Michael Fossel Michael is President of Telocyte

March 20, 2018

Aging and Disease: An Index

For those interested in knowing where this blog is going (or where it has been), here is an index of all previous and planned posts for this series on Aging and Disease. Note that the planned posts may change as we progress.

0.1 Prologue

1.0 Aging, our purpose, our perspective

1.1 Aging, what is isn’t

1.2 Aging, what we have to explain

1.3 Aging, what it is

1.4 Aging, the overview

1.5 Aging, misconceptions

2.0 Cell senescence, perspective

2.1 Why cells divide

2.2 Telomeres

2.3 Changes in gene expression

2.4 Changes in molecular turnover

2.5 Changes in molecular turnover, most molecules

2.6 Changes in molecular turnover, DNA repair

2.7 Changes in molecular turnover, Mitochondria

2.8 Changes in molecular turnover, extra-cellular molecules

2.9 Cell senescence and tissue aging

3.0 Aging disease

3.1 Cancer

3.2 Direct and indirect aging

3.3 Skin

3.4 Immune system

3.5 Osteoarthritis

3.6 Osteoporosis

3.7 Arterial (vascular) disease

3.8 CNS disease

3.9 CNS: Parkinson’s disease

3.10 CNS: Alzheimer’s disease

4.0 Treating age-related disease, what doesn’t work, small molecular approaches

4.1 What doesn’t work, killing senescent cells

4.2 What works, lowering risks

4.3 What works, resetting gene expression

5.0 Telomerase in the Clinic

October 10, 2017

Should everyone respond the same to telomerase?

A physician friend asked if a patient’s APOE status (which alleles they carry, for example APOE4, APOE3, or APOE2) would effect how well they should respond to telomerase therapy. Ideally, it may not make much difference, except that the genes you carry (including the APOE genes and the alleles for each type of APOE gene, as well as other genes linked to Alzheimer’s risk) determine how your risk goes up with age. For example, those with APOE4 alleles (especially if both are APOE4) have a modestly higher risk of Alzheimer’s disease (and at a lower age) than those with APOE2 alleles (expecially if both are APOE2).

Since telomerase doesn’t change your genes or the alleles, then while it should reset your risk of dementia to that of a younger person, your risk (partly determined by your genes) would then operate “all over again”, just as it did before. Think of it this way. If it took you 40 years to get dementia and we reset your risk using telomerase, then it might take you 40 years to get dementia again. If it took you 60 years to get dementia and we reset your risk using telomerase, then it might take you 60 years to get dementia again. It wouldn’t remove your risk of dementia, but it should reset your risk to what it was when you were younger. While the exact outcomes are still unknown, it is clear is that telomerase shouldn’t get rid of your risk, but it might be expected to reset that risk to what it was several years (or decades) before you were treated with telomerase. Your cells might act younger, but your genes are still your genes, and your risk is still (again) your risk.

The same could be said for the rate of response to telomerase therapy. How well (and how quickly) a patient should respond to telomerasse therapy should depend on how much damage has already occurred, which (again) is partially determined by your genes (including APOE genes and dozens of others). Compared to a patient with APOE2 alleles (the “good” APOE alleles), we might expect the clinical response for a patient with APOE4 alleles (the “bad” APOE alleles) to have a slightly slower respone to telomerase, a peak clinical effect that was about the same, and the time-to-retreatment to be just a big shorter. The reality should depend on how fast amyloid plaques accumulates (varying from person to person) and how fast we might be able to remove the plaque (again, probably varying from person to person). The vector (slope of the line from normal to onset of dementia) should be slightly steeper for those with two APOE4 alleles than for two APOE3 alleles, which would be slightly steeper than for two APOE2 alleles. Those with unmatched alleles (APOE4/APOE2) should vary depending upon which two alleles they carried.

To give a visual idea of what we might expect, I’ve added an image that shows the theoretical response of three different patients (a, b, and c), each of whom might respond equally well to telomerase therapy, but might then need a second treatment at different times, depending on their genes (APOE and other genes) and their environment (for example, head injuries, infections, diet, etc.). Patient c might need retreatment in a few years, while patient a might not need retreatment for twice as long.


February 24, 2016

New Thinking, Better Therapy

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The problem with prediction is that everyone disagrees about the future (and don’t look ahead anyway). Most of us look backward and assume that the view will be just the same (but more so?) if we turned around and looked ahead. The wonderful thing about hindsight is that not only is it easy, but everyone claims that they knew it all along once they can look in the rear-view mirror, but why not look ahead?

Let’s turn around and, just for a moment, try to look at where we’re going. We are right on the edge of a revolution in human medicine, and it’s easy to see if you look forward, not backward. Most people, researchers included, don’t look forward. Not only do they disagree that we’re about to change clinical medicine, but almost no one realizes that the change is already in progress. Oddly enough, even those who think of themselves as “at the forefront” of medicine are usually still looking backwards. They still focus on genes, genomics, and personalized medicine – all useful, but all of them 20th century concepts with 20th century assumptions – and miss the immense shift going on in epigenetics and our fundamental understanding of age-related disease.

It’s a though we were to search for our lost keys in the one place we didn’t lose them and that we’ve already searched – unsuccessfully – for years. We spend billions (actually hundreds of billions) of dollars and endless human resources searching for the key to Alzheimer’s disease in the one place that it doesn’t exist, then, rather than looking in a far more logical place, we give up or – perhaps worse – continue to throw immense amounts of money into the wrong place.

Do we really have endless money to waste ensuring failure?

The problem is that we can no more use genomics to understand and cure age-related disease than we could have prevented smallpox and polio using standard pharmaceutical drugs. Just as we needed to change our concepts and our tools – using immunization to address viral illness – so to do we need to update our concepts and our tools to cure Alzheimer’s disease and the entire gamut of other age-related diseases. Small wonder that we haven’t a single effective agent that actually changes pathology of any of these diseases. Not a one.

We throw money at symptoms, we turn our back on diseases.

Unfortunately, this basic naiveté with regard to disease also has inertial costs. I was on a call today with a major global pharmaceutical firm, whose stated criteria for which approaches to try next against Alzheimer’s disease is, first and foremost, the “consensus of current researchers”, those same researcher who consistently fail to find any effective interventions, anything that alters the progress of these diseases. If everyone agrees to continue searching in the wrong place, small wonder when no one finds anything. Worse yet, using consensus (it’s the way we did it in the 20th century, so it’s good enough for the 21st century), they ensure that other researchers will search the same place and that we will continue to throw money at failed assumptions and futile trials, rather than trying to actually understand fundamental pathology, reevaluate our assumptions, and moving into the 21st century.

Finding a cure for Alzheimer’s is feasible, but only if we look in the right place. We need to stop looking in the rear view mirror and focus on where we are going. It’s time to understand the role, not of genetics, not of genomics, not of personalized medicine, but the ongoing revolution in epigenetics and what it tells us about Alzheimer’s and other diseases, diseases that we once thought impossible to cure.

Things remain impossible only as long as your assumptions ignore reality.


November 10, 2015

Singularity: Why We Age

I hope that all of you will take a look at the free chapter of my new book, The Telomerase Revolution, that has just been posted on Singularity: https://www.singularityweblog.com/why-we-age/#comments. If you find the chapter provocative, please buy the book and read it carefully.

The question of “Why we age” (the title of the chapter excerpted here) is not only a good question, but probably all-but-impossible to answer with any certainty. For one thing, it’s notoriously difficult to do really good, meaningful experiments in answering evolutionary questions. We are stuck using either descriptive cases or experimental models that have short lifespans and arguable relevance to the questions we are asking. Moreover, part of the problem in understanding why we age is that — until recently — we really had no idea what we meant by “age”. There has long been an (often unstated and unexamined) assumption that organisms simply age because of entropy and that specific genes (as opposed to patterns of gene expression) determined aging. Not knowing how aging actually happened naturally led to faulty conclusions about why it happened.

Is my suggestion about “why we age” the correct one? I doubt it, but I suspect that my answer is likely to provide a slightly more realistic start on a reasonable answer because it begins with a more accurate understanding of what we mean by “age”.  If we want to explain why infectious diseases evolve over time, then it helps if we know about bacteria, viruses, chlamydial organisms, fungi, and prions. Once we understand what causes infectious disease, we can talk about the evolution of microbial organisms; once we understand what causes aging, we can talk about the evolution of aging.


September 22, 2015

Telocyte begins

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Our new biotechnology company, Telocyte, is moving along, as can be seen in our website. Our mission is simple: we intend to cure Alzheimer’s disease. We have no intention of “ameliorating”, “slowing”, or “improving the care for” Alzheimer’s disease. Instead, our goal is to prevent and cure it entirely. No one should ever have to “Live with Alzheimer’s”, any more than — in the 1950’s — we wanted our children to “live with polio”. What we want is not passive acceptance but an active cure.

We intend to show we can cure Alzheimer’s.

Join us as we demonstrate A FUTURE BEYOND ALZHEIMER’S.


September 8, 2015

The Telomerase Revolution – a Countdown

On Tuesday October 6th, four weeks from today, The Telomerase Revolution will be released by its publisher, BenBella Books. The Telomerase Revolution is a lucid and complete account of what’s been going on in the field, from its beginning to the current revolution in our ability to treat age-related diseases directly and effectively.

Full Cover for blog

As many of you know, the book is a best-seller already, solely on the basis of the number of pre-orders, which is delightful if slightly astonishing. It’s been getting rave reviews both on the grapevine and more officially (on its cover and on Amazon) from scientists and physicians, including from Len Hayflick who called it “superb” when he first read it. The book is dedicated:

To those with minds open to logic and eyes open to data:

May others be as open to you as you are

to the world around you.


To those who, aging and suffering,

hear others tell you nothing can be done:

They’re wrong.


Intended for the educated public and not merely for the medical or scientific community, The Telomerase Revolution is broken down into eight chapters. The 1st chapter – Theories of Aging – describes “the hoaxes, the myths, and the scientific theories that don’t quite account for everything.” In the 2nd chapter — The Telomere Theory of Aging – I give “an introduction to the theory of aging this book proposes and its historical development, including a discussion of misconceptions about the theory”. The 3rd chapter – Why We Age – is “a short scientific detour into the evolutionary reasons why we age rather than live indefinitely like the hydra”.

In the 4th chapter – The Search for Immortality – I finally turn our attention away from theory and toward the practical aspects matter most, “applying telomere theory to clinical problems”. We learn about what has been going on in the world of biotechnology until now, as we tried to take telomerase to the clinic, as well as why some of these attempts floundered and why other attempts are finally succeeding.

The next two chapters give us a clear explanation of how all age-related diseases cause problems. The 5th chapter – Direct Aging: Avalanche Effects – explains osteoarthritis, osteoporosis, skin aging and other diseases, explaining “how aging cells cause disease in similar cells and tissues around them”. The 6th chapter – Indirect Aging: Innocent Bystanders – gives us a similar clear explanation of the more frightening (and fatal) diseases, such as Alzheimer’s disease and vascular aging (including strokes and heart attacks) by explaining “how aging cells cause disease in different kinds of cells and tissues”.

All of which is fine, but can we do anything about those diseases? The 7th chapter – Slowing Aging – is a practical discussion of “what people can do now to optimize health and lifespan”, as opposed to waiting for the upcoming revolutionary interventions. Those newer interventions are discussed in the 8th and final chapter – Reversing Aging – in which we realize that our ability to cure age-related diseases at the most fundamental level is not waiting in some distant dream, but rather is almost upon us now: “It’s coming soon, and it will change human lives, and society in astounding ways”.

We are about to change medicine forever, by curing diseases that we have long feared, granting compassion and new hope to those who now suffer. This book is but the introduction to the work, as many of us, particularly at Telocyte, take understanding and hard work, and use our knowledge and effort to create cures.

Join us.

August 11, 2015

Can Diet Prevent Alzheimer’s Disease?

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No. Then why do I even bring this up? Yesterday, a patient asked me if Alzheimer’s disease could be prevented (or made less likely) if you ate the “right” diet. It’s a question that strikes not to the core of the pathology, but to the depth of our fears.

Historical precedents offer useful parallels and one of the most poignant of these is the polio epidemic that drew to a close with the advent of the Salk polio vaccine in 1954. In the 21st century, few of us understand how terrifying polio was then. Polio is easy to prevent now, but in 1950, polio was a nightmare: rampant, frightening, and enigmatic. How could you keep your children from dying, from ending up on an iron lung, or from being permanently crippled by a sudden, unexpected fever, quickly followed by disaster?

Just as with Alzheimer’s disease now, we groped for straws then, trying anything we could think of to avoid our horror. Then it was children, now it is parents and ourselves, but the tragedy is equally ubiquitous and equally terrifying. Polio scared us then, Alzheimer’s scares us now. Ironically, many of the same remedies were hawked then as are hawked now, although we have gussied up the terms a bit. Then it was nursing care, muscle therapy, oxygen, and diet; now it is nursing care, music therapy, monoclonal antibodies, and … diet.

In 1951, a book, Diet Prevents Polio, argued that the right diet could prevent polio or minimize its consequences. People took it seriously then because there was nothing else that anyone could do to protect their children from death and disability.

In 2015, people wonder if the right diet could prevent Alzheimer’s or delay its consequences. Some people take it seriously because there is nothing else that anyone can do to protect themselves or their loved ones from death and disability.

Asking if diet can help is like asking if you can make your car last longer by having the right fuel. It’s true that having the wrong fuel can shorten the life of your car markedly, but the difference between normal unleaded and a more expensive version isn’t going to make much difference. The life of your care depends on whether the car is poorly made or the used car is a “lemon”, you never check your oil, you ignore the engine warning light, you have bald tires and never replace them, or you drive like a fool. Almost without exception, the car’s lifespan is determined by how it’s made and how you drive it, not by the fuel you use.

Medically speaking, there are bad diets (all sugar and no protein, for example) that will lead to medical disaster, including obesity, diabetes, heart disease, and any number of other problems, but no diet could prevent polio in 1951 nor prevent Alzheimer’s disease now.

If you wanted to prevent polio, we needed a vaccine.

If you want to prevent Alzheimer’s, we need a cure.



July 15, 2015

How Does Alzheimer’s Work?


Alzheimer’s disease steals our souls.

We lose our humanity when it destroys the neurons that make up a critical part of our brains, but why those neurons die has always remained a mystery since “senility” was first noted, thousands of years ago. Even in the past century, since it was first described clinically by Dr. Alois Alzheimer in a 1907 medical article, we not only haven’t cured the disease, we haven’t even understood it. In this blog, we will come to understand exactly how it works — and what can be done to cure it.

Part of the reason we are slow to understand diseases (and many other things, for that matter) is the tendency to engage in magical thinking. We identify an association, mistake it for a causation, and then we are mystified when our naïve interventions fail. This error may seem obvious, but we make this same mistake repeatedly in medicine and in other aspects of daily life. In the case of Alzheimer’s diseases, we repeatedly identify a protein, a gene, or another product, and we naively try to intervene, then are left clueless and shocked when our best efforts fail utterly. The classic case has been that of beta amyloid plaques, common in most cases of Alzheimer’s disease, when we try to remove or prevent their formation and then cannot understand why all of our interventions fail so spectacularly. There have been hundreds of human trials aimed at beta amyloid, for example, yet none of them have proven effective. Why not?

Alzheimers disease cascade

The reason lies in magical thinking: knowing that some diseases (such as Sickle Cell) are clearly a genetic disease, and knowing that there are genetic correlations with Alzheimer’s disease, we conclude that Alzheimer’s is also a “genetic disease” and that if we could only find just the right gene, we would know how to cure the disease. Unfortunately, Alzheimer’s isn’t a genetic disease. Despite all of the candidate proteins, genes, and gene locations we are still investigating, these are correlations, not the cause of the pathology. Whether we look at beta amyloid (and its precursor protein in several variant forms), presenilin, APOE4, R4YH, UNC5C, SORL1, CLU, CR1, PICALM, TREM2, A2M, GST01 & 02, BAB2, CALHM1, TOMM40, CD33, ADAM10, PLD3, or any of the dozens of other candidates (the list grows longer by the day), none of these “cause” Alzheimer’s disease.

Alzheimer’s is not a genetic disease, Alzheimer’s is an epigenetic disease. All of those genes (I just saw another one published this morning) contribute to the risk, yet none of them — not a single one of the identified genes — causes Alzheimer’s. To quote a previous blog, each of them is a tree, but Alzheimer’s is a forest. When we focus on trees, we forget the broader pathology of the forest.

To use another common analogy, each of the genes identified with Alzheimer’s is like a submerged rock. As we age, the problem is not the hidden genetic rocks — such as APOE4 — but the fact that the water level is gradually falling, until the hidden rocks become exposed and cause a medical shipwreck. Treating APO-E4 will not resolve the problem. Alzheimer’s is not caused by the amyloid protein itself, which is necessary to neuronal function when present in appropriate amounts, but to the failure of amyloid clearance by aging microglia. The aging microglia becomes less and less capable of recycling and maintaining appropriate levels of not only beta amyloid, but a number of other things a well. This becomes apparent earlier in those with an APOE4 gene, but the problem is ubiquitous and not restricted to a single gene product. APOE4 wouldn’t be a problem is the microglial function was up to snuff, as it is in young adults. As the microglia age, as the water level falls, we expose the hidden rocks — the barely sufficient turnover of amyloid proteins in the case of those with two APOE4 alleles. To extend the water analogy, consider the two most well-known of those hidden rocks: APO-E4 and APO-E2. The first (the more dangerous allele) is a rock that lies just a few feet under the water, while the second (the safer allele) is a rock that lies a bit deeper down in the water. Neither of these hidden rocks are a problem when the lake water level is high (i.e., when we are young and our microglial clearance of amyloid is high). However, as the water level falls (i.e., as we age and microglial clearance begins to fall due to epigenetic shifts induced by telomere shortening), we expose first the APO-E4 rock (particularly in those with two copies of the APOE4 gene) and then, much later in life, the APO-E2 rock (in those who are lucky enough to have two copies of the APOE2 gene). Nor are these the only hidden genetic rocks. The rocks include not only the long list of “Alzheimer’s genes” given above, but literally hundreds of other risk factors, factors that become increasingly exposed as our microglia age and fail to protect us. As we age, as the water level falls, we expose risk-after-risk, rock-after-rock, gene-after-gene until we run aground and our minds go down for good.

The solution is not to find each and every genetic rock and hope to prevent disaster by filing down the rocks one-by-one, but to simply raise the water level again. Once we reset gene expression — not only theoretically, but based on animal trials — the pathology resolves. When we go after the key causal element in the pathology, when we reset gene expression in the microglial cells, the neurons are no longer at risk. If we want to cure Alzheimer’s, we need to aim at the cause of the disease, not at the genes, not at the proteins, not at the tangles, not at the microaggregates, and not at the plaques. To date, not one of these approaches has been effective.

Alzheimer’s doesn’t begin in the neurons; Alzheimer’s begins in the microglia. The key to curing Alzheimer’s is not to identify genes, but to reset gene expression and the key to resetting gene expression is to use telomerase therapy.

June 23, 2015

It’s the Forest, Not the Trees

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Last weekend, a global entrepreneur asked me about the difference between much of the current research and what we’re doing. He cited the example of a particular compound (NAD+), but any number of other compounds could be given as examples. My answer was that most researchers are focused on their one particular tree and can’t see the forest.

Almost all current research narrows itself by looking at results, and ignoring causes. Imagine that I’m treating a patient with diabetic ketoacidosis by only treating one of their many metabolic results, such as a low potassium or an elevated blood acid level. Both of these results are typical in patients with life-threatening ketoacidosis, but neither of them is the cause of the problem. If I treat these results by adding potassium or lowering acid, will it solve the problem? No, not even close. That’s not to say that such narrow approaches don’t have benefits, but they don’t strike to the cause of the problem and they certainly don’t cure the patient. I may raise the potassium to normal levels, but I still haven’t made the patient healthy. In the case of severe diabetic ketoacidosis, giving potassium is fine, but giving hydration and insulin is better, and replacing the insulin-producing cells that made the patient a diabetic in the first place would be best of all.

Cure the cause, not the result.

We make the same error in trying to treat Alzheimer’s disease by thinking that it’s just a problem of beta amyloid deposits or tau protein tangles. What we should be doing is going “upstream” and asking why the deposits and tangles occur in the first place. Never mind the results, what’s the cause? It’s not surprising that all of the hundreds of human trials aimed at beta amyloid in Alzheimer’s disease have uniformly failed to modify the course of the disease. These trials attach results, not causes. We should be aiming at the microglial cell aging that initiates the process. I wish the best of luck to my colleagues who focus the results of disease, but they focus on single trees and they completely ignore the forest.

They go after diseases result-by-result, and tree-by-tree.

In Alzheimer’s disease research, focusing on arginine, tau tangles, APOE4, or beta amyloid is like focusing on specific instruments when we should be looking at the entire orchestra. We need to replace the score, but most current research is aimed at the specific instruments and saying that we need to replace the violin. And then the flute. And also the bassoon. And what about that oboe? And we almost forgot the piano! Oh, and don’t forget the piccolo. And the bass drum while we’re at it. Oh, my god, where’s that cello gone?

The reality is that if they’d just get the conductor (the telomere) to play the right score (the epigenetic pattern typical of a young microglia), then they wouldn’t have to deal with a hundred different instruments one-by-one, piecemeal and — if the truth be told — completely ineffectively. Whether we look at symphony orchestras or forests, the same answer applies. To put it back into the forest metaphor, the cure for Alzheimer’s lies not in a particular lichen growing on the funny-looking root on the northwest corner of one particular beech tree in the 186th quadrant of the forest, but in the entire forest itself.

It’s the forest, not the trees.


May 12, 2015

The Telomerase Revolution

My new book, The Telomerase Revolution, is now finished and is being copy edited by the publisher. Oddly enough, it’s already selling well in preorders. Amazon.com says that it is now the “#1 release in medical research”, which is a delightful surprise, since it won’t actually be published and available to the public until October. For those of you who would like to order a copy, here is the link to Amazon.com:

  • http://www.amazon.com/Telomerase-Revolution-Enzyme-Aging%C2%85-Healthier/dp/194163169X/ref=sr_1_1?ie=UTF8&qid=1426777801&sr=8-1&keywords=telomerase+revolution

The book is a careful and clear discussion of how aging works in cells, how it causes the clinical diseases of aging, and what we can do to cure age-related disease. There is a good clear chapter on vascular aging and neurodegenerative disease — especially Alzheimer’s disease — that a lot of reviewers find especially intriguing. Len Hayflick, the researcher who first described cell aging more than fifty years ago, calls the chapter “superb”. Matt Ridley, author of several best sellers including The Rational Optimist, Genome, and The Red Queen, says that he read the chapter with “real fascination” and tells me “I badly want to read more of the book”.

If anyone would like to do a book review, please contact me, and I will arrange to send you a review copy.

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