Michael Fossel Michael is President of Telocyte

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

Filed under: Uncategorized — admin @ 10:15 am

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.

April 21, 2015

Biotechs on the Edge

An odd thing is happening in the world of biotechnology: an avalanche is starting.
The context is also interesting, for over the past twenty five years, a profound revolution has occurred in our understanding of aging. Where once we took aging for granted, we now reexamine the process, looking for a way to reverse it. Where once only the most avant-garde of researchers thought that perhaps we might someday learn to slow the process, now the belief that we can turn back the fundamental cellular processes has gradually become a tenet of the mainstream. Where once we looked at diet or hormones, now we look at cell aging; where once we looked at genes, we now look at epigenetics.
And where once we were pessimistic, we now see the logic behind optimism.
In my upcoming book, The Telomerase Revolution, I explain how aging works and how we can intervene to cure age-related diseases, but I also look back over the past twenty five years of biotech in aging research. Oddly enough, in every single case, the failures have not been due to flawed science, but to flawed human beings. Poor decisions, paranoia, an inability to believe one’s own data, distrust, poor public relations, bad business ethics, these are all the failures of flawed human beings, unable to avoid shooting themselves in the foot — often fatally, which is an extremely odd anatomic result, but there it is. Biotech death by foolish behavior.
And yet the science was solid.
So perhaps it’s not surprising that I finally see a new generation of biotech startups, all aimed at the holy grail of age-related disease: resetting gene expression in aging cells and thereby curing age-related disease. Perhaps it was due to the gradual growth of inescapable data, as mice and rats in Boston and Madrid have driven home the point that aging can be altered and that diseases can be reversed. Perhaps it was the coming-of-age of a generation who, when asked to explain aging, began their answers with a short explanation about telomeres and aging cells. Or perhaps it was simply about time that we got things right.
Whatever the reason, the avalanche is beginning. I see investors, lay people, entrepreneurs, and businessmen moving steadily to support biotech ventures aimed directly at resetting gene expression, resetting cell aging, resetting age-related disease, and doing what was assumed to be impossible a mere generation ago.
It’s an avalanche that — by 2020 — will demonstrate that we can not only commiserate about Alzheimer’s disease, but we can cure it. In most cases, we will not merely slow the diseases of aging, not merely fight them to a grudging standstill, but reverse their pathology. None of our current therapies for vascular disease, osteoporosis, osteoarthritis, or (least of all) Alzheimer’s disease are “disease modifying”. Our current therapies offer little solace and no hope of cure, yet a cure is precisely what the newest crop of biotechnology companies are pursuing. Of the growing number of biotechnology companies now on the edge of success, some will fail, but the avalanche is already heading down the mountain and it’s gathering speed.
It won’t stop until we get to the bottom of age-related disease.

April 15, 2015

Alzheimer’s, Microglia, Mitochondria, and Arginine

Every several weeks, I notice publication of yet another article trumpeting another aspect of Alzheimer’s. Where once it was APOE-4, AB42, or SS31 (an antioxidant peptide), more recent work emphasizes arginine metabolism in the microglia. The good news is that research community has — ponderously and hesitantly — finally begun to shift the clinical focus from the neuron to the microglial cells, a shift that many of us have been pushing for almost two decades. Neuronal damage was always the more obvious pathology, at least under the optical microscope, but it was never the underlying cause of the cascade of damage that results in Alzheimer’s disease. Gradually, we have come to realize that the microglial cells, and often vascular changes, play an early role in starting the avalanche of this horribly tragic pathology.
And yet, even now, it is frustrating to watch how much of the research creeps along, staring myopically down at trivial and secondary problems. It’s not so much that we see the trees and ignore the forest, but that we see the specific lichen on the specific root of a specific type of tree, while missing the interactions and overall pathology that drives the entire forest. The recent focus on arginine is a case in point, but SS31 is a parallel example. In the case of arginine, we notice the microglia; in the case of SS31 we notice the mitochondria, but in both cases we fail to look harder and deeper and we fail to understand the broad processes that drive these changes.
Mitochondrial dysfunction within the microglia is a good example. The dysfunction is not seen in germ cells, nor in young somatic cells, but is prominent in aging somatic cells. How can a germ cell lineage, carrying a line of 1.5 billion year old mitochondria, have normal function, while a somatic cell, having undergone a few dozen divisions in a few dozen years, suddenly have a dysfunctional mitochondria that was doing well for the last few billion years? Actually, we know the answer to that. Not only is it due to changing gene expression within the cell nucleus, slowing the production of many key enzymes needed in the citric acid cycle within the mitochondria, but we know that when we reset this pattern of gene expression in the nucleus, the mitochondria resume normal function. While the aging cell makes less ATP and a higher proportion of ROS as the damaged mitochondrial enzymes permit electrons to “slip” down the chain, but these changes are entirely reversible when we reset telomere lengths within the nucleus.
Nor does it stop there. Just as the aging cell begins to have a lower ATP/ROS ratio, so too do the lipid membranes begin to leak those ROS species, so too do our scavenger enzymes (like SOD) fail to capture those escaped ROS species, and so too do our cells fail to rapidly recycle the molecules damaged by those ROS species. And in every case, these four issues can be traced directly back to the slower turnover induced by a changing pattern of gene expression within the nucleus, which is orchestrated by a gradual telomere loss.
Such changes can be (and have been) reset in human cells, in tissues, and in animal models. So why not reset the microglial telomeres and cure Alzheimer’s?

April 7, 2015

Biotech and Alzheimer’s

At the moment, there are four companies planning human trials to reset telomeres using telomerase genes. In every case, the intent is to put the telomerase genes (hTERT and hTERC) into human patients in an effort to cure age-related diseases. Let’s look at the diseases and then the companies involved.
Essentially, all age-related diseases occur because of cell aging. In the cases of osteoarthritis (chondrocytes) and osteoporosis (osteoblasts and osteoclasts), this process is straightforward. In the case of heart disease, it’s a bit more complex: the heart cells don’t die because they age, but because the arterial cells age. The endothelial cells, that line your coronary arteries for example, divide, loose telomere length, alter their gene expression (which is the key to the whole cellular pathology), and become dysfunctional. The result is gross changes in the wall of the artery: cholesterol plaques, inflammation, mast cells, foam cells, and general histological mayhem. And when the artery gets clogged, or when clots break off, the heart (and other organs) pay the price. In the case of a heart attack, the heart is the innocent bystander, whose cells die not because they age, but because of the pathology in the vessels that supply them. Much the same occurs — indirect aging — in neurodegenerative diseases such as Alzheimer’s disease. The innocent bystander is the neuron, that neither divides nor ages, but which is critically dependent upon the surrounding cells, especially the microglial cells. These cells, responsible for metabolically supporting the neurons and clearing beta amyloid, for example, show the initial aging changes. Their telomeres shorten , their gene expression changes, and they no longer clear beta amyloid as well. This process — “microglial activation” — is the initial step in Alzheimer’s dementia and — like all other age-related disease — is ultimately the result of cell aging.
As we finally begin to understand age-related disease and the cell aging that causes it, we are faced with the obvious question. Can we reverse the process? At present, medical therapy has no way of altering the underlying disease processes of any age-related disease, whether osteoarthritis, osteoporosis, atherosclerosis, Alzheimer’s disease, or any other common aging condition. But what if we could reset gene expression, reset the epigenetic pattern to that of young cells? We’ve known that we could do exactly that — in the lab — since 1999, but can we do it in humans? A number of studies have shown we can do exactly that in mice and rats, particularly in Maria Blasco’s lab in Madrid, but what about human patients? How long must we wait to cure Alzheimer’s disease?
At present, there is a small Canadian company that has failed to “gel” (or get financing), a new biotech group in Seattle that intends to go “offshore” (if they can get financing), and two linked companies that intend to progress to human trials as rapidly as possible. These latter two consist of a US-based biotech company (Telocyte) and a sister organization (non-profit) in the UK. Telocyte is aimed directly — and solely — at curing Alzheimer’s disease.
Telocyte sees no reason to wait, nor should you.

March 17, 2015

Curing Alzheimer’s Disease

Filed under: Aging diseases,Alzheimer's disease,Uncategorized — admin @ 4:10 pm

 As I write this in March of 2015, there are 1,315 registered clinical studies of potential interventions for Alzheimer’s disease (see ClinicalTrials.gov). While it is hard to define clearly, many of these studies deal with nursing issues, rather than medical interventions aimed at preventing or curing the pathology itself. Of those that are testing potential medical interventions, the huge majority of the interventional compounds have beta amyloid as their primary target, while a very small minority have tau protein as their target. In all cases, such interventional studies have been disappointing until now and — given their assumptions — will continue to prove disappointing. Enormous amounts of money is still being funneled into fruitless clinical trial, based on fundamental misconceptions about the pathology of Alzheimer’s and about cell aging in general.

We use 21st century methods to test 19th century concepts.

Consider an apt parallel in how we once thought of other diseases, such as polio in the late 1940’s. A careful review of the medical literature of those days, much of it still on paper rather than electronic, is revealing.

Before the Salk vaccine, there was an almost universally pessimistic (an often unspoken) assumption that polio must be accepted. The question wasn’t one of cure, but of care. The most we could do was to improve iron lungs, leg braces, and nursing care. The medical literature addressed ways to improve pulmonary care for those in iron lungs and medical economists fretted over the likely future costs of long-term nursing care for polio victims. Few people, among them Jonas Salk, believed that the disease might ever be prevented or cured. Most people were wrong: polio is now rare.

More than half a century later, there is an almost universally pessimistic (and often unspoken) assumption that dementia is inevitable. The question isn’t one of cure, but of care. The most we can do is perhaps slow the inevitable decline, marginally improve memory, and provide better nursing care. The medical literature is full of ways to address beta amyloid deposition and medical economists fret over the likely future costs of nursing home care for Alzheimer’s patients. Few people truly believe that Alzheimer’s can be prevented or cured. Most people are wrong: Alzheimer’s may be prevented and cured.

The assumption that the best we ever can do is slow the inexorable decline of Alzheimer’s is based on a misconception about how cell aging — and Alzheimer’s disease — works. Both the logic of the pathology and a growing literature support the etiology of Alzheimer’s disease and other central neurodegenerative “diseases of aging” as beginning not in the neuron, but in the microglial. These cells show early cell aging prior to the clinical diagnosis of degenerative disease. The ability of microglia to clear beta amyloid declines, as does the general ability to support normal neuron function, and the result is gradual neuronal dysfunction and neuronal loss. Therapeutic interventions aimed at beta amyloid, tau protein, or the neuron itself, are missing the target. Such clinical trials will continue to be – predictably — disappointing. Aiming at beta amyloid protein and dying neurons can no more cure Alzheimer’s disease than we can cure polio with leg exercises and iron lungs. If we want to prevent and cure the disease, we must address the pathology where it begins, not in the cells that are mere innocent bystanders.

Over the next few years, it is our intend to show that we can both prevent and cure Alzheimer’s disease by running human trials that will reset gene expression and undercut the basic pathology of Alzheimer’s disease.

We invite your support.

December 9, 2013

Aging: philosophy and reality

Filed under: Aging diseases,Telomerase,Telomeres,Uncategorized — admin @ 3:57 pm

Aging: philosophy and reality

Michael.fossel@gmail.com

 

            What is aging?

            There are literally dozens of answers to that question, even if we restrict ourselves to purely academic views. In the days when I was the executive director of the American Aging Association, there were – or so it seemed – as many aging hypotheses as we had members of the association. Almost all of the ideas, however, had a few problems. For one thing, each hypothesis tended to explain only a limited area of observation, such as a select body of data (just somatic cells) or a narrow part of the biological world (just mammals), rather than being in any sense universal.

Many “theories of aging” excluded tortoises, hydra, plants, nematodes, lice, seaweed, mammalian fertilization, germ cell lines, clones, or anything else of real interest. In fact, many “theories” exclude everything except human aging, and usually not all of that. Too bad: looking at the exceptional and the broadest biological sample are how you get the most scientific insight. Some species, for example, never age in the first place, which many “theories of aging” ignore completely. The second problem was that most theories were actually inconsistent with the available data, particularly when you looked at the details. Wear-and-tear theories, for example, don’t explain the immortality of the germ cell line. The most damning problem however, was that most aging “theories” simply weren’t testable: they were interesting ideas, but you could neither prove nor disprove these ideas.

In short, they weren’t theories at all.

            A theory must be comprehensive, accurate, and testable. Even now, most “aging theories” are still merely observations or intuitive guesses about a narrow segment of our world. For example, some people believed that any animal had a limited number of heartbeats and that this figure somehow underlay all of aging. The fact that plants and some animals lack hearts and still age was somehow ignored, as was the observation that the facts were actually entirely inconsistent with the data. Heartbeats simply don’t predict aging.

Not that the idea made sense anyway.

            Similar problems underlay most other theories, even theories that – for no logical reason whatsoever – seem to have general acceptance among the public. Endocrine (and similarly the “vital substance”) theories of aging, for example, assume that the aging clock for your entire body lies in some set of endocrine glands, but if endocrine glands time aging in the rest of your body, then what times aging in the endocrine glands? And how do we explain aging in cells? How about animals or plants that lack the candidate endocrine glands in the first place? Of course, the data shows that endocrine replacement may or may not have benefits, but has no effect whatsoever on aging. So much for endocrines. The idea was premised on correlational observations, which would be like saying that since gray hair correlates with aging, we need only dye your hair and you’ll be young again.

            Well, perhaps not.

            Various wear-and-tear theories are no better, even if they suit our intuitions about entropy and how our cars, houses, and cell phones “age” over time. Actually, however, living things simply don’t undergo entropy the same way at all. There are a number of idea that are central to the idea of wear-and-tear – free radicals, mitochondria, cross-linking, lipofuscin, DNA damage, waste product accumulation, and others – but none of these remain credible explanations when arrayed against the data. For example, germ cells don’t age and cell aging can be reliably reset at the time of fertilization. So much for the universal nature of wear-and-tear as an explanation for biological aging. If cells merely undergo wear-and-tear and then fall apart with time, then why don’t these cells fall apart and why can we reverse the entire process quite reliably?

There is an entire group of evolutionary theories – the disposable soma, group selection, antagonistic pleiotropy, and others – that are reasonable enough if all we want is an evolutionary explanation. These provide teleology, but don’t explain the underlying biological processes that are occurring in the organism as it ages (or doesn’t). But when we ask these theories to explain the actual pathology of aging, they point vaguely at wear-and-tear theories and shrug. Good evolutionary science perhaps, but they miss the point. We would like to know exactly what does happen as we age, not why it should happen.

            While these notions fail to explain the available data – including the fact that fertilization resets cell aging, for example – the more daunting issue is that most of these explanations are not theories at all, but merely loosely-stated hypotheses.

The critical element to ANY scientific theory is that is must be disprovable.

I could tell you that “invisible and unknowable forces cause aging”, but if they are invisible and unknowable, then they can’t be proven or disproven. This is a faith, not science and certainly not an explanation of aging. I have every respect for faith, but faith isn’t science and faith doesn’t help me provide clinical therapy or offer a viable explanation for how to improve medical care when you get sick.

A good theory makes a testable hypothesis.

At the moment, there is only one theory of aging that meets our three criteria of being comprehensive, consistent with the known data, and testable. That theory – the so-called telomere theory of aging – is, unfortunately, rarely spelled out in detail and almost universally misunderstood in the first place. For example, many people assume that this theory suggests that aging is determined by telomere length, while in reality it suggests that aging is determined by a changes in telomere length.

The telomere theory of aging has so far been tested in cells and tissues and in both cases the results were consistent with the theory: when you reset telomere lengths, you reset aging, whether in humans or in animals, in cells or in tissues. The theory has also been tried in vivo, using an oral compound, and the initial results likewise support the theory. These various experiments underline the importance practical interventions over simplistic explanations: if you can’t change it, you can’t prove it. Science demands that a theory be testable; the medical viewpoint demands that a theory offer a potential intervention. If you can’t test it, then it isn’t science; if you can’t intervene, then it isn’t medicine.

Our intent is to test a theory, but far more importantly – to us and to everyone else – our intent is to offer interventions.

November 22, 2013

Extending Life, Not Misery

Filed under: Uncategorized — admin @ 6:37 pm

Extending Life, Not Misery

Michael.fossel@gmail.com

 

Most of us assume that aging equals illness.

To be honest about it, we don’t usually put it that bluntly and we often deny it, even to ourselves, and yet we tend to assume that unless we are struck down suddenly – an unexpected automobile accident, a sudden pneumonia, a fatal heart attack – we will gradually lose the ability to care for ourselves, lose the ability to live in our own homes, and lose the ability to enjoy our lives. Are we wrong?

What if we could cure age-related disease?

What if we could be older, true, but be as healthy as the average young adult? The assumption – aging equals illness – shows itself in how we respond to the question “Do you want to live to be 120?” Most of us don’t. The Pew Foundation, and then the Canadian Association of Retired Persons, asked this exact question. The majority of us said we wouldn’t want to live that long, even if people had access to “medical treatments that slow the aging process and allow them to live decades longer”.

But look carefully at what the question implies.

Most of us – having close friends and relatives with Alzheimer’s disease or who live in a nursing home – immediately translate the question from “do you want to live to be 120” into “would you be willing to live in a nursing home, unable to care for yourself, for another 30-40 years?” We make this translation unconsciously, but quite naturally: after all, that’s what it means to be that old, doesn’t it? When look at the question with this assumption in our minds, why would we want to live to be 120? Not surprisingly, most of us wouldn’t. Why would you – or anyone – want to be kept alive even longer, unable to feed yourself, unable to recognize your own children, and unable to enjoy life around you? Not surprisingly, most of us would prefer an easier fate, a sudden illness for example, rather than submitting to decades of nursing care.

But let’s change our question a bit.

Instead of “do you want to live to be 120 (in a nursing home)?”, let’s ask about a different outcome. Imagine that we could prevent Alzheimer’s disease, prevent heart disease, prevent osteoarthritis and all the “…the thousand natural shocks that flesh is heir to”. Imagine that you could have the health and function of a 30 or 40 year old. What if we could “turn back the clock” and prevent age-related disease? If you could have the health of a much younger person – even at 120 – what would you do then? Look at the question now, with different assumptions. The question becomes more interesting: “Do you want to live to be 120 if you could have the health of a young person?” It’s such an odd, such an unbelievable (beyond the pale?) question that most of us discount it immediately, and yet…

And yet perhaps it’s not so odd a question after all. As it turns out, a great deal of research shows that we may soon do exactly that. We can now reverse aging in human cells and in human tissues in the laboratory and at least one Canadian biotech firm is about to take the same approach in curing age-related diseases. They may well change everything you think you know about aging and disease. Older yes, but why not healthier as well?

The original question assumed a tragic end. At a very real level, the Pew Foundation was asking us if we wanted to be unhealthy for a longer time. A better question is whether or not we want to be healthy for a long time. It’s a much better question, particularly in light of what is about to happen to our ability to cure age-related disease.

Or try an even better version of the question. 

If you had only two choices, would you rather suddenly become 30 years old or suddenly become 90 years old? Would you like to have the health of the average 30 year-old  or would you want the health (and the health problems) of the average 90 year-old? What if you could live to be 120,  not by living longer in a nursing home, but by being healthy, living in your own home, and being free to enjoy an active life? But is this realistic?

It is if we can cure age-related disease, and we may soon do precisely that.

Some of us discount the question for other reasons, feeling it would be wrong to “grasp after youth”, yet we chose health every day, with nary a pause for thought. We even chose the mere appearance of health, even when it does nothing to improve our health. It’s not surprising that we should take antibiotics for pneumonia and replace our aging knee joints when osteoarthritis prevents our walking without pain, but we also dye our hair and pay a truly astonishing amount for Botox, when neither of these provides anything but an illusion.

Soon, however, we will be able to prevent and cure Alzheimer’s disease and regrow our own natural knee joints, so that they work as well as they did when we were young adults Would you want to play tennis at age 90 if your knees and your heart were healthy?

Until now, when it came to aging, the medical community has also tended to “answer the wrong question”. We still think of aging as inevitable and age-related disease as incurable. But the outcome is that we often discount disease in our elderly patients, treating them often as not only incurable, but invisible. Few of us would be callous enough to ignore the suffering of children, yet some of us have quietly ignored suffering in the elderly, perhaps not because we don’t care, but because we feel impotent in the face what we thought of as inevitable disease.

Research now shows that this view is naïve. Aging is not inevitable nor is age-related disease incurable. We need to take the results we have in cells and animal studies and go further: we need to eradicate the diseases of aging. Suffering is not inevitable, nor can we afford to ignore the elderly. Over the past century, we worked hard – and worked together – to cure polio and other common diseases of the young. Compassion for the young is common; an equal compassion for the old should be no less equally common. It is time to find out what compassion and hard work can accomplish.

It is time to save both our health and our lives.

November 12, 2013

Telomeres and Cancer

Filed under: Uncategorized — admin @ 4:09 pm

Telomerase and Cancer

Michael.fossel@gmail.com

 

 

Telomerase does not cause cancer.

The statement is accurate, but it’s not that simple nor is it a naïve concern.

Telomerase and cancer are clearly linked – telomerase has been called “the two-edged sword” with aging being one edge and cancer the other – and the question thus deserves a more complete and more sophisticated answer. As always, discussions that involve causation tend to miss the point, resulting in misconceptions and errors. Instead of asking about causation, consider a few questions that are far more practical and clinically useful:

          If we increase telomerase in somatic cells, would the incidence of cancer rise in an average group of healthy patients?

          If a patient already has cancer and we increase telomerase in their somatic cells, would that patient get better or worse?

          If we have a population of healthy patients and we wish to decrease the overall incidence of cancer, would it be better to increase or decrease telomerase activity?

These sort of questions are much closer to the nub of what we actually want to know, as they constitute useful clinical information, information that is useful to both the physician and the average patient. Putting it bluntly, if I want to be healthy, do I want telomerase or not? To answer just as bluntly, you generally want more telomerase rather than less, or to put it more accurately, you generally want longer telomeres rather than shorter telomeres.

The reason the answer is “generally” true is that elongating your telomeres – like almost every function in biology and every therapy in medicine – has both an upside and a downside. The upside is that longer telomeres stabilize your genome, and hence lower the probability of cancer. The downside is that – once you have a cancerous cell – cancer needs to maintain telomeres just to survive. In other words, long telomeres prevent cancer, but cancers require telomeres or they may spontaneously go into remission.

There is a balance of risk. If you don’t have cancer, you definitely want long telomeres. If you already have cancer, you would prefer it if the telomeres in your cancer cells would continue shortening and kill the cancer cell before the cancer cell kills the rest of you.

Consider why this balance occurs. In normal cells, the repair and recycling of cellular elements – in this case we can focus on DNA repair – depend on changes in telomere length: as telomeres shorten, DNA repair slows down. In the young cell, DNA maintenance is stunningly accurate and efficient. In the aging cell, DNA maintenance has become slipshod, showing decreasing accuracy and efficiency. In old cells, the genome is no longer defended as competently and the outcome is an increasing number of mutations and errors, leading to cancer. To put it simply, the longer your telomeres, the more stable your genome. As telomeres shorten, genomic stability falls and cancer incidence rises.

On the other hand, once a cell’s genome has accrued enough errors to become cancerous, there are still three internal cellular obstacles: DNA repair, the cell-cycle braking system, and telomere loss. If DNA repair fails (which occurs as the telomere shortens), then cell division is generally halted as the cell detects DNA errors. However, as the telomere shortens, the cell also becomes sloppier in applying the “brakes”: the aging cell is more prone to continue dividing even in the face of DNA damage that would halt a younger cell. This leaves the telomere as a final defense. In normal aging cells, shortened telomeres result in a failure to divide (or to put it more accurately: a slower rate of division, a decreased likelihood of continued division, and an increased likelihood of apoptosis or even necrosis). If the cancer cell no longer divides, then it isn’t a clinical problem. If it can’t grow, it can’t kill you. Unfortunately, there are a number of ways that cancer cells elude the problem of telomere loss, at least for a while, and almost all of them involve maintaining telomere length. Not surprisingly, telomerase is expressed in about 85% of human cancers and telomerase inhibitors are seen as potential cancer therapies. If we have cancer cells, then we would prefer it if their telomeres would be entirely lost, resulting in dead cancer cells. If you already have cancer and we re-extend your telomeres, that wouldn’t cause cancer, but it might increase the ability of your cancer to survive and metastasize.

In short, telomere extension might increase mortality in patients with a pre-existing cancer, but if patients don’t already have cancer, then telomere extension would prevent cancer from occurring in the first place. Neither telomerase nor long telomeres cause cancer, but either telomerase or long telomeres could permit cancer to grow once it gets a foothold.

To return to our practical questions, let’s construct some evidence-based, rational clinical advice for a hypothetical patient population. If a patient comes to us with a known prostate cancer, we would probably recommend against a telomerase therapy. This recommendation is not because telomerase causes cancer, but because telomerase therapy might increase the likelihood that the cancer would continue to grow and would metastasize. On the other hand, if a patient comes to us with no known cancer, we would recommend telomerase therapy to prevent getting cancer in the first place.

This is not a new therapeutic dilemma: it’s actually true of a great many other clinical options. Consider exercise: does it cause heart attacks or is exercise good for you? Most of us – both physicians and the general public – are in favor of exercise as a preventative action: patients who exercise are considered to be less likely to get a heart attack, for example. On the other hand, if a patient has just had a heart attack this morning, we certainly don’t recommend that they run a marathon this afternoon. Does exercise “cause” heart attacks or does it prevent heart attacks? Exercise doesn’t actually cause heart attacks, but it can contribute to them or trigger them if you already have enough atherosclerotic disease. Most of us, however, think of exercise as healthy, and with good reason.

Overall, telomerase therapy is – like exercise and with similar caveats – a beneficial clinical intervention, but one that must be discussed in context.

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