to over 90. I don’t know what is more important out of these two, keeping mental stress down or CR. Probably keeping mental stress down. Another woman, Chinese American, I know is 97. She does not practice CR at all, but she eats whole grain congee every day and is quite religious (Christian), and takes tons of supplements. Then, there is my mother-in-law, who is Scottish Canadian living in Gold Coast in Australia by herself in 55+ communities, who is 92. She doesn’t practice CR, is not careful with her diet, takes a whatever medicine her doctor prescribes. But believes her role is to give smiles to everyone. Her mantra is “Don’t worry, be happy.” Sorry for the long winded comment, like everyone else, trying to figure out what makes people live long.

    • Ole you are absolutely right on Apigenin for SASP, inflammation and boosting glutathione amongst many other benefits including cancer prevention and against existing cancer which I have covered in my blog post.
      On Andrographolide yes there is one single study that mentions adverse action against CEC but there is also Dr. Sheu of Taipei College of Medicine which shows it in fact is beneficial in CEC dysfunction. There are many other powerful benefits of andrographolide shown in various studies including being one of the most powerful activators of Nrf2 which in turn ups HO-1, autophagy also Nqo1 which in turn ups NAD+ much more consistently then NR (as deduced by Vincent Giuliano) and we now know the rejuvenative benefits of upping NAD+, suppresses inflammation (inhibiting Nfkb and cJNK) including neuroinflammation which is highly interconnected to oxidative stress, it also upregulated UPS – one of the very few natural molecules impacting strongly so many major pathways of aging. Anything potent may have side effects which is why many long term trials are needed. But one of the methods which may be useful is reducing doses. So how do we reduce dose without diluting the potency: By synergistic pairings. With andrographolide it’s Sulforaphane. Together one needs very small doses to achieve same results.

      • Thanks for your answer Akshay. As usual, it’s the dose that makes the poison. I will look deeper into the synergistic effects of combining andrographolide and sulforaphane.

  11. I have read up on telomeres a bit in the past days. I have never been a big fan of telomere driven aging and now after reading through 10+ papers I have even more question marks, like
    1. WHat is the rate of telomere attrition in humans? In mice? In C elegans? In yeast?
    2. Is the attrition rate consistent across tissues? If yes, how?
    3. Is there telomere maintainence in tissues with rapid turnover?
    4. Is there any research out there proving causal role of telomere length on living animals? Like intermittent TERT expression in vivo in model animals?

    • I agree GaborB. Have you read about the latest study from Dr. Issa at Temple University? They found the rate of epigenetic drift (methylation drift) determines lifespan. They found it to be consistent in their tests in mice, monkeys and humans. They also found that CR slows the rate and could be the reason why it has such diffuse benefit on aging. Now the hunt starts for what else can slow the drift and better still what can reverse it. Is this what young blood does in Parabiosis?

      • I just read this news too. Not entirely new, Alan Green posted a paper showing how dwarfism, CR or rapamycin slowed down the rate of epigenetic drift.

        But slowing down MTOR and mtROS is one thing, but how do we turn epigenetic aging back?

        Blasco, Jesus, dePinho etc have shown ectopic HTERT expression in mice does lead to rejuvenation and some resetting of epigenetic state. But as far as I know this is only in cycling cells. To accomplish it in all cells it looks like we will have to do something truly scary, like an intermittent expression of the Yamananka factors.

        Interesting what you say about GHK Akshay, I’ll look into it. Anything to help get those gene expression patterns back to youthful levels!

        • Thank you Mark. I was going to investigate about whether rapamycin and metformin slow the rate of drift so I am glad to read that rapamycin does. This adds to the consistency of the finding. You must have read that cycloastrogenol activates telomerase. Yes Yamanaka factors right now looks very scary but we don’t know what may emerge from Church Lab – it’s obvious I am a big fan of George Church. But there other approaches to reversing epigenetic drift. Some of them may turn out to be safe. I for one want to launch a project with some AI and algorithm masters who are contacts to build a program that can exhaustively identify the epigenetic changes related to aging by comparing young and old epigenomes of various sample ages.

          • That sounds interesting. You mentioned previously you were looking to trial an antiaging approach but didn’t give details. I suspect that epigenetic drift might be fairly random, just a general deregulation leading to a loss of balanced expression (aside from that caused by telomere loss, which is more program like) But it would be interesting if a pattern emerged. We also dont know how much of aging is down to this effect.

            It seems to me that cycloastragenol is a very weak telomerase activator. Perhaps that is not surprising given what we know of how thoroughly its expression is locked down in most human cells. We really need to find out exactly what those locks are but we don’t yet. And that is why Blasco et al tend to use a virus to temporary express HTERT rather than turning on what’s already there.

            So what is your favourite anti inflammatory then? Lowering inflammation is a pretty good way of making the most of the limited telomerase expression in our stem cells, in my opinion.

          • Hi Mark,
            Elizabeth Blackburn who got Nobel prize for discovery of telomerase has a radically concept of telomerase than you.
            She has written an entire book about the natural regulation of telomerase. Those things that decrease and those things that increase and how to maintain healthy level of telomerase.
            To me, saying cells have 40 divisions before telomeres are shot is like buying a printer and thinking it runs for about 4 hours. You just to buy new ink cartridges.

            Telomerase is tightly regulated in cells for very good reasons.

            I suggest everybody read book Telomere Effect to understand how to create a telomere friendly life style.

          • Hi Alan
            So do you think that Blackburn believes that by life style alone that you can violate the Hayflick limit and just keep going? I can’t recall what she said.

          • The AI and Algorithms program would be a new project for me for which I will need to get the team, the science blueprint and then funding in place. My current trials are to validate my theory on how aging is implemented. So I am still trying to figure out the cause but have achieved personal clarity on how it is executed which is explained briefly in my post ‘mechanism of aging’ on my blog. Basically aging lowers efficiency of repair mechanisms across board and disturbs youthful homeostasis. Another realization is the amount of interconnections involved. So I am going after resetting some major pathways of aging for which I have researched for years to identify the most potent natural activators and upregulated. Then I want to leave it to the interconnections and cascades to see as a whole the protocol can mitigate the deterioration caused by aging. Vince is right one can only die if the deterioration succeeds on our most vulnerable part. I can’t see how we can fall over and die if theoretically we can maintain youthful homeostasis. During our prime our repair mechanisms areso powerful and brilliantly engineered. You are right on inflammation – it is a thread that is present in the whole dress. On supplements as they now say about vitamins it’s also true for super nutrients 95% just make expensive urine. The key I have discovered is bioavailability and synergistic pairings. Our trials are evaluating the following safety, bioavailability, dosage, efficacy and synergies of the natural molecules and compounds.

          • Hi Mark,

            there is a pattern in the epigentic changes. Otherways the Horvath and other epigenetic clocks would not work so well. There is an epigenetic clock of aging that only measures 3 cpg sites. Horvath’s one measures 366 sites but he uses different weights for each site.
            Besides it is now well researched that age related hypermethylation mostly affects PRC2 binding sites. PRC2 binding sites are usully associated with the developmental program.

          • Hi GaborB,

            Is the epigenetic clock like the clock they use in tennis match or like the clock they use in a football game.
            In regard to tennis match, the clock says how long playing; but the match can be 30 minutes or 10 hours and length of match has no relationship to time on clock.
            We all know how clock works in football game.
            So which clock is it ?

          • Hi Akshay
            I’ve been studying this stuff since 2012 when this study was published and created quite a stir: ” The prolongation of the life span of rats by repeated oral administration of C 60 fullerene ” It was given to middle aged rats and prolonged their lifespan by over NINETY percent. More than anything ever.
            I refer you to a comprehensive review of this by Vince on antiagingfirewallls:
            Buckyballs, health, and longevity 12 Nov 2012 , and then again
            Update on C 60 25 Feb 2014
            Just to whet your appetite he says this, ” C 60 rapidly clears from the body so some long lasting shifts must have occurred in cells and organs must have been created. I hypothesize that other more fundamental mechanisms are at play…. these may well involve quantum level phenomena largely ignored in biology up to this point…. if this is so we may be on the verge of surfacing new biological mechanisms critical to health and longevity – ones unknown and not imagined until now”
            All of this from a quantum physicist.
            As an aside , those who conducted the rat experiment claimed that they are convinced that the only reason that the rats eventually died was because they stopped giving them the stuff.
            But C60 can be quite toxic if not done very properly. But still.

          • The decay of radioactive isotopes is random, but on average the rate of decay is extremely predictable giving rise to the most accurate clocks in existence.

            The rate of epigenetic drift is what I thought allowed clocking, not the methylation status of any given site. That is why you need a great many sites to give you an accurate picture of someone’s age.

            Alan, if we continue the analogy of the atomic clocks, MTOR level is the radioactive half-life, the more radioactive it is, the quicker the decay.

            Nevertheless I can see where you are coming from GaborB, some sites are more vulnerable to change and this change might then make other changes more or less likely.

            So what would the consequences be of methylation at sites associated with the development program?

          • If only someone would replicate that one C60 study, but with more rats!

            But it appears the preparation of the C60 and Olive Oil is critical, and easy to get wrong with harmful effects, at least in rats.

            Incidentally I am not convinced C60 is rapidly removed from the body. There are pictures in the paper you mention Paul, showing accumulation in the spleen. If you get chance to speak to the authors Paul, that could be a good question for them.

          • Hi Mark, all kind of chemical reactions have their chance to occur in fluid. Some very low, some higher. Enzymes are there to raise the chances for a few reactions. So if there are sites with age associated methylation and there are sites with no age associated methylations there must be some form of control involved. I suspect it is the histone code which drives those changes.
            This is even more likely, because there are only 3 DNA methylation enzymes, whereas there are many histone methylation, demethylation, acetylation, deacetylation, etc enzymes. I think nobody has investigated throroughly the histone code as much as they had studied telomeres and DNA methylation.

            DNA methylation might just be a blunted projection of the histone code.

            In the 1950s people know biochemistry, so they blamed ROS, in the 1990s people got to know telomere biology, so they blamed telomeres, in the 2010s people got DNA methylation chips with half a million sites, so they blame DNA methylation.
            One day we get to know the histone code.

  12. Also this
    Fullerenes as anti-aging antioxidants. Galvin YP Curr Aging Sci 2017 56-67
    This stuff may be a true breakthrough but I’m too afraid to try it.

    • Unfortunately i cant get access to that paper, even with Sci-hub.

      The consensus I believe is that C60 is a potent mitochondrial antioxidant. In Olive oil it may have other effects. I tried the formulation from Vaughter Wellness and found it made working out easier. Hard to know what long terms effects might be, but I felt it was doing the opposite of boosting NAD+, I.e. giving my mitos a free ride and discouraging mitophagy. I could easily be wrong. I eagerly await further work.

      • I can’t access the complete paper either. Can’t believe that you had the chutzpah to actually try the stuff.More work should be done on it

      • Hi Mark,
        Nice to know you have tried it and it improved workouts.
        I see it as analogous to activated charcoal, which is used as universal poisoning antidote due to extremely large surface area.
        Buckyballs effect seems due to physical shape having so many available carbon atoms acting as great anti-oxidant.
        My point about activated charcoal and buckyballs is not about signaling or organic type chemical reaction; more like just a big mop.
        Since Josh initial post Jan 2013 had very many responses and almost all good.
        Most typical response seems to be increases in physical performance consistent with your comment. Judging by all the providers, seems to be very many people, especially old people using it. Typical comments ring true that people like the stuff.
        Another product never to be reviewed by FDA.

        • That’s a good analogy Alan, I like it.

          Assuming it is a super duper antioxidant, how best to use it? Maybe as an anti apoptosis agent for those cells with very sick mitochondria. That matches the results in the 2012 paper, where it protected rats from some nasty poisons, it memory serves.

    • Hi Everybody using C-60 Buckyballs.
      Paul just posted reference about Buckyballs
      Josh posted about Buckyballs 1/29/13.
      At that time many people responded were using c60.
      so who is using it now and what have been results.
      Anybody with pet rats using Buckyballs.

      • There is an update on this now – Ichor have successfully floated another venture (antoxerene) which is looking into this, including more mouse trials to try and determine why they have both good and bad results depending on the formulation of the C60 and olive oil. So expect back news in 2018.

        • Good to know. Thanks for the update. Looking forward to get some update in 2018!

          I am not surprised that they have good and bad results. If it was straightforward to reproduce, we would have already seen some publications. There was a trial in Russia on mice in collaboration with the Major Mouse testing program around 2015 and they were not seeing signs of life extension at that time. However, I cannot find the link anymore. They have probably focused their efforts elsewhere.

  13. I had another thought regarding C60. It may work to extend the lives of rats by preventing cancer metastasis. In that famous 2012 paper the remarkable thing was that none of the C60 treated rats got cancer. That is unheard of in a rat.

    And we know from papers such as:

    A Mitochondrial Switch Promotes Tumor Metastasis, Cell Reports 2014 (free access)

    That it is a change in the mitochondria that triggers cancer metastasis and that MitoQ (a mitochondrially targeted antioxidant) can prevent that.

    Could C60 be the anti cancer agent we’ve been looking for?

    I hope we’re not going too far off topic here.

    • That’s a very good thought and I’m going to look into that aspect more thoroughly now.
      I remember reading that Blagosklonny was criticized by some for not really preventing aging with rapamycin, but only PREVENTING CANCER.
      I need to go back and read Vince’s and Josh’s posts more carefully .
      Where again did you get it Mark?

      • The C60 in olive oil? From Vaughter Wellness.

        It’s inexpensive, and I expect you only need to take a teaspoonful occasionally to get the benefits, if you believe as I do that C60 stays in the body for a long time.

    • Hi Mark.
      Those are very good thoughts and help possibly explain what is going on with C60.

      As regards “aging”, that is a undefined term. It could be considered an increase risk of death, or the SUM of all sorts of all bad things happening. As regards rapamycin, rapamycin does one thing, it inhibits TOR. Inhibition of TOR prolongs lifespan in all things including yeast and worms, which don’t die of cancer. So people who say rapamycin does prevent “aging” are raising a semantic issue regarding what they think aging is. For me aging is a basket term for a group of heterogeneous diseases. I guess for some people “aging” is something indivisible, as in the phrase:
      “one nation, under god, indivisible, with liberty and justice for all” LOL

        • Hi Akshay,
          Of course, I disagree with you 100%.
          The main point is understanding aging is not a parlour game; it is a matter of life or death.

      • Rapamycin preventing cancer but not aging is a misunderstanding from people who don’t understand what MTOR does. Cancer is all about growth and inhibiting MTOR inhibits growth, therefore it inhibits cancer as well as the excessive growth that is a hallmark of aging.

        I am sure you know this Alan, but the tale of the discoverer of rapamycin taking it for years to keep his cancer at bay is a great story. Sadly it does not have a happy ending, as he stopped rapamycin to see what would happen.

  14. There is constant damage happening in our body – one data says 60,000 insults a day to DNA on avg. When we are in our prime our repair mechanisms cope with damage. Hayashi from Tsukuba University says rate of damage is same for a 20 yr old and a 90 yr old. What changes as we age is rate of repair. Hayashi also showed that damage is reversible. So theoretically if our rate of repair goes back to prime levels we can go back to how we looked and felt in our prime within a period that each tissue/organ takes to renew. Today’s reality is there is no truly life extending anti aging therapy that has been consistently translated to humans. Rapamycin, metformin and CR have a common thread: hormesis. Even in fruits like tomato or nuts like peanuts upon boiling which causes a type of heat stress the hormetic response ups the nutrients by 7x to help cope the stress. The biggest benefit of hormetic response in humans who have already undergone unrepaired damage progressively is change of gear to repair and renewal from growth mode – this is what Blagosklonny is pointing to due to inhibition of Mtor. But a hormetic dose when increased turns into toxic dose and therefore the benefits act more like a booster rather than a cure of aging. The best we can do till then as we age is take nutrients that up repair and renewal.

    • Hi Akshay,
      Blagosklonny has 2011 paper, “Hormesis does not make sense except in the light of TOR-driven aging.”
      The paper starts with line, “Paraphrasing the famous quote “Nothing in Biology Makes Sense Except in the Light of Evolution”, one can say that nothing in aging makes sense except in the light of TOR-driven quasi-programmed aging, a continuation of developmental growth driven by growth-promoting pathways. And life span extension by mild damage makes no sense, if aging is a decline caused by accumulation of damage.”
      For me, there was no understanding of aging prior to 2006 with Blagosklonny paper, “Aging and Immortality, Quasi-Programmed Senescence and its Pharmacologic Inhibition.”
      However, we known most people do not have sufficient mental plasticity to change a very well established idea. This means that anybody who had a well established idea of what is aging, could never accept the Blagosklonny idea unless they were able to clear their brain of everything they believed about aging and start all over. Very few people can do that. This means that most people who began studying aging prior to 2006 can’t escape from their beliefs prior to 2006.
      Also consider that in USA more people believe in creationism than in Darwinism, which shows rather limited ability of human brain for science theory.

      • Hi Alan,

        in fact I started my personal research on aging with Blagoskonny. I have read all his papers I could find and at first he was very convincing but later it started to annoy me that he was so centered on rapamycin. Besides I havent seen an overwhelming amount of data that rapamycin could meaningfully extend lifespan.
        From a concise theory of aging I would except mice that live 10+ years. Or 3 year old mice that are like 6 month old ones.
        I am not sure for example how Blagoskonny explains rejuvenation processes in germline or ipscs or somatic nuclear transfer. Blagoskonny is very attractive because he comes with a prescription drug off the shelf but I am not convinced that mTOR inhibition is really more than just alleviating the hardships of aging.

        • Hi GaborB,
          I suggest you consider aging a Ven diagram with circles A, B, C and X.
          A is hyperfunction driven by TOR, B is mitochondrial and ROS related disorders, C is disorder due to short Telomeres and X is unknown number of circles due to now undefined problems.
          Aging is the sum of all circles which compose Ven diagram.
          Blagosklonny calls circle A, aging and all other circles “post-aging syndrome” in that they usually presented later than circle A as regards clinical disease. (That part is not proven.)

          What rapamycin does is reduce TOR and thereby reduce diseases caused by elevated TOR. Now seems that in 60-90 year old time frame, very much of aging and age related disease caused by elevated TOR and can be alleviated by lowering TOR.

          After treat circle A, and after providing rapamycin treatment, will see what everything outside circle A looks like. I think most of aging will be outside circle A; but treatment with rapamycin should go a long way to help preserve quality of life and keeping people healthy in 60-90 age group.

          • Hi Alan
            Dare I say it but you may have underestimated rapamycin. In From rapalogs to anti aging formula, he states ” Given that rapamycin consistently extends maximum lifespan in mice , rapamycin will likely allow mankind to beat the current record of human longevity, which is 122 years. Yet rapamycin will not extend lifespan as much as we might want.

    • Hello Akshay,
      Took a look at your blog.
      In my opinion, number one problem in anti-aging is JUNK SCIENCE
      I suggest whenever you make statements and recommendations as to supplements etc you provide reference in science journals so we can evaluate the quality of the science supporting the statements.
      This is a very science oriented blog and Josh setting the tone provides references for all his statements and almost always links to those references.
      Very many people here have provided excellent references which have been extremely helpful.
      As “Dirty Harry” said, “opinion are like assholes, everybody has one”.
      What matters is real science based upon papers in science journals, that people can evaluate for credibility.
      Any statement about how specific supplement prevents cancer should be accompanied by papers in science journals demonstrating the data supporting the statement. Journals that are open access or you can provide the link etc.
      Of course, you have your own blog; but this is very much a real science oriented blog.

      • Hello Alan,
        I agree with you fully that Josh has a much more superior and scientific blog – mine would be more of an amateur researcher in comparison. Though I must point out that while compiling natural molecules and compounds that have shown benefits against cancer I have only selected ones which have multiple studies results from reputed labs. I have also cited those studies with the name of the scientists and the labs/Universities/Institutes. It took a lot of effort to sift through all kind of junk to identify and compile them. I also have mentioned a disclaimer if you noticed which said I am not recommending any natural molecule or compound and every reader should make their own research and consult their doctor before considering any. I list them as a free resource.
        With regards to aging on my blog I am sharing the result of my deduction from my own trajectory in anti aging research. A reader has a choice to believe disbelieve read or not read. Nevertheless each of my deductions are only based on studies done by reputed labs. I have my favourites like Sinclair, Hayashi, Church, Vince, Watson, Rosedale. A reputed University is convinced enough about my deductions with regards to upregulating certain key repair mechanisms that progressively falter with aging to invest in trials to test the theory. A leading Cardiologist and Surgeon who has been invited to speak at 140 medical symposiums in 30+ countries too is a believer and an investor and our entire team consists of PhDs in related fields many of whom have worked previously on drug dev research at Pfizer and GSK. We may fail completely but some of us have clarity that we may succeed. So far I have not found our deductions to be contradicting Blagosklonnys view on aging. Hormetic reaction is a evolutionarily conserved response to stress for survival of species. Unrepaired damage progressively lowers systemic functional efficiency. mTOR is the most powerful sensor that determines we grow or repair. Either mTOR is activated or Autophagy is activated. Inversely related. Either accelerator or brake. This is consistent with what I believe. What Blagosklonny says about mTOR I agree. Inhibition of mTOR ups repair and removes junk. Incidentally almost all natural compounds and molecules selected by us inhibit mTOR – not constantly but only up to the needed repair rejuvenation level is achieved. I have formed a view based on studies of reputed labs that actuation of repair systems is effected by activators and inhibitors. As we age for unknown reasons inhibitors begin to progressively dominate. I have cited examples of studies of reputed scientists that support this. What I have also seen evidenced in studies is that this loss of homeostasis if corrected would reverse the damage caused by inhibition of repair efficiency. We will soon find out if we can bring back the balance of activators and inhibitors of repair systems to levels seen in young controls. And also whether this reverses the deterioration caused by loss of repair efficiency. I rate all of you as more intelligent and more scientific then me and my team. My team and I are just exercising our right in making our tiny effort to test our theory.

        • Hi Akshay,
          Thank you for very nice statement.
          I apologize if I seemed to be picking on you.
          Majority of readers here are very interested in and users of supplements.
          In USA, these are now hard times for people who believe in facts and science.

          • Alan thank you for kind words and not all – I have decided to be a student all my life always ready to learn more or be corrected. Vince Giuliano has the ability for deep analysis of the underlying molecular mechanisms. Even he has been taking supplements. The key is to ensure one has the sound understanding of the science behind it and know how to ensure sufficient bioavailability. I read somewhere that 95% fail there as usually cellular absorption rates are very low. I too read your web pages. Really liked the way you shared your own experience with rapamycin and some very valuable inform on what dosage worked and the science behind the noted side effects and why such a dosage avoids that. Getting a successful case study like this explained by a knowledgeable doctor is a rare treasure in anti aging for the rest of us.

        • Hi Akshay, I liked your blog and wish you luck in your venture.

          In my view aging is quite simple, but the consequences and the un-doing of it are very complex.

          MTOR drives protein synthesis, the harder you accelerate your foot on the pedal (Blagosklonny car analogy) the quicker you grow, but the quicker you die through premature (non-replicative) senescence.

          High MtROS damages the proteins (and DNA) that are being produced in response to MTOR, following the same car analogy a more efficient engine means less damage and less repair is required. Mice have high MTOR to grow and breed quickly before they are killed, so no evolutionary need to lower MtROS (MTOR would kill them regardless), so they have to rely on repair mechanisms (antioxidant response, etc.), which is not as good as not doing the damage in the first place.

          Hormesis is when you temporarily up MtROS (exercise, ketogenic diet, some supplements) to up the antioxidant and mitophagy (lower future ROS) response. Useful in humans (not in mice) but has a narrow range. This could kill the old and frail. Also, try telling an athlete at the top level he needs to train through injuries and that taking antioxidants will not help him recover and see him laugh. There are limits to NF2.

          Your idea of returning certain key pathways such as NAD+, p53/FOXO, NF2/NF-kB, etc. to youthful homeostasis is a good idea, but there are probably many, many more such balancing acts that are out of wack that we are yet to discover. Hence you will have to aim to reset gene expression as thoroughly as possible to catch them all otherwise there will be other issues down the line. Even then some of the damage that has been done might not be repairable, even with a youthful system, so we will need to get rid of that too via a SENS approach.

          Personally I feel I have MTOR and MtROS under some semblance of control. I expect to live healthily for a good long while. Rejuvenation will need much more though.

          • Hi Mark, thank you for your kind words about the blog. I have been reading your comments here and am always impressed with your knowledge on various. We are in sync – I agree with what you have said – currently I do not have the knowledge and expertise on the ability to intervene directly at the gene transcription translation level. Counting on the likes of George Church for that. What I have clarity on is what is happening with some of the major repair and clearance systems as we age. It also took a lot of research to identify each of the interventions that would correct the balance between activators and inhibitors of key repair mechanisms. You are right this may not make a systemic impact as aging but what is going for us is the incredible amount of interconnectivity. For example if we sit to list out all that Nrf2 activation triggers it would be staggering. And it is only what we have found out so far. There are other very powerful pathways I have identified some of which are not so well known. So our strategy is to rebalance these major repair pathways and see how much benefit it can deliver. I totally agree with what Dr. Rosedale said ‘If we can repair every damage as it occurs we can live forever’

          • Hi Akshay
            Just wanted you to know that the curaderm that you wrote about in your blog worked like a charm on a patient with basal cell skin cancer, no surgery required.!
            I’m also trying to set up a meeting with Dr. Shamsuddin to discuss IP6. His work is incredible and he doesn’t get enough credit for what he’s discovered

          • Hi Paul this is amazing news! You are probably the best doctor a patient in America can hope for due to the amount of research you sacrifice time to do and your openness to look at alternative remedies as long as they satisfy your study of clinical evidence. And you did win best doctor in America award 5 years in a row so others too feel the same 🙂
            Personally you have made my day because of getting direct feedback on a success. Would love to hear about your further interaction with Dr. on IP6. Godspeed!

          • >the harder you accelerate your foot on the
            >pedal (Blagosklonny car analogy) the quicker
            >you grow, but the quicker you die through
            >premature (non-replicative) senescence.

            I haven’t been convinced by this because there is so much change in epigenetic expression over a lifetime. There’s nothing stopping the body from driving hard during development, then taking the foot off the gas once maturity is reached.

            Furthermore, it’s the animals and plants that grow continually through their lifetimes that seem to be immortal (or close to it), demonstrating that growth is compatible with absence of aging.

          • Josh,

            I think it is the conflict between an arresting signal and MTOR that is causing cell senescence due to protein build before failed mitosis. Ever-growing creatures lack the arresting signals so don’t suffer from this.

            I totally agree that the human body can and does throttle back growth, as we see from the drop in sex hormones, etc. I wonder how much of the aging we observe is secondary; an adaptation to dial down MTOR, and how much is due to the primary effect.

            I too would love to see an epigenetic blog post Josh. We really need to start looking into that mechanism. We know its related to MTOR from the papers weve seen on the Horvath clock and CR, but no details.

  15. Hi Everyone
    I’ve been thinking about my prostate of late, my uncle died of prostate cancer at my age, and am wondering about rather drastic measures to prevent it from happening to me.
    I fully agree with Blagosklonny when he states in one of his many papers that when we fight and postpone aging, we are also preventing or postponing age-related diseases. To defeat one is to defeat the other. After all, as he says, we die from ARD’s and not from aging per se. No one died of ” aging”.
    So in that vein, and again using myself as an example, there are three major ARD’s in the U.S. Cardiovascular disease ( heart attack and stroke), cancer, and Alzheimer’s.
    All of us can get a very excellent, informative, and prognostic test called a coronary calcium screen. It’s non-invasive and if you score a zero you’re not having CVD over the next 5 years ( and maybe longer) .
    If Alzheimer’s doesn’t run in the family and you get some simple genetic tests as well you’re probably good there too. Besides which it’s more rare than the other two.
    Now let’s consider cancer. the big 3 in men are colon, lung and prostate. Colonoscopy is both sensitive and specific and serves as a great screening tool for those reasons. Lung, simple, don’t smoke or quit immediately.
    But prostate is a problem. The screening test, PSA, is very sensitive but not specific, so it goes up with all kinds of things prostate related, and not necessarily cancer, though it catches cancer, but ALOT of false positives leading to unnecessary procedures etc.
    And to make it worse , the US task force proclaimed that it had no effect on mortality rates, and that’s the bottom line.
    Consider this, about 1 in 7 men will get prostate cancer, and there is an annual death rate of about 24000, give or take obviously
    Now a PSA under 2.0 does make it very unlikely to have cancer.
    Also realize that standard prostate surgery has a high rate of complications including impotency and ED ( 30 to 40 %).
    However , there have been some significant recent advances such as high intensity ultrasound therapy and lasers. The HIUT pulverizes the gland via heat, and does a similar thing. But, the incidence of impotence is Zero in experienced hands and ED about 10%. You can check my figures by looking at the UK experience with this and seeing their presentations on the matter to urology and oncology European groups. They have done this a long time. FDA recently approved it here.
    So why not at age 55 , when the risk starts to dramatically rise, every male get this procedure done prophylactically. It would be one major cancer down. If your PSA is under 2 then just follow it. Otherwise get rid of it. You don’t need it. The 10% ED risk is a pain, but almost all surgical risk depends on the skill and experience of the surgeon. That number considers all surgeons .The risk of the procedure is very very low.
    So it’s one BIG disease down the drain and good riddance to it. It will prolong our lives.

    • I would have thought that intermittent rapamycin treatment made prostate cancer far less likely, so if you’ve been on it a while I would expect a low PSA score. If not then you need a higher dose. I’d try that before going near a preventative surgical procedure.

      • I may try that for 6 months first. But you don’t know if you had an underlying indolent cancer before even starting rapamycin.

      • Hi Mark
        By the way, what was your impression of how magnesium reduces or eliminates dangerous DNA-R loops, and in that manner mimics CR, and may lead to an increased lifespan.

        Abraham KJ. Nucleic Acids Res. 2016 44 (88) 8870-84
        Szafranski ,K Nucleus 2014 5 (1) 56-65 October 2017

    • Dr. Rivas,
      I had a PSA of 3.75. My primary wanted to do a prostate biopsy.. Went to Dr. Graeme Steele at Brigham and Womens in Boston for a second opinion. Dr. Steele is considered the Urologist Urologist. One of the top Urologist in the country.. He ran a PSA free, and a PSA % free on me and they were normal.. He said, that these two test tell the real tale on having a biopsy and all the ramifications that come with those results.

      • Van
        This is actually very true. A free PSA does add some significant specificity , which is much lacking, to the test. For instance, with your total under 4, a free PSA level of 25 or higher reduces your risk of cancer to only 8%. Dr. Steele, who forgot more about prostate cancer in the past 24 hours than I’ll ever know, is absolutely correct.
        Ask him this for me, since high intensity ultrasound has such a low incidence of adverse effects, and so many men get prostate cancer ( by the age of 100 the incidence is 100%), so why not just wipe the little monster out?

        • Few comments about prostate cancer:
          True incidence of prostate cancer very high men age 100; but that is microscopic foci of cancer found at autopsy which are totally asymptomatic. What means somethings is actual death and morbidity.
          A few facts and stats from Zero, a prostate cancer newsletter:
          Probability of developing prostate cancer birth to age 70 and older 1 in 11; birth to death, 1 in 8.
          5 years survival 2006-2012, whites >99, African American 97 %.
          The 10 year survival is 98% and 96% 15 year survival,
          Early diagnosis saves lives.

          Note: There is zero scientific evidence to support this fear; but I would be worried that if I had normal prostate removed to prevent development of prostate cancer; 6 months later I might find out had cancer of pancreas (5% survival). Just joking but point is lots of bad diseases out there.

          Also what a physician reports his procedure had only minor side effects; it might seem pretty fxxxing major to you.

          • Hi Alan
            Always good to have a pathologist’s input on these things, but still 24000 deaths a year is a pretty big number for one cancer type, especially coming from an organ that has very little usefulness. It is really my main point that while PSA is picking up tons of cancers due to its high sensitivity, most of these are of the slow indolent types. It can’t grab the poorly differentiated ,very aggressive types fast enough , hence the zero influence on mortality rates on the disease. So in essence we have a gland that has little purpose, except that it can kill us, and no reliable early screening measures.

  16. Hi Josh
    I understand the theory but since starting rapamycin I’ve lost 12 pounds, my endurance has markedly improved, my cognitive acuity has improved, and everyone around me says that I’m 20 years younger.
    Alan had a more dramatic response even.
    So theory be damned, if you excuse the expression.

    • Hi Paul,
      Nice to see your comments about cognitive ability and endurance. Weight loss is something objective can see on scale but cognitive ability and endurance is subjective.
      It was said people would have to wait 30 years to know if any benefit from rapamycin; reality is see results in weeks to months. Rapamycin benefits were thought of in terms of lifespan extension or protection against age-related disease; what was not expected is immediate improvement in quality of life.

      • Hi Alan
        But why is that? It can’t be explained solely by inhibiting geroconversion. It’s too rapid an effect. It’s like some sort of rapid repair mechanism at play.
        Endurance is not purely subjective , I can go at least 30% further now.

        • I’ve wondered about this myself.

          mtROS is a likely explanation. We know both CR and Rapamycin drop ROS lower even that what is normal in young people. If the body suddenly has that much less oxidation to deal with then repair might be able to get ahead of damage and actually reverse some aspects of aging.

          For my own part I’m close to 40 but my athletic performance has continued to improve. Despite two young children and no time to train I can lift more weight, run faster, etc than i could in my 20s. I find myself able to continue to push my limits. It will be interesting to see if this continues.

          • Hi Mark
            Your explanation seems sound.
            As ForJosh’s comment that turtles and trees continuously grow and yet live long, isn’t that because they don’t have a senescence issue?
            Glad to hear that about your performance levels;was wondering if it was just in my head.
            The right dose is a challenge. I’m only on 2mg/week. Do you think it’s too low?

          • Hi Mark,
            That’s incredible. Wish I had started anti-aging at 40 instead of 73. Of course, when I was 40, I couldn’t even spell ageing.

          • It makes sense, doesn’t it? Hard exercise raises ROS enough to cause de-coupling and mitophagy. But if your normal physiological levels of ROS are lower you can in theory carry on for longer before this point is reached. Its all about moving the check and balance points of the body away from firefighting and towards health.

          • On senescence Paul, yes that is my understanding. If you don’t stop growing there is no clash between MTOR and an arresting signal so no geroconversion. Of course there might be some arresting signals, say due to short telomeres or a cancer mutation, but much less than in a species who is programmed to arrest growth all over the body at a certain point.

    • Hi Paul,

      Thanks for sharing that extraordinary improvement. This is great.
      Would it make sense to do a short term pilot study using weekly rapamycin and monitoring various heart parameters in few volunteers? My thinking is that if we can prove that short term rapamycin improve heart function objectively then this could be a game changer. I am not a doctor nor an expert in biology so maybe I am over-simplifying the procedures and so on. But it seems to work so well that there should be a way to scientifically prove the benefits.

      • Hi Aldebaran
        It’s a great idea but you’d have to identify a group of people with age-related cardiomyopathy and do echocardiograms.May be difficult to identify that group.They did it with middle aged dogs though; worked like a charm.

      • Hi Aldebaran,
        I am intrigued by your comment that “game changer”. I have considered such a study on random group people 65-75, before and after echocardiograms. I’m sure same results as Kaeberlein dog study. That is not the issue.
        The issue is at end of day, rapamycin still just a generic drug. How does the results get any news coverage ? How does anyone find out about results etc ?

        • Hi Alan,

          Maybe my initial enthusiasm needs to be tampered by the reality of medical studies. I don’t have any practical experience in that domain. My understanding is that there is currently no drug on market that provably reverse cardiomyopathy (please correct me if I am wrong). So having such a drug would be a real breakthrough for millions of people. Then, how can there be no way to communicate that to the public? Please again forgive my lack of understanding of how the medical domain works if my question is too naive.

          I have spent some of my summer vacation with a known cardiologist and next time I have a chance, I’ll discuss with him about that.

          • Hi Aldebaran,
            Thanks for comments.
            Note that age-related cardiomyopathy is not a real thing, at least not a real thing that traditional medicine thinks exists.
            I was medical examiner for 10 years and that was a diagnosis I never wrote on a death certificate as cause of death. Now I would like to go back and change a few death certificates.

          • Hi Alan,

            Thanks for clarifying. Looks like it is more complicated than I thought to prove that rapamycin does objectively improve the heart function in the short term.

          • No Aldebaran,
            It is not hard to prove.
            The issue is will anybody care if the drug that reverses age-related heart damage proven on ejection fraction of echocardiogram is a generic drug and not a brand name drug.
            More specifically than will anybody care, would it ever become news.
            So is it even worthwhile to do such study if likely to be ignored by a 5 trillion dollar medical system that has no interest in rapamycin.

          • Hi Alan,

            You are raising a good point. Certainly, no company will care about rapamycin. I was hoping that at least many doctors would be interested to know that rapamycin reverses age-related heart damage. That would be a first good step in my mind. However, I might be wrong.

          • There are companies interested in developing ‘safe’ rapalogs. They can charge the earth for them and claim rapamycin is not safe. Just like long telomeres are not safe so we all need to have super expensive stem cell treatment 🙂 It’s enough to make you believe in consipiracy theories!

    • Paul, I am considering rapamycin, but I am unsure of the dosage and frequency. (I am in my late 40’s). Don’t want to suppress immune function too much and for too long. How do I get started without feeling completely like a guinea pig?

        • From a scientific point of view, it would be great to get more hunan data points on this! And of course I hope you get positive results too Ole.

          You said you were at 2mg/ week Paul.

          That’s the dose I’m on. I’ve also experimented with grapefruit juice, which slows rapamycin’s clearance from the body (downregulates CYP3A4) Makes it more like 5 or 6mg/week I reckon, so I think you’re safe to increase the dose if you want, but I’d go easy on any other AMPK supplements if you do.

          • Thanks for the insights Mark, always greatly appreciated. I’ll try the grapefruit juice. The AMPK activator that I’m on would Be berberine to try to lower insulin and IGF levels. But it does fatigue some.

          • Hi Mark,
            Number 1 thing I tell everybody is don’t take rapamycin with grapefruit juice.
            Package says, don’t take with grapefruit juice.
            FDA warning says don’t rapamycin take with grapefruit juice.
            Number 1 principle of taking any medication, don’t take with something that interferes with metabolism.
            Number 1 thing that makes weekly rapamycin safe compared with daily rapamycin is metabolism to low nadir levels before next dose.
            Rapamycin is a prescription drug so the physician who prescribes rapamycin can tell patient, “don’t take with grapefruit juice.”

            Question: But what if I want to make rapamycin more dangerous, what can I do ?
            Answer: Take it with grapefruit juice.

          • Hi Paul,
            The idea is rapamycin as used in transplant medicine has a flat curve, take daily. Weekly dose has a steep curve. Usual half life @ 65 hours, so weeks @ once every 2.5 half lives.
            Use with grapefruit juice might increase half life to perhaps 168 hours.
            Now once a week is once every half life.
            Shifts from steep curve to flat curve.
            Net result of grapefruit juice, increase risk to impair activity mTOR2.
            So my guess is 2 mg with grapefruit juice weekly is more similar to 1 mg daily than 5 mg once a week.

          • Quite right Alan, best to be careful with prescription drugs so I shouldn’t advise others to use rapamycin with grapefruit juice. We don’t know exactly what that would do to the half-life curve. I can say on my part though, that it has not been harmful. Occasionally I get a mouth ulcers after multiple cycles, so I leave it an extra day before my next dose or take a lower dose. This is consistent with the rapamycin still being present in my system.But that has not happened for some time.

            Here is a relevant article

            ‘grapefruit juice harnesses the power of sirolimus’

          • Hi Mark,
            Didn’t read that article as oncology.
            However, using grapefruit juice with rapamycin and cancer is good idea. In cancer want very high levels. Frequent GI problems with high oral dose.
            With grapefruit juice can maintain higher levels with lower dose with grapefruit juice. So agree if Oncologist told you to take grapefruit juice with oral rapamycin it would be good idea to follow that advice and sounds very reasonable.

            As I said, I thought 2 mg a week with grapefruit juice was more similar to 1 mg daily than 5 mg once a week. One mg daily is very well tolerated dose although associated with increased risk mouth sores. I have had no mouth sores in 20 weeks; although mouth sores not worst thing and clear quickly when hold meds for 1 week.

            The main point is there is daily rapamycin and intermittent rapamycin. I am proponent of intermittent rapamycin for anti-aging. In intermittent rapamycin don’t like grapefruit juice as changes shape of curve from steep to more level. In this way lowers maximum dose you can take and raises nadir level before new dose.

            So all about shape of the curve you want for metabolism of dose. We both agree grapefruit juice slows metabolism rapamycin. To me, that is a bad thing with use in anti-aging; but might be good think in cancer treatment.

  17. Hi Aldebaran
    It could be done like this: a group of 20 people with cardiomyopathy that isn’t too severe, let’s say an ejection fraction of 35 to 45%. Half get placebo and the other half weekly rapamycin over a 3 month period.
    If we show a statistically significant improvement in the rapamycin group over such a short period of time ( using P values), I think that it would draw some attention, but the conclusion would be that it needs further study and with a larger number of participants and the results would need to be repeated.
    Now these are justifiable concerns, but now funding becomes a big issue and a repeat study would probably never be done.

    • Hi Paul,
      Very much welcome your input.
      I see study as partially self funded and outside funding for echocardiograms.
      20 random people 65-75. No clinical heart disease sufficient to require cardiologist, Not on digoxin. Not clinical heart failure.
      6 months, Echo before, echo after.
      No control.
      Results are statistically significant improvement ejection fraction and subjective improvement quality of life.
      Does that kind of study make a difference. Is it worthwhile to add expense 2 echocardiograms.
      Other problems with study: for various reasons there would be no IRB and so not able to be registered with government trials.
      Note at conclusion of Kaeberline study only 24 dogs; but everybody loves pet dogs.

      • Hi Alan
        Here’s a great example of it. In 2014 I read the following study: Belcaro G ” Pycnogenol and Centella Asiatica for asymptomatic atherosclerosis progression” Int Angiol 2014 33 (1) 20-26.
        They took a group aged 45-60 with group( iv ) atherosclerotic plaque lesions. The control group was instructed on diet and exercise only, whereas another group followed those recommendations as well as 100mg of pine bark extract with 100mg of gotu kola extract. Two common and dirt cheap supplements.
        They looked at the percentage of plaques progressing from class 4 to class 5 over a 30 month period. The control group saw a 21.3% progression over this period, the supplement group had an amazing 1%progression.
        Plaque progression was an incredible 95% less in the supplement group over the control.
        Do you think that that study ever saw the light of day? What percent of people with CAD are aware of this? How many doctors had cute little drug reps visit them with this news while offering free trips to the Bahamas? NONE.
        PS ( I take both daily and my coronary artery calcium score remains at zero)

        • Paul there seems to be consumers who read up on such backing studies and make their purchases. Horphag Research the Swiss company that is behind many clinical trials of their patented product Pycnogenal crossed $500 annual sales avg 15-20% growth yoy primarily with this one single product which they sell at $2,500/kg

          • I’m glad to hear it Akshay, but I still fear that most don’t know about it. Also, the gotukola piece is essential to stabilize the dangerous soft plaque.
            My patients sure don’t know about it.

          • @Akshay,

            spot on. You’re 100 right.

            Pycnogenol is ‘probably’ useless. However, Gotu Kola is fantastic. In addition it works very well for anxiety.

        • Hi Paul,
          Thanks very much; but hoping for more encouraging answer.
          As an aside, very interesting comment about pink bark and gotu kola extract. Everybody show know that it is destabilization of soft plaque that is what kills you in acute myocardial infarction. Stents of obstructing lesion will not save you from asymptomatic plaque that suddenly destabilizes.

          You dialed into the exact point I was afraid of regarding echocardiogram study. However, since everybody knows about Kaeberlein dog study, maybe if same results in human study could piggy-back onto Kaeberlein dogs.

          • Go to and get regular pine bark extract 100mg ( 300) count. Works the same and my partner and I have them all sent to an independent lab for verification of authenticity. Only $ 19.99 for 300.

          • Never know what to make of life extension. They do unearth some gems but then they sell the product at very high prices, while always claiming better absorbtion. They do reference all of their studies though. And they contribute to research.

          • Paul thanks for the suggestion. I tried and got this message from Vitacost
            “Certain products cannot be shipped to the destination country you have selected. Please remove the item(s) from your order to proceed with checkout. ”

            They will not ship to Australia ?
            That’s a bit stupid of Vitacost.

          • Paul
            I went to Iherb and got it there no problem. And not too pricey either. I did contact Vitacost by email but so far nothing has changed.

    • Hi Paul,

      I definitely understand the that if the larger study is not funded, it will be very frustrating and disappointing for the people who would have spent their time in doing the first study. This is a big concern. Thanks for clarifying.

  18. C60 update from ichors therapeutic:

    This explains the current status of C60 at ichors.
    As Mark said, they think that interim results on mice will be available early 2018.

    “Additionally — what we all care about — is whether or not the lifespan effects of C60oo reported by Baati are real. To this end, we have started a small lifespan study (initiated May, 2017) using freshly prepared, carefully quality controlled C60oo. Our animal model is a C57BL/6 BALBc F1 cross. Animals (n=10/group) are being treated with olive oil or C60oo in exact accordance with the Baati dosing schedule, starting at age 24 months. Although we typically prefer to run lifespan studies with n=35 or greater, we should achieve statistical significance with this group size if the lifespan effect is true. We have also begun building relevant IP around the space so that we can move forward with an FDA compliant translational pathway if positive results are observed.

    I will share interim results when one of the two groups (control or treatment) reach 50% mortality. We expect this to occur sometime around January 2018.”

    • I want to see this result replicated. But this is a little concerning: ‘We have also begun building relevant IP around the space so that we can move forward with an FDA compliant translational pathway if positive results are observed.’

      According to their website they already have a trade name ‘BuckyProtector’, a ROS Sponge.

      It’s C60 in olive oil for goodness sake. Say what you like about quality control, it ain’t that hard to make. I’ll get the equipment and make it myself before I pay FDA prices.

      • They said mice had 24 months at beginning of treatment (~720 days). They’ll reach 50% mortality relatively soon. I am not an expert but 900 days is quite old for a mouse no? Of course starting that late, they certainly don’t expect huge life span improvement but just any statistically meaningful improvement would be great.

          • Starting with older mice allow to complete the study quickly. My guess is that, they just want to know if C60 does something real as soon as they can. If they do see any statically life span improvement in this quick study, they’ll probably start another with younger mice to access the real potential. Ideally, they should have probably started both studies in parallel (with young and old mice) if their budget was not limited. This is the way I understand their motivation to start with old mice.

          • That makes sense, although with only 10 mice per group the life extension will have to be pretty big.

            Kelsey Moody was also saying they have an idea about why there have been difficulties replicating the original results, so hopefully subsequent work will reveal that too. I expect it is something to do with the Olive oil, which isn’t really a very stable delivery method. I expect they’ll use something else eventually.

  19. Off topic again, but has anyone seen this news from yesterday?

    ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy, Nature (2017) doi:10.1038/nature24016

    The whole picture isn’t clear but it looks like APO4 carriers’ microglia are reacting in a far more inflammatory fashion to tau that those with APOE2 or APOE3. I’m not sure whether this is because of the presence of amyloid beta clumps or not, but it may well be that the recent failed trials using immunotherapy to clear AB would be effective as a vaccine.

    • Not to say the study is uninteresting, but no person under 30 suffers from AD. What triggers the deleterious effects of these genes at a certain age? Michael Fossel proposed a very good metaphor over at his blog, that biological age is like the decreasing water level on a lake. Lower the level and rocks that were underwater now appear. APO4 would be like one of those rocks.

      It is also worth noting that microglia, like other glial cells, continue dividing through our lifetimes and suffer telomere shortening. A point that M. Fossel has also made many times.

      • I seem to recall reading a book on telomerase by Michael Fossel MD,PHD. In it he was a big believer in TA 65 if my memory serves me. I wonder if he still is? He certainly never associated long telomeres with cancer risk.

      • A few facts about AD pathogenesis.
        ApoE4 is devastating to microcirculation. Damage to microcirculation is major early step and can be demonstrated 20-30 years before dementia.
        During active disease microglia play large role to promoting disease through inflammation.
        If short telemeres were a major factor as regards microglia, short telemeres would mean less microglia etc.
        AD is an age-related disease because high mTOR is driving factor. As age-related disease because full blown pathology takes 20-30 to develop,

        • Many ways to look at this. Astrocytes help clear beta amyloid, so yes short telomeres are involved in the decline of clearance. MTOR drives excessive prolifiteration so will drive telomeres to shorten in these cells. It will also up production of amyloid beta in the non-dividing cells. So I see telomere theory of aging fitting quite well within the general MTOR model, and there effects on AD are interdependent not independant.

          • Hi Mark
            Glad you interested in AD, few more pathways
            Rapamycin blocks increased production Anyliod beta
            Rapamycin blocks steps causing hyper phosphorylation Tau,
            Amyloid beta and hyperphosphorylated tau then act as misfolded protein
            Misfolded proteins promote more misfolded proteins.
            Then microglia respond misfolded proteins with intense inflammation.
            The stage set for all this by destruction micro circulation . This step also blocked by MTOR especially in ApoE4 carriers.
            Anybody studying AD before understanding role of mTOR, obsolete concepts

        • Astrocytes clear amyloid beta and they proliferate so excessive MTOR could lead to short telomeres and therefore worse amyloid buildup. That’s in addition to the harm caused by short telomeres in microglia. So telomere theory of aging from Michael Fossel fits very well into MTOR framework on this case. MTOR could also drive greater amyloid production in non dividing cells too.

  20. Hi Mark,
    The ApoE4 has a very interesting disinformation side story.
    About 17% population has ApoE4 allele and these people at extraordinary risk for AD.
    The rest of population doesn’t really need to worry about AD as only 20% risk and median age of onset age 84. So lot more things to worry about like heart disease and cancer.
    But the small group with ApoE4 have @ 46% risk and age of onset 8 years sooner, around 76 median age. Having an almost 50% chance of getting AD at age 76 is reason to panic.
    However, just like the captain on the Titanic, nobody ever wants to tell people the truth as don’t want to cause alarm.
    So if look at statements from AD associations play down risk ApoE4 and say no reason for test.
    Now if all the carriers of ApoE4 knew they were carriers, they would be screaming, “we need prevention treatment”.
    And in this regard, known since 2010 that rapamycin prevents AD in very excellent mouse models of AD. And decreasing mTOR gene from 2 genes to 1 gene, also prevents AD in mouse models of AD. (after AD has developed rapamycin not any help). Just my opinion, but as a pathologist, the brain destruction in AD so great, I don’t think even God could cure AD. AD needs prevention.
    So does anybody here think they then did human trial to see if rapamycin prevented AD in people like prevented in mouse AD models, say a test on persons who are carriers of ApoE4 and at @ 50% risk.
    Right, No clinical trial on humans

  21. Akshay
    It may be smartest to use rapamycin on say every Sunday, and LDN on Tues., Thurs ., and Sat.., only.( for cancer prevention). They will be doing different things on different days. Might be safest and best approach, but only a guess on my part. And I’m often wrong.

  22. I am also thinking about taking weekly rapamycin myself. However, this is a tough decision because of all the possible side effects. In particular:
    – my skin might improve and my wrinkles might reduce
    – my heart function might improve as much as 30% in the worst case
    – I might avoid getting Alzheimer disease in my 80 or 90
    – in the long term, I might even live longer and in better health
    Fortunately, we have such a good health system that I am sure almost no doctor in the country would ever advise any of his patient to take weekly rapamycin

    • LOL, I can let you know where to find it Akshay without a prescription. Lots of hassle but after much work I now have several years of personal supply in my cupboard

      • Hi Mark
        I’m at this LDN symposium where there are very legit doctors, MD’s and PHD’s , from all over the world giving incredible accounts of how well this drug works.
        Cancer growth inhibitor
        you should really check it out.

        • LDN comments
          Checking out LDN in wikipedia, they didn’t have anything supportive about claims.
          As regards LDN symposium, I guess everybody there would like LDN or probably wouldn’t get invited. My impression is the higher the quality of institution and people doing the research, turns out to be inversely proportional to chance of positive results.

          My impression, LDN increases endophins so I would expect it to be “feel good” drug. As feel group drug could have “placebo-like” effects in that patients feeling good might honestly report improvement in symptoms.

          At any rate, my research about LDN was just a few minutes; so will have to wait for Paul to present some high quality research from symposium and whether Paul found other quality papers disputing those finding.

          I admit that I usually think most everything is crap, but as soon as I saw good data about NR, I did a 180 and purchased NR and took 500 mg today.

          • You need to check out THE LDN BOOK . Dr. Bihari had very well documented records of high response rates in cancer patients. Several studies on remarkable responses in crohn’s, ms , and fibromyagia. No money in this drug so will never have a large well funded study. The past chief of neurology at Hershey Medical Center gave data on both clinical response and MRI changes in MS patients.

      • Hi Mark,

        Thanks. Appreciate your offer. Are you confident that the stuff that you get is the real stuff with proper dosage?

        I will first try to convince my Doctor to prescribe rapamycin because it is the easiest solution. If this does not work (as I suspect) I will try to visit Alan or Paul (since I would prefer to see a doctor before taking the stuff). Only problem is they live far and I need to find the time to travel (which is kind of tough currently). If I cannot find the time, I’ll get back to you.

        Thanks again

  23. This symposium is a little dull right now so I’m scouring through Oncotarget, the journal where Blagosklonny is editor-in-chief, and came across this:
    Six Plant Extracts delay yeast chronological aging through different signaling pathways. Oncotarget. 7 (32) 2016 Aug 9.
    I recall Josh doing a post in 2015 on a possible anti-aging polypill where there would be additive effects. This study was quite convincing regarding these 7 plant extracts, both individually and in in synergy.
    Black Cohosh
    Celery seed
    Passion Flower
    White Willow Bark. This one in particular increased the mean lifespan of yeast by 475% and the maximal cls by 369% ! More than rapamycin did.
    This study got through the peer review of Blago and others, all of these PE’s are relatively harmless, and may have very significant effects.
    I will be adding these to my rapamycin and ldn

      • Yes it is but less chance of GI issues. If you look at the study showing life extension with ASA, it took a ton of aspirin ( at least in mice)

        • This reminds me the results obtained on mice with alphastradiol at ITP. Very impressive life extension on males but not on females (median ls increase 19% max ls increase 12%). Max ls increase was even better than rapa + met on males: (median 23%, max ls: 10%).

          Problem is: at the high dosage they use is it feminizing? Not sure how to interpret the following.

          “Although 17aE2 is generally thought to be ‘non-feminizing’, there is evidence that 17aE2 can have uterotrophic effects (Clark et al., 1982). 17aE2 at 4.8 ppm, as used in our previous report (Harrison et al., 2014), had no significant effects on uterine weight when fed to ovariectomized mice (Fig. S2, Supporting information, P = 0.44). However, we considered the possibility that it might be uterotrophic at the higher dose (14 ppm) used in our current study. We therefore tested for estrogenic effects of the 17aE2 at 14 ppm in young- and middle-aged ovariectomized UM-HET3 mice bred at UT. As shown in Figure S2 (Supporting information), the 14.4 ppm 17aE2 diet fed to ovariectomized mice for 6 weeks increased uterine weight to a level statistically indistinguishable from that of intact controls. Additionally, mice fed the high dose had mean uterine weights significantly higher than that of the ovariectomized control group (P = 0.0014).”

          • I think males should avoid anything estrogenic including black cohosh and even soy. The synergy of rapamycin with metformin has been discussed. I find metformin difficult to tolerate, but a lecture today by a prominent British oncologist, professor Angus Dalgleish, revealed that in cancer patients metformin is extremely well tolerated even at high doses. He discovered the CD4 receptor site involved in HIV by the way.
            In cancer patients he uses ldn, metformin,and cannabinoids with remarkable success, with or without adjuvant radiation and chemo.
            He has a remarkable theory about how cannabioids work in cancer. The cell death occurs after a patient has been on them for a while and then the substance is withdrawn. He believes that the cancer cells may get ” hooked ” on the cannabioids and then die from the withdrawal. Amazing theory from a very bright guy.

          • I was not aware that soy is estrogenic so I will try to avoid it.

            Interesting information about cancer. My understanding is that sugar is the primary energy source for cancer cells so I would think that anything reducing blood sugar should help such as metformin (but maybe it helps through a different mechanism). I have also learned from you about LDN as a possible therapy for cancer so no real surprise here. However, it is completely new to me that canabinoids can fight cancer as well.

            I hope Angus Dalgleish has patented its anti-cancer cocktail so that a company can be interested to finance all the trials.

          • Hi Aldebaran,
            Yesterday you presented an extremely interesting paper about how estrogens resulted in remarkable life extension in male mice.
            The maximum extension was 19% which compared very favorably to maximum life extension seen with rapamycin in male mice of 23% (2014 study)
            The substance used did not have a direct effect and appeared to be a pro-drug and required conversion into active form. They mentioned in female mice with functioning ovaries there was an estrogenic effect seen by increase size uterus. Female mice seem to already have beneficial estrogenic effect and their life span was not increased.
            In male mice the drug is probably converted into active estrogen in testis as testis makes estrogens. In female mice ovaries make estrogens but requires functioning ovaries, ovulation and production of corpus luteum which makes estrogens.
            The mechanism of action was not explained or whether estrogens had general anti-aging effect or specific anti-cancer effect.
            Other studies have shown interaction between estrogens and mTOR and so effect of life extension in male mice may be to lower mTOR. So estrogens and rapamycin may both lower mTOR; but by different mechanisms.

            Estrogens and testosterone are not female and male hormones. Both hormones are present in females and males in different amounts and both have very many effects.
            My general impression is testosterone stimulates mTOR and decreases lifespan and estrogen decreases mTOR and increases life span; however effect with estrogens can be mixed.
            If Paul thinks estrogens are harmful in males; then perhaps he could present some scientific studies supporting that claim. My impression is that in aging animals, testosterone is bad and estrogen is good as relates to life span.

    • Hi Paul,
      Big time thanks on this one.
      This is one remarkable paper. Open access paper. title “Six plant extracts delay yeast chronological aging through different signaling pathways, Lutchman.
      106 references.
      Needs intense study, but all products safe. Also signaling pathways in yeast generally conserved through evolution and present in mammals.
      Plants always like to say, “anything bacteria can do, plants can do better, we are the world’s best chemists.”
      This could be major.

      • Hi Alan,
        2017, News Center, Stanford University,
        “Caffeine may counter age-related inflammation”
        Go back to diet coke WITH Caffeine, no reason to drink crappy tasting caffeine free diet coke.
        And coffee lovers: everything about coffee is great including the caffeine.

Leave a Reply

Your email address will not be published. Required fields are marked *