Michael Fossel Michael is President of Telocyte

February 1, 2018

Aging and Disease: 1.0 – Aging, Our Purpose, Our Perspective:

Aging is poorly understood, While the process seems obvious, the reality is far more complex than we realize. In this series of blogs I will explain how aging works and how aging results in disease. In passing, I will touch upon why aging occurs and will culminate in an explanation of the most effect single point of intervention, both clinically and financially. We will likewise explore the techniques, costs, and hurdles in taking such intervention into common clinical use in the next few years.

The approach will be magesterial, rather than academic. I do not mean to preclude differences of opinion, but my intent is not to argue. I will explain how aging works, rather than engage in theoretical disputes. Many of the current academic disputes regarding aging are predicated on unexamined assumptions and flawed premises, resulting in flawed conclusions. Rather than argue about the conclusions; I will start from basics, highlight common pitfalls in our assumptions and premises, then proceed to show how aging and age-related diseases occur.

Since this is not and is not intended to be an “Academic” series (capitalization is intentional), I will aim at the educated non-specialist and will usually omit references, in order to make engagement easier for all of us as the series proceeds. If any of you would like references, more than 4,200 academic references are available in my medical textbook on this topic, Cells, Aging, and Human Disease (Oxford University Press, 2004). For those of you with a deep intellectual exploration of this topic, I recommend you read my textbook. Ironically, my academic textboo is still largely up-to-date with regard to the patholgy and to the aging process in general, if not so with regard to current interventional techniques for human clinical use.

The first book and medical articles that explained aging were published two decades ago, including Reversing Human Aging (1996) and the first two articles in the medical literature (both in JAMA, in 1997 and 1998). There are no earlier or more complete explanations of how aging works, nor of the potential for effective clinical intervention in aging and age-related disease. Since then, I have published additional articles and books that explain the aging process and potentially effective clinical interventions. The most recent, and most readable of these (The Telomerase Revolution, 2015) is meant for the lay reader and is available in 7 languages and 10 global editions. For those of you who want to know more, I encourage you to explore this book, which was praisde in both The London Times and the Wall Street Journal.

Finally, the focus will be the theory of aging; a theory that is valid, accurate, consistant with known data, predictively valid, and testable. This will not be a narrow discussion of the “telomere theory of aging”, which is a misnomer, but a detailed discussion of how aging works and what can be done about it using current techniques. A factual and accurate explanation of aging relies on telomeres, but also must addrss mechanisms of genes and genetics, gene expression changes and epigenetics, cell senescence and changes in cell function, mitochondrial changes and ROS, molecular turnover and recycling, DNA damage and cancer, “bystander” cells and “direct aging”, tissue pathology and human disease, and – above all – how we may intervene to alleviate and prevent such disease. The proof is not “in the pudding”, but in the ability to save lifes, prevent tragedy, and improve health.

The proof is in human lives.

This theory of aging has several key features. It is the only theory that accounts for all of the current biological and medical data. It is internally consistent. It is predictively valid: for the past 20 years, it has predicted both academic research results and the clinical outcomes of pharmaceutical trials accurately and reliably in every case. These predictions include the results of monoclonal antibody trials in Alzheimer’s disease, as well as other Alzheimer’s clinical trials, other clinical trials for age-related disease, and animal research (in vivo and in vitro). Perhaps the most fundamental feature of this theroy of aging is that it is an actual theory, i.e., testable and falsiable. A “theory” that cannot be disproven isn’t science, but philosophy. Many of what we think of as “theories of aging” cannot meet this criteria. If they cannot be disproven, they are not science, but mere will-o’-the-wisps.

If the theory of aging has a single name – other than the “telomere theory of aging” — it might be the epigenetic theory of aging. Despite misconceptions and misunderstandings about what it says (both of which I will try to remedy here), the epigenetic theory of aging has stood the test of time for the past two decades. It remains the only rational explanation of the aging process, while remaining consistent, comprehensive, and predictively valid. When it predicted failure of an intervention, the intervention has failed. When it predicted an effective intervention, the intervention has proven effective. Whether it’s the telomere theory of aging or the epigenetic theory of aging, in this series, we will proceed to get our conceptual hands dirty and look carefully at what happens when aging occurs, why it happens, where it happens, and what can be done about it. We’re going to go at this step-by-step, going into detail, and showing why we can intervene in both the basic aging process and human age-related diseases.

I doubt you’ll be disappointed.

 

Next blog:       1.1 – Aging, What is Isn’t

January 23, 2018

Aging and Disease: 0.1 – A Prologue

Aging and Disease

0.1 – A Prologue

Over the past 20 years, I have published numerous articles, chapters, and books explaining how aging and age-related disease work, as well as the potential for intervention in both aging and age-related disease. The first of these publications was Reversing Human Aging (1996), followed by my articles in JAMA (the Journal of the American Medical Association) in 1997 and 1998. Twenty years ago, it was my fervent hope that these initial forays, the first publications to ever describe not only how the aging process occurs, but the prospects for effective clinical intervention, would trigger interest, growing understanding, and clinical trials to cure age-related disease. Since then, I have published a what is still the only medical textbook on this topic (Cells, Aging, and Human Disease, 2004), as well as a more recently lauded book (The Telomerase Revolution, 2015) that explains aging and disease, as well as how we can intervene in both. While the reality of a clinical intervention has been slow to come to fruition, we now have the tools to accomplish those human trials and finally move into the clinic. In short, we now have the ability to intervene in aging and age-related disease.

Although we now have the tools, understanding has lagged a bit for most people. This knowledge and acceptance have been held back by any number of misconceptions, such as the idea that “telomeres fray and the chromosomes come apart” or that aging is controlled by telomere length (rather than the changes in telomere lengths). Academics have not been immune to these errors. For example, most current academic papers persist in measuring peripheral blood cell telomeres as though such cells were an adequate measure of tissue telomeres or in some way related to the most common age-related diseases. Peripheral telomeres are largely independent of the telomeres in our coronary arteries and in our brains and it is our arteries and our brains that cause most age-related deaths, not our white blood cells. The major problem, howevere, lies in understanding the subtlety of the aging process. Most people, even academics, researchers, and physicians, persist in seeing aging as mere entropy, when the reality is far more elusive and far more complex. Simplistic beliefs, faulty assumptions, and blindly-held premises are the blinders that have kept us powerless for so long.

It is time to tell the whole story.

While my time is not my own – I’d rather begin our upcoming human trials and demonstrate that we can cure Alzhiemer’s disease than merely talk about all of this – I will use this blog for a series of more than 30 mini-lectures that will take us all the way from “chromosomes to nursing homes”. We will start with an overview of aging itself, then focus in upon what actually happens in human cells as they undergo senesceence, then finally move downstream and look at how these senescent changes result in day-to-day human aging and age-relate disease. In so doing, when we discuss cell aging, we will get down into the nitty-gritty of ROS, mitochondria, gene expression, leaky membranes, scavenger molecules, molecular turnover, collagen, beta amyloid, mutations, gene repair, as well as the mathematics of all of this. Similarly, when we discuss human disease, we will get down into the basic pathology of cancer, atherosclerosis, Alzheimer’s, osteoporosis, osteoarthritis, and all “the heart-ache and the thousand natural shocks that flesh is heir to”. We will look at endothelial cells and subendothelial cells, glial cells and neurons, osteoclasts and osteoblasts, fibroblasts and keratinocytes, chondrocytes, and a host of other players whose failure results in what we commonly think of aging.

I hope that you’ll join me as we, slowly, carefully, unravel the mysteries of aging, the complexities of age-related disease, and the prospects for effective intervention.

December 29, 2016

The Ethics of Gene Therapy for Alzheimer’s Disease

The Ethics of Telomerase Treatment

 

The rationale behind telomerase therapy was first published in the medical literature two decades ago1 and has been updated and supported in academic textbooks2 and a more recent book for the public3 as well. The theoretical basis was cogent, even twenty years ago, and evidence has continued to support the hypothesis since then, in human cells, in human tissues, in informal human trials, and in formal animal trials. The potential implications of telomerase interventions in human age-related disease are unprecedented, well-supported, consistent, and feasible. The surprise is not that this approach is practical, but that it has taken so long to get telomerase therapy into clinical trials.

The reasons for the delay are complex and subtle, but are part of human nature.

For one thing, the clinical use of telomerase requires a novel and more sophisticated understanding of the aging process itself – at the genetic and epigenetic level – than has been the case until recently. Whenever a new scientific paradigm comes into play – whether a geocentric solar system, biological evolution, quantum mechanics, relativity, or anything else – it takes time for us to outgrow previous, less accurate models and to accept a more complex, but more accurate understanding of reality. Reality is not a democracy and a consensus is no guarantee of truth.

Putting it bluntly: old theories never die, their proponents do.

A second problem is credibility. In the case of telomerase clinical trials, there have been a number of cases in which individuals or companies (impatient with the regulatory delays so common in modern drug development) have attempted “end runs” of social and regulatory acceptance. Unfortunately (and perhaps unfairly), these off-shore human trials are often judged as lacking credibility and this can also undercut the credibility of other attempts. If a company evades the FDA (or the accepted regulatory agencies in other countries, such as the EMA or CFDA) and runs small off shore trials their results are not only specifically disbelieved, but result in general disbelief, even of serious biotech endeavors that DO attempt to meet FDA requirements. Moreover, the companies that attempt “end runs” often seek publicity and the outcome can be a perception that while there is significant publicity, that’s all there is. Unfairly or accurately, the academic judgement becomes one of “incredible claims, but no credible data”. Fair or unfair, just or unjust, such is human nature and such is the nature of clinical research in today’s world.

A third problem is a general misunderstanding of the role of telomerase in cancer. Telomerase never causes cancer, although small amounts can be necessary to permit cancer. More striking, however, is the role of telomerase in genomic stability: telomerase upregulates DNA repair, drastically lowering the risk of cancer. Dividing cells – including cancer cells – require at least minimal telomerase, yet a significant presence of telomerase (and sufficiently long telomeres) is protective against cancer. Some have even suggested that cancer is a disease of the young, and attribute it to the presence of telomerase, but the clinical reality is that cancer increases exponentially with age and that this increase is directly attributable to the down-regulation of DNA repair due to telomere shortening. In short, telomerase can be used to prevent cancer.

A fourth problem is a naïve conception of the pathology that underlies Alzheimer’s disease (and other age-related diseases). Citing data on mice, genetically altered to express a human amyloid protein, they extrapolate the results to human Alzheimer’s patients without appreciating the complex cascade of pathology that actually occurs in humans, let alone the differences between mice and human patients.

Finally, some people argue with the ethics of treating Alzheimer’s disease in clinical trials at all, let alone by using gene therapy. One wonders whether they have ever spend a year or two watching a loved one slide down into the abyss. I have known hundreds, perhaps thousands, of Alzheimer’s patients and their family members. Almost without exception, most would do literally anything, try literally anything in an effort to find a cure. The pity of AD is that it is 100% fatal and there is NO effective therapy – at the moment. While few of us would risk an experimental gene therapy (even one as promising at telomerase) to treat wrinkles or osteoporosis (particularly since neither one is fatal), all of us would consider such therapy to treat Alzheimer’s disease. It is scarcely surprising that scarcely a day goes by without someone contacting me, asking about potential treatments for Alzheimer’s disease. These are not people who live in ivory towers, these are not people with a “degree in microbiology”, these are people who are deeply and personally affected by the tragedy.

They’ve BEEN there. They UNDERSTAND.

One critic of gene therapy noted that: “there are 7 patients killed by gene therapy clinical trials” (over the past 20 years). Compare this with the seven hundred thousand Alzheimer’s patients who died in 2016 alone of not having had gene therapy. Why would I choose to be one of 700,000 deaths per year?

For those of us who have spent decades treating dying patients, for those of us who have Alzheimer’s disease, and for those of us who are terrified by what is happening to those we love who have Alzheimer’s disease, the ethics of using gene therapy to try curing the most frightening disease on earth are clear enough.

The ethical weight lies on the side of compassion.

 

 

  1. Fossel: Reversing Human Aging (1996) . Banks and Fossel: Telomeres, cancer, and aging – Altering the human lifespan (JAMA, 1997). Fossel: Telomerase and the aging cell – Implications for human health (JAMA, 1998).
  2. Fossel: Cells, Aging, and Human Disease (Oxford University Press, 2004).
  3. Fossel: The Telomerase Revolution (BenBella Press, 2015).

May 12, 2016

Telomeres: Are They Worth Measuring?

It’s funny how often we make assumptions that are not only wrong, but that we are completely unaware of making. Having spent more than twenty years dealing with the clinical implications of cell aging, telomeres come to mind as an immediate example of this mistake.

Hardly a week goes by without another claim that some particular intervention alters telomere lengths in human patients. Without exception, they are measuring telomeres in peripheral white blood cells. It’s easy to get blood samples and measure telomeres in circulating white cells. Unfortunately, not only are these telomeres the ones that matter least, but (if you’re trying to prove the value of your intervention) they’re almost worthless.

Measuring telomeres in your blood to see how old you are is a bit like looking at your hat size to figure out how tall you are. Whether it’s your peripheral blood telomeres or your hat size, it’s still the wrong measurement for the job.

There are two problems with measuring telomeres in blood cells (even totally ignoring arguments about technical methods, unreliable laboratories, and the mean length versus the shortest lengths of those telomeres).

The first problem is that the blood cells aren’t the key cells when it comes to aging and age-related diseases. If you really want to know where you stand clinically, you should be measuring the telomeres in the endothelial cells lining your coronary arteries, the glial cells in your brain, the chondrocytes in your joints, or several other places more closely related to the most common (and fatal) aging diseases. Few of us are willing to have biopsies taken from our coronary arteries, our brain, or our joints, but just because we are a lot more relaxed about giving a blood sample doesn’t mean that the blood sample is worth getting. It barely reflects what’s going on in your white cells, let alone what is going to end up causing disease and death.

The second problem is a more subtle, but more important. It boils down to this: most of your white cells aren’t circulating in your blood and the ones that do circulate are changing and dividing all the time, making them a poor reflection of what’s happening to the stem cells in your marrow. I wrote an academic review article about this in 2012 and discussed it in The Telomerase Revolution, but let’s look at it here. Imagine you can instantly and accurately measure every telomere in the body, including those in the bone marrow and peripheral venous circulation. Oddly enough, you’d discover that the blood tests aren’t reliable indicators of what’s happening in the marrow.

Let’s say that you measure all of the telomeres at time A and again at time B. In between A and B, you use an intervention such as gene therapy, TA65, mediation, dietary change, or whatever you think might be effective. At time A, you find that the telomeres in the hematopoietic cells of the marrow are 12 kbp long. At the same time (due to stress, infection, poor diet, inflammation, and generally poor health habits) there is rapid peripheral turnover, cell division, and telomere loss in the peripheral blood. As a result, the mean telomere length in the blood sample is only 8 kbp.

We then intervene.

At time B, you find that the telomeres in the hematopoietic stem cells in the marrow are now only 11 kbp long (showing that the patient has gotten older). Also at time B, since we might now have lowered stress, removed infections, decreased inflammation, and generally made the patient “healthier” with whatever intervention we may have chosen, their peripheral cells are now turning over more slowly, dividing less frequently, and losing less telomere lengths once they leave the marrow and enter peripheral circulation, so that the mean telomere length in the peripheral blood sample is now 9 kbp.

We could claim (as many articles do) that our clinical intervention “lengthened the peripheral telomeres!” The truth is that our intervention didn’t lengthen anything and we’re deluding ourselves (and whoever believes our claims). The peripheral telomeres that we sample at time B might be longer than the ones we sampled at time A, but the telomeres of the cells back in the marrow now have shorter telomeres. Our intervention may well have made the patient healthier and we might actually have slowed down the rate of telomere loss, but we definitely didn’t lengthen any telomeres, no matter how proudly we pat ourselves on the back.

Peripheral leukocytes are routinely used to assess telomere lengths (which is fine as far as it goes) and then used to assess clinical interventions, which is overreaching. If we do serial measures of peripheral telomeres every few months for a few years, then the validity will increase somewhat, but peripheral telomere measurements (no matter how often you measure them) are intrinsically an unreliable and invalid biomarker for what we really want to assess, which is “whole body telomere changes” or at least “marrow telomere changes” (in the case of blood cells).

Most of the available literature which suggests that we can slow or reverse telomere losses is – if it’s based on peripheral blood samples – misleading at best and unethical at worst.

December 31, 2015

A Gerontological Reality

An odd thing came across my desk yesterday: a reminder that some people, without meaning to, encourage not only a sense of futility and gloom, but in their dark view of the world, they end up encouraging disease, including Alzheimer’s. In the middle ages, it was common to attribute disease and suffering to god’s will and, after all, who were we to intervene in what god intended? Labor pain, plague, and a myriad sufferings were – again with a sense of futility and gloom – accepted and instead of encouraging our fellow human beings to alleviate suffering, we actively suppressed the compassion that might have brought relief.

Now, we look back on the misguided superstitions of the middle ages as something we have – in our maturity as civilized human beings – outgrown. And yet, we haven’t grown up enough, for while we no longer blame god for our troubles, we are just as eager to ensure that we can’t solve them. In my recent book, The Telomerase Revolution, I suggested that not only could we cure Alzheimer’s disease and that we could make such care affordable, but that it would be more affordable than our current health care, both for the individual and for society. Far from being a treatment for the few, it would be a treatment for all. After all, why pay enormous costs for long-term nursing home care, when we could pay a small cost to be healthy? Far from further dividing us into “two kinds of human beings” (consider that we currently divide the old and the infirm, or those with Alzheimer’s, from the young and healthy), we could provide the gift of sanity and health to all of us, without regard to age, without regard to wealth.

The consequence? A healthier, more compassionate culture.

If this is a utopia, the it’s not the first one. Prior to the discovery of antibiotics, prior to the availability of insulin, prior to polio vaccine, each of these ideas were utopian, yet now they are merely reality. Or perhaps not merely, for these utopian medical advances saved lives. Oddly though, we have never lacked for naysayers, who once – as they now do for Alzheimer’s – view these advances with fear and trepidation, seeing not the joy, the love, or the improved health, but the “ruin of their hopes in an utterly alien world”. How does curing polio ruin hopes? How does curing Alzheimer’s give us an alien world? The ruin of hopes, the alien world is the world that Alzheimer’s patients live in now, along with their families who watch the premature loss of their loved ones (of which there are already far too many). Would anyone really want to live in a world without Alzheimer’s? Yes, most of us hope for exactly such a “utopian” world and some of us are working hard to make it a reality. Curing Alzheimer’s is an attainable dream, not a utopia and most certainly not a dystopia.

May you all have a happy new year, and may the coming years soon see a future beyond Alzheimer’s disease.

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 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.

July 20, 2015

Why Solanezumab Disappoints

Insanity is doing the same thing over and

over again and expecting different results.

                                    – Variously Attributed

 

[This blog was written and published on Monday July 20th, two days prior to the announcement of the results of Eli Lilly’s clinical trials of solanezumab for Alzheimer’s.]

 

Until now, there have been only two globally-approved drugs for Alzheimer’s disease (Aricept and Namenda), and neither of these have been shown to slow, let alone stop or reverse Alzheimer’s. Most current clinical hopes have been pinned to various attempts to use monoclonal antibodies to attack beta amyloid in the brain, and none of these have been shown to slow, let alone stop or reverse Alzheimer’s disease either.

At the current meeting of the Alzheimer’s Association (July 18-23, Washington, DC) there has been growing interest in the latest clinical trial of this disappointing approach, as Eli Lily announces (on Wednesday July 22nd) the latest results of using solanezumab (also called “Soli”), a drug which was a disappointment in its initial clinical trials. Nevertheless, and to the surprise of many, the FDA gave Eli Lilly permission to continue their phase 3 trials and expectations increased the price of the Eli Lilly stock as the upcoming announcement of the results approaches. Unfortunately (not only for the company, but for all of us), the results will be equivocal at best and certainly won’t show that we can slow, stop, or reverse Alzheimer’s.

Why not?

Why don’t any of the drugs that target beta amyloid have any effect on the underlying disease process? Why have all of the monoclonal antibody drugs — with Soli just the latest heartbreaking therapeutic (or non-therapeutic) disappointment — failed to stop the disease?

The unspoken assumption has been that beta amyloid “causes” Alzheimer’s.

Oddly enough, the assumption is false: beta amyloid doesn’t cause Alzheimer’s disease. Small wonder then when our attempts intervene in the wrong target fail every time. Mind you, beta amyloid is clearly implicated in the pathology and it clearly plays an important role, but to say that is “causes” Alzheimer’s is to confuse cause and effect. If we have a patient with an infection, a high fever, and an elevated white blood cell count, we wouldn’t blame the fever or the white cells for the infection. Likewise, it would be silly (and dangerous) to “treat” the infection by simply removing the patient’s white cells. Yet this is the same sort of logical error we routinely make with Alzheimer’s disease. We know that almost all cases of Alzheimer’s disease show amyloid deposits at autopsy (or now, using other tests, even in living patients with Alzheimer’s), and we know that amyloid deposits can damage neurons, but to automatically conclude that that’s the entire ball game is to go well beyond reality and enter the realms of wishful thinking (or insanity, if we were to believe the quote given above).

None of the clinical trials aimed at removing beta amyloid have ever shown efficacy.

The problem is that amyloid is the wrong target and monoclonal antibodies against amyloid are the wrong intervention. The current failure of solanezumab is simply one more in the list of such failures. If trying the same failed approach over-and-over is insanity, then sanity would be to try a new intervention, an intervention based on a sophisticated appreciation of the actual clinical pathology. In my new book The Telomerase Revolution, I not only discuss that more sophisticated view of the pathology, but how we plan to intervene in a more rational and effective fashion.

June 9, 2015

Epigenetic versus Genetic Disease

Last week I attended a global conference on aging research. The presentations were professional and thoughtful, as befits an organization of researchers with impeccable academic and clinical credentials. These are bright, well-educated people who work hard to understand not only the basic science that underlies aging, but the possible interventions that might cure age-related diseases. My role was to consider becoming their executive director and to discuss my thoughts on how to improve — and ensure the viability of — the organization.

Oddly enough, my biggest fear was that they might find themselves side-lined and outmoded by the plethora of advances that are leading the way, advances that promise to revolutionize both our understanding of aging and our ability to treat disease. I had the nightmarish image of a group of well-meaning and well-trained researchers who are blithely marching off the cliff en masse, happy and blind, certain of their small (and ultimately unimportant) piece of the aging puzzle.

The problem is that science changes.

Science has a history of progressing in straight lines until reality abruptly intrudes. We happily refined the epicycles needed to prove a geocentric universe until Galileo substituted a heliocentric universe. We happily refined classical physics until Einstein and quantum mechanics showed us a more complex reality. At the moment, in biology, we happily refine the genetics of disease, while most age-related disease is — as it turns out — actually epigenetic.

Whether we look at the role of APOE4 in Alzheimer’s disease, or the role of cholesterol metabolism is atherosclerosis, a careful view of the literature (and the pathology) shows us that these and other age-related diseases are not genetic in the classical sense. We might reasonably call sickle cell disease genetic, but Alzheimer’s disease is epigenetic. Where genetic diseases are relatively simple to understand, epigenetic diseases are a bit more complex.

An analogy that might help understand the critical difference can be found in my new book, The Telomerase Revolution. Imagine a large lake on which we speed back and forth during our lives. A few of us, unfortunately, have exposed rocks — genetic diseases — that tear out the bottom of our boat, ending our lives. All of us, however, have hidden rocks as well — epigenetic diseases — that are innocuous enough unless we lower the water level. In the case of aging, exactly such a lowering occurs: as telomeres shorten, they change the pattern and extent of gene expression. It is this epigenetic change — lowering the water level — that results in our increasing risk of disease as we age.

Now in the case of a strictly genetic disease — such as sickle cell, we might reasonably ask how we can “fix” the gene. In the case of epigenetic disease — such as Alzheimer’s — however, the problem is not the hidden rocks (the various alleles that associate with Alzheimer’s, such as APOE4), but the fact that the water level is too low. The way to cure Alzheimer’s disease is not to find each and every rock and try to “fix the gene, but to simply raise the level of the water again.

This is precisely the aim of genetic therapy aimed at telomerase.

May 27, 2015

Four Ways to Lengthen Telomeres

Many of you have asked about Helen Blau’s work at Stanford, using telomerase mRNA [FASEB Journal]. Helen sent me a copy of her article when it came out and I’m a serious fan of her work. As some of you know from my upcoming book, The Telomerase Revolution, there are four approaches to resetting telomeres: 1) put in a new telomerase gene, 2) activate the telomerase gene that is already in cells, 3) put in the mRNA (as Helen’s group did) for telomerase, or 4) put in the telomerase protein itself.

 

The first problem with mRNA is that the molecule is incredibly fragile and has a short half-life at body temperature, making it hard to work with in the lab (in vitro) and even harder to work with in patients (in vivo). The second problem (with both mRNA and protein) is that you only get one copy of the final telomerase enzyme, whereas if you put in the gene or activate the gene, you get multiple copies of the enzyme and a lot more “bang for your buck”. In short, mRNA is great, but has a low ROI, clinically speaking. The third problem, a recurrent one in this field, is that if you read either Helen’s paper or the slew of media articles and interviews since publication, the emphasis is always on treating “genetic disease” (such as one of the muscular dystrophies) rather than “aging disease” (such as Alzheimer’s). There is an unspoken and almost universal assumption that genetic diseases like the various muscular dystrophies are “real”, but aging diseases like Alzheimer’s aren’t true “diseases” at all, but they “just happen because things wear out”. This common assumption leads most researchers to focus on inherited genetic conditions exclusively and completely ignore normal aging processes and their associated clinical pathology – such as Alzheimer’s. Even when researchers DO focus on Alzheimer’s they operate on the assumption that it must involve a “bad gene” (such as APOE4).

 

Both assumptions are false, but are shared by most of the academic and medical research community, even if neither assumption is ever clearly stated or acknowledged. Since researchers “know” that aging is not a classic genetic disease, they are equally complacent in thinking that aging diseases cannot be treated by a genetic approach. The result is that almost no one approaches aging diseases in a practical way, using fundamental interventions such as telomerase mRNA, telomerase activation, telomerase protein, or – as in our case at Telocyte – telomerase gene therapy.

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