Ten Questions and Answers with Dr. Michael Fossel

Michael Fossel, M.D., PhD, is the author of The Telomerase Revolution, The Immortality Edge, and Cells, Aging, and Human Disease. He is the president and co-founder of Telocyte, a company that aims to use telomerase therapy to cure Alzheimer’s.

Dr. Fossel believes that the shortening of telomeres, the caps on the ends of chromosomes, is the fundamental process behind aging, and his most recent book makes a convincing case for it. You can read an explanation of the telomere theory of aging here. In essence, as telomeres become too short after repeated cell divisions, the cell is unable to clear damaged molecules, and ultimately enters a state of senescence, and this is responsible for aging.

As I read the book, a number of questions came to mind, and Dr. Fossel agreed to answer them.

If the theory holds true and the technology is successful, we could be on the verge of a huge breakthrough in aging. Dr. Fossel asserts in his book that within a decade or two, we will be able to extend human life to up to several centuries in length.

Below are my questions with Dr Fossel’s answers. I thank Dr. Fossel for responding to my questions.

1. Some components of an aged cell appear to be very difficult or impossible to degrade, for example lipofuscin. How would the resetting of telomeres solve this problem?

A. Actually, lipofuscin, like almost all molecules, is NOT a molecule that passively and gradually accumulates, but rather represents a dynamic pool in which it is continually being produced (anabolism) and broken down (catabolism). The reason that it increases in some cells is that the overall rate of turnover (both anabolism and catabolism) decreases and permits the gradual increase in the percentage of denatured molecules. Parallels are found in all other molecular pools (such as beta amyloid), both intracellularly and extracellularly, as well as in cell populations themselves (such as occurs in the dynamic turnover of bony matrix via osteoblasts v osteoclasts). In short, we need to remember that lipofuscin is not simply “garbage” that accumulates passively, but is actually a reflection of slower cell product “recycling”. The rate of that recycling is directly correlated to telomere loss: the shorter the telomeres, the slower the rate of molecular and cellular turnover. Once we increase telomere length, we increase gene expression, increase molecular turnover, and bring lipofuscin levels back to those typical of “young” cell function.


2. You write in your book about how the shortening of telomeres changes gene expression so that molecular turnover becomes slower and damaged molecules accumulate. Yet the pattern of gene expression changes, not merely slows, with some gene products becoming more abundant with age, for example TNF alpha. Why does a change in the pattern and not merely the rate of gene expression contribute to the accumulation of damage?

A. It always depends on the gene in question. In the case of most inflammatory gene products, for example, the result in increasing (and increasingly inappropriate) gene responses. Overall, most enzymes, for example those involved in DNA repair, show a decrease and almost all protein and other molecular pools (lipids and glycoproteins, for example) show a slower rate of turnover. In the case of many markers, however, such as inflammation, ROS (production, leakage, and concentration), the levels rise, often due (as with ROS issues) to the slower turnover rates of the enzymes responsible for those levels. The key is that gene expression CHANGES and while almost all direct changes are to lower gene expression, indirect changes are legion. If I, for example, lower the gene expression of one gene, it may well induce a secondary increase in the expression of a second gene. That’s the beauty and the complexity of epigenetic (as opposed to genetic) relationships.


3. Perhaps the most accepted theory of aging at the moment concerns the pro-aging effects of insulin and IGF-1 signaling. Can that be reconciled with the telomere theory? What are its shortcomings, if any, in your opinion?

A. That’s not a theory, has no logical supportive data, and is naïve. They look at a small segment of biology and (unsuccessfully and with internal contradictions) try to paste together a theory. It’s no better than trying to explain aging by reference to hormones or ROS alone: it fails to explain anything but the most myopic selection of data, clinical facts, or interventive predictions. Phlogiston was a better basis for physics and humors a better basis for medicine than is the attempt to explain all of aging on the basis of insulin and IGF’s.


4. Another theory has it that aging is a “quasi-program” (Blagosklonny), a continuation of the development program. Do you think this is plausible/correct? Does it conflict with the telomere theory?

A. Aging certainly isn’t merely something that “happens”, but I have a hard time fitting it into a single teleologically loaded word such as “programmed” or even “quasi-programmed”. Once we pick a loaded word like that, people (on both sides of the argument) stop thinking. It reminds me of the problem that occurs when we label (for example) penicillin as an “antibiotic”. We then stop thinking reasonably and begin to assume that it can’t be an anti-viral, anti-chlamydial, or anti-fungal agent. As you may know, penicillin is an excellent agent for causing seizures if applied to the vertebrate brain after removal of the meninges, yet no one thinks of it that way. In regard to aging, however, I would say that aging is NOT a continuation of “the” developmental program that takes an organism from zygote to adult. I would, however, say that aging has advantages to species adaptation and survival. Once again, however, I deprecate the use of the word “programmed” simply because it carries unintentional denotational baggage and misleads the discussion into the idea of teleology, as though nature “chooses” to have us age. Nature has no “intentions” and doesn’t “program” what happens to biological systems. That is wobbly thinking of the worst sort and makes me suspect that humans are incapable of facing reality at all. Nature simply is: aging occurs because some species that age are a bit more likely to survive (as species) that others that don’t. Things that survive, survive. That’s all there is to evolution.


5. What would you say would count as evidence against the telomere theory of aging?

A. There is no evidence against the telomere theory of aging, but there are a great many people who don’t understand the telomere theory of aging. They start with naïve misunderstandings, erroneously attribute them to “the telomere theory of aging”, find irrelevant counter-examples, and then declare victory. The most common example is telomere length. People note that some mouse varieties have longer telomeres and shorter lifespans than humans and conclude that the telomere theory of aging is wrong. The telomere theory of aging would actually say that telomere length per se has absolutely nothing to do with aging in cells or otherwise. Cell aging is NOT related to telomere lengths but to CHANGES in telomere length. In my book, I’ve cited several other examples of naïve criticisms, often based on either an ignorance of the theory or an ignorance of human pathology, but there are several other similar “strawman arguments” made that are not so much “evidence against the telomere theory of aging” as they are evidence against the knowledge and the logical abilities of those who espouse them.


6. Would you agree that interventions that result in good health, for example exercise or fasting, result in slower telomere shortening, and that conditions that cause worse health, say obesity or smoking, increase telomere shortening?

A. Yes.

7. You state in your book that within the next decade or two, we will be able to lengthen the human lifespan to perhaps several centuries. What is the ground for such optimism?

A. Theory, cell data, tissue data, and organism data. That includes both animal and human studies.

8. Is there currently a good way to lengthen telomeres or activate telomerase? Is there good evidence that TA-65 works?

A. There is fair evidence (not “good”, just “fair”) that TA-65 works in humans.

9. It seems to me that interventions that increase autophagy, such as intermittent fasting or the use of autophagy promoters like hydroxycitrate or resveratrol, are the best way we currently know to increase turnover of damaged molecules and hence to counteract the aging process. Would you agree?

A. No.

10. You emphasize in your book that cell division and not passage of time causes aging. Yet the accumulation of iron (and to a lesser extent other metals) promotes aging and disease, an effect which could be ascribed to the passage of time. The human body has no means of excreting excess iron. Wouldn’t this issue need to be dealt with in addition to lengthening telomeres?

A. Not true. The human body DOES excrete iron, it just has no ACTIVE mechanism for excretion and it can’t excrete excess iron beyond a fixed amount. There is passive excretion in both menses and stool, which roughly balance intake over the lifetime, but there is an overall imbalance if the menses are too great (iron loss) or if iron intake is even slightly too high (iron gain). In most healthy adults (even in old age) the passive loss of iron is sufficient to prevent an overall iron saturation.


Notes: Calorie restriction is currently the most robust means of increasing lifespan, and much of its efficacy appears to be due to increased autophagy, which breaks down and recycles damaged molecules. (Question 9.) Unfortunately, men and post-menopausal women do not have menses, and many adults have far too much body iron, as documented in my book. (Question 10.)


Leave a Comment:

Aaron says April 20, 2016

This is one of the more fascinating interviews I’ve ever come across. If I wanted anyone to see where modern masculinity has dissappeared into I’d link this.

But is TA-65 the only direct method to stop the shortening of telomeres?

    undercover slob says April 27, 2016

    Your comment itself is extremely fascinating. If only it came with a modicum of elaboration.

BC says April 20, 2016

I have followed telomere shortening theory for close to a decade, and believe that it holds quite a bit of merit. However, I also think that other factors are at work (notably, question 9 above). Dr. Fossel seems to have a hammer (telomere shortening theory), and thus views everything as a nail.

Daniel F says April 20, 2016

Glad Dennis inserted his views on Q9 and Q10 at the end. That was exactly my reaction as well when reading Fossel’s responses.

    P. D. Mangan says April 21, 2016

    Thanks, Daniel. I almost didn’t, on the grounds that I asked him, so he answered. But I believe he’s wrong and seemingly dogmatically dismissive – as for iron, he clearly doesn’t know the research. As a thought experiment, if glial cells in an Alzheimer’s brain, loaded with iron, had their telomerase switched on and rejuvenated themselves by higher molecular turnover, the iron would remain. Cells don’t normally expel iron from inside without hormonal signals such as from hepcidin, and even if it is expelled, it remains within the body. No amount of cell rejuvenation could get rid of excess iron, as I see it; in any case, Fossel does not believe it’s a problem.

    undercover slob says April 27, 2016

    I was curious as to why there was no immediate follow up to his flat disagreement to question 9. I mean, why not a simple, “could you expound upon that?” But Fossel did mention iron excretion through stools in addition to menses.

      P. D. Mangan says April 27, 2016

      Hi undercover, I put my questions to him via email. I suppose I could have followed up, but he’s a busy man and I was just happy that he deigned to answer anything at all. It’s not like I’m Joe Rogan or something.

Abelard Lindsey says April 21, 2016

It’e nice to see a blog associated with the male-oriented/alt-right/neo-reaction space take a pro-life extension point of view. Being in the life extension milieu myself, I am quite familiar with Dr. Fossel’s work (as well as Aubrey de Gray’s SENS work). So much of the alt-right/neo-reaction scene seems to be so hostile to the possibility of radical life extension (such as the recent “return of kings” posting). Good for you guys.

I’m wondering how to get the alt-right/neo-reaction scene to stop being so hostile to radical life extension (and cryonics, BTW)

BTW, my fitness program is very similar to that advocated here as well as my supplement regime.

    P. D. Mangan says April 21, 2016

    I think lots of people are, if not actively hostile, at least naive about life extension and haven’t given it much thought. Reminds me a bit of writing about the importance of IQ: you immediately get a chorus saying “IQ isn’t everything!” Of course it isn’t. Plenty of important things in the world to think about besides anti-aging, doesn’t mean it isn’t worth striving for.

      Abelard Lindsey says April 29, 2016

      Your point is valid. However, I still maintain that the whole manosphere/alt-right/neo-reaction blog scene is infected with too many deathist weenies. I have no use for these people at all. If “nature” demands my death, I have no use for it either.

      Abelard Lindsey says April 29, 2016

      I’m going to say it straight. I consider my life to be my highest moral value. I am interested in anti-aging life extension and consider myself a “transhumanist” (what a loaded term) for all practical purposes. I have no use for and will have nothing to do with any meme that questions my right to pursue my own life interests. If the alt-right people have a problem with this, they can shove it.

James says April 22, 2016

Frankly he comes across as a bit of c**t. Q3: he didn’t bother answering the question of consistency, instead offering bizarre comments on Insulin-Aging theory (“has no logical supportive data”… what does that even *mean*?). Q5: In good Popperian fashion, you asked what *would* count as evidence against his theory and he answered a different question, namely *is* there any evidence against. Q9: a literally pathetic reply. Q10: admittedly this question was a little ambiguous but he chose the least charitable way to interpret it (you meant there’s no specialised mechanism for removing excess iron but he interpreted the question as claiming there’s no mechanism for removing any iron).

And again frankly, in my experience, this is a typical reflection of the state of MDs and PhDs produced in the USA, including supposedly good schools like his alma mater Stanford. Poor reasoning, impoverished instincts, foggy vision. A total mess.

    P. D. Mangan says April 23, 2016

    Since Dr. Fossel was good enough to answer my questions, I din’t want to say much other than my two main areas of disagreement. But he does sound annoyed and dogmatic. In his book, he (for example) dismisses the paleo diet with arguments that have themselves been dismissed ages ago. (“Hunter-gatherers didn’t live very long, so the diet sucks!”) And here, ideas he disagrees with get similar cavalier dismissal. It seems like they must take an attitude course in medical school.

    undercover slob says April 27, 2016

    Quite clearly, you are claiming that the guy is an unabashed hypocrite…and he may be, but it didn’t see his answers as so misleading. For instance, I don’t consider his answer to #9 as “pathetic” so much as a follow up explanatory question needs to be asked. If he didn’t grant that, then it would have showed his true character. Furthermore, I feel that he did address the question in #10 as it was stated in both spirit and letter. Perhaps it’s just that he’s over rating the effect that stool excretion has in lowering iron.

    Thanks to both parties involved, I thought it made for an at once odd and intriguing interview. I would have like to have seen more, though.

Daniel J Antinora says April 25, 2016

Answer four is funny. He does exactly what he claims we shouldn’t do.

Stefan Sladecek says April 28, 2016

As a PhD-level biochemist myself, I’m a bit shocked about the highly dogmatic and single-minded answers of your interviewee, which appear to me mostly as a marketing call for his company.

Aging is such a complex process that every attempt to reduce it to just one cellular process, in his case telomere shortening, is oversimplification at best and non-serious science at worst. There are so many things deteriorating as we age, which do not have a common cause, that his approach is almost ridiculous.
The interviewee has a point that its not the course of time, but cellular divisions that cause aging. But you cant have (healthy) life without cellular division. One of the hallmarks of aging is reduced cellular division, which automatically means reduced regenerative capacity. If you stop cells from dividing, you dont regenerate any more. Thats just a fact.

For all scientifically interested people, I highly suggest reading this review from Kroemer and colleagues (which I know PD Mangan is also a big fan of), in which the manyfold aspects of aging are nicely laid out

While it pays to study all molecular, cellular and organismal aspects of aging to hopefully find ways to delay it (for which caloric restriction and intermittent fasting is a supreme, cheap and natural way), it is naive to postulate that we will be able to expand our lifespan to centuries in the near future or even ever.

I hate to break it to all people which take themselves so important that they dream of living several hundred years, but lets face it: We are not made for this. Birth, growth and decay are fundamental aspects of life and a regular generational turnover is in the highest interest of the species.

While it is obviously not in our personal interest to age and decay, that’s why is needed for the species to survive…and let’s face it, nature doesnt give a shit about individuals, but on the other hand each species has an intrinsic strong will to survive at all cost. But that also implies that we all have to die to make way for the generations after us – and its okay like that and also a duty which we have towards our children and grandchildren.

Dont get me wrong: Aiming for an optimized lifestyle which permits delayed aging, extension of healthspan and probably also a few years of lifespan is definitely worth it and and I do that myself as well with great results, but there is general agreement in the scientific community that our biologic constitution allows us a maximum of ~120 years

    Ollie says April 28, 2016

    I appreciate the link and I concur that the answers presented by Fossel were indeed dogmatic and single minded. I also agree that the average human body, as presently constructed, can hope for an age of 120 years at the very best, given current standards of medical intervention.

    That said, the idea of a set limit of 120 is not necessarily defensible by ideas of technical limitation, nor can it be defended on the grounds of characterizing it as a duty to some nebulously defined future generations.

    We are apt to look at birth, growth and decay as fundamental aspects of life, but on further examination, we find that they are more interconnected and complicated than we would have hoped. There have been many constructs that we ascribed to fundamental and immutable aspects of nature, until striking counter-examples presented themselves, and changed our understanding for the better.

    As Kroemer and many others point out, there are far more factors involved in the aging process than just telomere shortening. As time goes on, a more coherent and comprehensive view of how aging works is developing. I have no doubt that we will one day glean truly effective clinical interventions from this research, but for now the science is still in its infancy. It’s easy to look at the complete hogwash often associated with life extension as well as the very paltry effectiveness of what does work and look on it with disgust. Personally, I find any kind of study that fails to establish a definitive mechanism of action to be close to useless. That research finds its home in supplement pitches and breathless Daily Mail articles. That said, even this caliber of effort is helping pave the way for a better understanding of what it really means to be “old”, at least on a biomechanical level. When we truly understand the nature of the problem, we will be able to build real solutions.

    Of course, my description of individual aging as a “problem” is begging another question, as you so aptly imply. Nature doesn’t care about individuals, and the survival of species is the driving principle in biology, so individual longevity isn’t necessarily a virtue. For this, I counter with a question of my own. The idea of a regular generational turnover being in the highest interest of the species is a supposition that bears closer examination and consideration. Certainly, we have organisms with exceptional generational turnover, and that turnover has wrought concurrent success in population count and geographic distribution. Reflect on the fact that those wildly successful species are primarily mere microbes, microbes with rather limited lifespans.

    I look at the idea of dramatically increased in human lifespan not as an evolutionary dead end, but an opportunity – a further refinement – in an evolutionary path that may ultimately end “humanity” as currently defined, but leave a genetically connected and far fitter successor species in its place. Now, there’s a lot of bombastic conjecture associated with the idea of “transhumanism”, but lets toss out the Kurzweil-machine-consciousness-singularity stuff out and focus on what we do know about biology. The biological characteristics of every organism on this planet were developed over countless generations. That generational progression is largely stable over time, but it can be subject to forces that create significant changes with the passage of time. Evolution has happened, it is happening, it will continue to happen, and we are not exempt. With the power of genetic engineering and medical intervention, the evolutionary path of an organism is no longer beholden to the slow process of reproductive sorting. With that in mind, we must ask the question of how the future of mankind will look. Certainly, there is a real possibility that a species like ours could thrive with an even shorter lifespan, provided it made up the deficit through reproduction. There is also a possibility that the trend could go in the opposite direction, with higher lifespans and lower reproduction. Perhaps the real duty to future generations is not to leave them to repeat endlessly the short lifecycle we have now, but give them the time and ability to live and grow beyond our current limitations. In other words, do we want to simply create future generations, or would we like to have better, smarter, wiser, longer-lived future generations?

      Stefan Sladecek says April 29, 2016

      Although I like many of your thoughts, the concept of “transhumanism” is nebulous at best to me, as ending sexual propagation would definitely be against the interest of our species. With all due respect, but the concept is very egotistical, as it neglects the fact that the wheel of life should and has to continue to turn and turn and turn…

      Moreover, even if we would still propagate, how about the fact that women’s fertility declines beyond 30 and ends at 50. Now you may tell me that using future biological engineering, we may extend the reproductive age as well, but is that really something you see as desireable – 70 years old women having babies?

      For sure, with some future interventions, we can squeeze out some extra years on average, but our biologic facts wont change through that. And even IF we would engineer our genome in a way that it is transmitted to following generations, it wont be that easy (moreover bearing in mind that in your concept, we wouldnt really reproduce anymore and thus could not transmit possible genetic advantages to next generations).

      In all honesty, the idea of re-engineering our genome isnt appealing to me at all, rather a horror-story of genetic freaks. And even IF it would work to for example introduce “longevity genes” (which dont exist as such, but just to exemplify my thoughts…), we can exchange our whole genome with optimized DNA-sequences.

      Dont forget: In your VW, you can upgrade to a better motor and do some other kind of tuning, but at the end of the day, its still a VW, not a Mercedes – I hope that analogy makes sense

neven says April 29, 2016

To push your analogy a bit further – if you keep replacing VW parts long enough, eventually you will have a Mercedes.
I think it is presumptuous to assume that we can never escape some basic written-in-stone tenets of evolution. We can argue about a time-frame, but never-ever? Not even in 100 years? Can you even imagine what technology will be like then? I mean, we can almost make biological organs now, and that is just a tiny sliver of things to come. I think when one dogmatically argues that we will never be able to live forever, this gives theories (however well they approximate reality now) a God-like status, which is not much different from what religion does.

Practically, the only thing that really matters is whether we can manage to reach the actuarial escape velocity for our own age group. I may or may not, but it is definitely worth trying.

    Stefan Sladecek says April 30, 2016

    But thats exactly the point…you exchange ALL parts, but the frame/chassis is still a VW…

    I fully agree that it is worth trying to take every lifestyle-measure to extend your life to the max, but if everyone would start to get replacement organs all the time (leave apart the fact that it is unlikely to ever be feasible on a large scale), we would waste so much financial and other resources to keep people, which are biologically meant to decay, alive.

    There is surely a lot of technology ahead that we can not even dream of, but living forever will always remain a dream. A very egotistic dream that is, as it would mean the end of evolution, those few generations would be the last ones , live on forever and thats it…dream on

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Harry Krehm says October 17, 2017

We were corresponding earlier this year but I unfortunately lost your email address.. Dr. Oz had a physician on his TV show who was advocating as a cure for Alzeimers , to put the patient into Ketoacidosis by diet, what is your take on this?

    P. D. Mangan says October 17, 2017

    Hi Harry, my take is that a ketogenic diet is the way to go for Alzheimer’s. Ketoacidosis is a pathological state though which no doctor would deliberately put anyone into.

Harry Krehm says October 17, 2017

As a follow-up to my recent e-mail the author of “the End of Alzeimer’s” was Dale E. Bredsen, MD who you are probably familiar with.

    Harry Krehm says October 18, 2017

    Sorry am I confusing a ketogenic diet with ketoacidosis?

      P. D. Mangan says October 18, 2017

      Yes. Ketoacidosis is a pathological state seen in type 1 diabetcs and it results in ketone levels about 20 times higher than in nutritional ketosis, as well as a drop in blood pH.

        Harry Krehm says October 19, 2017

        Thanks for the explanation– and here’s my joke for the day. ” this contender won a gold medal at the Olympics—he was so thrilled he had it bronzed!”

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