Michael Fossel Michael is President of Telocyte

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.

 

July 20, 2016

Curing Disease: More Insight Instead of Mere Effort

 

Curing disease correlates with insight, not blind effort.

There is an eternal trade-off between insight and effort. If we think carefully, understand the problem, and plan, then effort is minimized. If (as too often happens) we think carelessly, misunderstand the problem, and rely on hope instead of planning, then effort is not only maximized, but is usually a complete waste. Lacking insight, we foolishly flush both money and effort down the drain. In the case of clinical trials for Alzheimer’s disease – and in fact, all age-related diseases – this is precisely the case.

The major problem is a naïve complaisance that we already understand aging pathology.

If there was a single concept that is key to all of aging, it is the notion that everything in our organs, in our tissues, and in our cells is dynamically and actively in flux, rather than being a set of organs, tissues, cells, and molecules that statically and passively deteriorate. Aging isn’t just entropy; aging is entropy with insufficient biological response. Senescent cells no longer keep up with entropy, while young cells manage entropy quite handily. At the tissue level, the best example might be bone. We don’t form just bone and then leave it to the mercy of entropy, rather we continually recycle bony tissue throughout our lives – although more-and-more slowly as our osteocytes lose telomere length. This is equally true at the molecular level, for example the collagen and elastin molecules in our skin. We don’t finish forming collagen and elastin in our youth and then leave it to the vagaries of entropy, rather we continually recycle collagen and elastin molecules throughout our lives, although more-and-more slowly as our skin cells lose telomere length. Aging is not a process in which a fixed amount of bone, collagen, or elastin gradually erodes, denatures, or becomes damaged. Rather, aging is a process in which the rate of recycling of bone, collagen, or elastin gradually slows down as our shortening telomeres alter gene expression, slowing the rate of molecular turnover, and allowing damage to get ahead of the game. We don’t age because we are damaged, we age because cells with shortening telomeres no longer keep up with the damage.

The same is true not only of biological aging as a general process, but equally true of every age-related disease specifically. Vascular disease is not a disease in which our arteries are a static tissue that gradually gives way to an erosive entropy, but an active and dynamic set of cells that gradually slow their turnover of critical cellular components, culminating in the failure of endothelial cell function, the increasing pathology of the subendothelial layer, and the clinical outcomes of myocardial infarction, stroke, and a dozen other medical problems. Merely treating cholesterol, blood pressure, and hundreds of other specific pathological findings does nothing to reset the epigenetic changes that lie upstream and that cause those myriad changes. Small wonder that we fail to change the course of arterial disease if our only interventions are merely “stents and statins”.

Nor is Alzheimer’s a disease in which beta amyloid and tau proteins passively accumulate over time as they become denatured, resulting in neuronal death and cognitive failure. Alzheimer’s is a disease in which the turnover – the binding, the uptake, the degradation, and the replacement – of key molecules gradually slows down with telomere shortening, culminating in the failure of both glial cell and neuron function, the accumulation of plaques and tangles, and ending finally in a profound human tragedy. The cause is the change in gene expression, not the more obvious plaques and tangles.

Our lack of insight, even when we exert Herculean efforts – enormous clinical trials, immense amounts of funding, and years of work – is striking for a complete failure of every clinical trial aimed at Alzheimer’s disease. Naively, we target beta amyloid, tau proteins, phosphodiesterase, immune responses, and growth factors, without ever understanding the subtle upstream causes of these obvious downstream effects. Aging, aging diseases, and especially Alzheimer’s disease are not amenable to mere well-intended efforts. Without insight, our funding, our time, and our exertions are useless. Worse yet, that same funding time, and exertion could be used quite effectively, if used intelligently. If our target is to cure the diseases of aging, then we don’t need more effort, but more thought. However well intentioned, however much investment, however many grants, and however many clinical trials, all will be wasted unless we understand the aging process. Aging is not a passive accumulation of damage, but an active process in which damage accumulates because cells change their patterns of gene expression, patterns which can be reset.

Curing Alzheimer’s requires insight and intelligence, not naive hope and wasted effort.

 

 

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.

January 20, 2016

Long Past Time

History provides perspective, probably because we keep repeating it.

Several hundred years ago, smallpox was the scourge of Europe. Treatment, such as it was, consisted of compassion, fluids, and a gamut of various herbs, bark, roots, and fungal preparations, none of which changed the mortality. The diligent healer of the late middle ages tried hard to find just the right plant preparation that would prevent or cure smallpox. By the late 1700’s there had been multiple cases of successful use of cowpox to vaccinate (from the Latin vacca for cow) people, with good results, culminating in Edward Jenner’s publication in 1798. Mind you, like many human discoveries, the process had actually been around a long time, if not particularly well known, well understood, or even believed.

Regardless of its provenance, regardless of its success, the major problem facing those who used vaccination to prevent smallpox was not technology, but common preconceptions. The idea of using an active biological agent – the cowpox virus – flew in the face of the common certainties about how to treat disease. Everyone “knew” that treatment lay in finding just the right plant, whether a root or a bark. Herbalists knew that if they worked hard and put enough resources into finding that perfect mixture of plant compounds, they could cure smallpox. The fact that they were looking in the wrong place, didn’t seem to occur to them.

Back to the future and listen to the echo of history.

We now know that we can reset gene expression in the microglia that play the key role in driving the pathology of Alzheimer’s disease. The data has been accumulating for 20 years, as have the numerous articles in the medical literature and the books and textbooks on this field. And yet, regardless of its provenance, regardless of its success, the major problem facing those who work to prevent and cure Alzheimer’s disease is not technology, but common preconceptions. The idea of using an active biological agent – like the human telomerase gene – flies in the fact of common certainties about how to cure Alzheimer’s. Everyone “knows” that treatment lies in finding just the right drug, whether monoclonal antibody or small molecule. Pharmacology companies know that if they work hard enough and put enough resources into finding that perfect set of molecules, they could cure Alzheimer’s. And once again, the fact that they are looking in the wrong place, doesn’t seem to occur to them.

The echo is hauntingly familiar. Once again, the advance of medicine lay (and will lay) not in finding the right herb (or the right antibody), but in finding a sophisticated and accurate understanding of the disease we are trying to treat. Just as nothing worked in the 18th century until we understood vaccination as a way of preventing smallpox and other viral diseases, so nothing will work in the 21st century until we understand resetting gene expression as a way of preventing and curing Alzheimer’s disease.

It’s time to start looking in the right place.

And it’s long past time to cure Alzheimer’s disease.

December 21, 2015

Alzheimer’s isn’t just forgetting, it’s forgetting our assumptions

The rate-limiting-step to innovation is assumption.

Often, we have the infrastructure, the knowledge, and even the intelligence we need to move ahead, but stumble and fall over our own assumptions. Why didn’t Europe use immunizations hundreds of years earlier than it did? Why didn’t we discover – and make use of – the steam engine in ancient Rome? Why did flight, electricity, or sailing ships come about when they did? Why not earlier? Occasionally, we lack a critical piece of technology, one that slows us down for decades or even centuries. Occasionally, it’s an odd piece of data, a fact, a small subset of knowledge.

And sometimes, it’s a simple lack of intelligence: we simply aren’t very smart.

One key to being not-being-very-smart occurs when we make the wrong assumptions. Again and again, we misunderstand the nature of reality, while assuming that we already understand completely. Physics was all but certain – just prior to the end of the nineteenth century – that we knew all of physics except for a few niggling little details, but those “little” details left room for quantum physics and, ultimately, an electronics revolution, hence cell phones, the internet, computers, and computer blogs, like this one.

Assumptions have a way of limiting our vision. Obviously we can’t fly because, after all, how could something heavier than air possibly stay up in the air? Yet tons of steel and plastic manage that feat every day throughout the world. Obviously we can’t sail around the world because, after all, how could you avoid falling off the edge? Yet once again, the assumptions about “the world” were a bit off the mark.

Our assumptions about Alzheimer’s disease are – albeit with a desperately tragic languor – slowly beginning to change. The change involves a set of related, but slightly different assumptions, that are finally giving way. One assumption is that beta amyloid and tau proteins, are the cause instead of a result. Another assumption is that the cause lies within the neurons, which are merely innocent bystanders. We likewise assume that the cause lies in the genes, looking harder and harder in the wrong location, while ignoring the role played by changes in gene expression. A final assumption is more subtle: when we look at pools of molecules, such as beta amyloid, we look at them as a static accumulation of damaged molecules. We completely ignore the hallmark of biological processes, the dynamic turnover of all such pools. We then go on to focus myopically on the damage and completely ignore the broader and more critical question: why does molecular turnover slow down as we age, thereby permitting the damage to accumulate in the first place?

Today’s new federal budget has a 60% increase in funding for Alzheimer’s research, bringing total funding ($936,000) to just short of a billion dollars. Next year’s NIH budget also calls for just short of billion dollars ($961,000) for Alzheimer’s funding. Given the money going into Alzheimer’s, the risk is not that we lack funds, but that we lack insight. We will be funding research on sensors, biomarkers, and nursing care. Of the money that goes toward finding a cure, some will be aimed at sleep quality, diet, inflammation, and genetics. But how much of this will be – ultimately – fruitlessly spent on projects that don’t cure Alzheimer’s disease? We need to spend, but spend wisely. Throwing money does not per se conquer a disease that steals the minds and souls of those we love. We need to throw it accurately.

We need to reassess our assumptions and look, very carefully, at reality. If we want to cure Alzheimer’s disease, it will not be solely a matter of good intentions, political will, and funding. It will be because, finally, we chose to understand how Alzheimer’s disease works.

And we chose to cure it.

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.

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.

May 6, 2015

Lymphocyte telomeres are not a good disease marker

A friend pointed out that a recent Danish study suggested that short telomere lengths in circulating peripheral lymphocytes account for about a quarter of the variance in mortality. Does this mean that lymphocyte telomere lengths (LTL’s) are really only a minor factor in age-related disease and mortality? Probably, but it’s not the important question. A better question is whether or not telomere shortening accounts for age-related disease and mortality, which it does.

In regard to the Danish study, I would expect that result. People seldom die directly as a result of immune senescence and to the extent that they DO die of immune senescence, the figure of 25% of the variance strikes me as about right. Most people die of vascular aging and there is no a priori reason) to believe (nor data to suggest) that the telomere lengths of the vascular endothelium have any direct relationship to the telomere lengths of circulating lymphocytes. People may have short endothelial telomeres in their coronary arteries and advanced vascular aging, without necessarily having short lymphocyte telomeres that show up when we look at the circulating blood cells. Endothelial cells (which cause vascular aging) are not the same as lymphocytes (which are involved in immune aging). Within any one patient, we would expect some correlation between the rate of telomere loss in one type of cell (endothelial cells) and the rate of telomere loss in a different type of cell (lymphocytes), but the correlation will not be high and will certainly not be causal. It’s disappointing to see large (and expensive) clinical studies that try to chase down lymphocyte telomere lengths and expect them to predict overall disease. Lymphocyte telomere lengths will be related to some diseases (cancer comes to mind, and the data supports this relationship) but not to other diseases. For those of you who would like to know more, read my biomarker paper for a partial discussion of this illogical thinking (Fossel, 2012). Whatever were they thinking (or NOT thinking)?

If we want to accurate predict (I’d rather cure) the risk of age-related diseases and death, we would need to acquire reliable measures of changing telomere lengths in, for example, the vascular endothelium and microglial    cells, as well as other cells and tissues. I’m sure that the circulating lymphocytes account for some of the variance in mortality, but not only can’t we restrict ourselves to lymphocytes, but there remain the (totally ignored) issue of circulating vs other, non-circulating lymphocyte reserves. Even if we can prove that lymphocyte telomere lengths (LTL’s) rise with a prolonged intervention (for example, using dietary change, telomerase activators, exercise, or other potential interventions), a peripheral increase in telomere lengths may still mask a decline in actual decline in overall telomere lengths as newer lymphocytes enter the circulation from the marrow and other repositories. The cells haven’t “become younger”, rather we are merely sampling a different set of cells.

My usual analogy applies here. If I were to sample the ages of the residents living in a single city block and find that over a twenty year period the mean age of the residents goes from 70 to 30 years old, that does NOT mean that we have made those residents any younger, only that the older residents have moved (or died) and that a totally different population of younger residents has replaced them. In fact the overall population of the city (or the country) may have undergone an increase in mean age, even if the particular city block that I measure shows a decrease in the mean age of its residents.

In a parallel fashion, when we measure circulating LTL’s, we are only measuring a single sample of circulating lymphocytes, not an entire population of the body’s lymphocytes. So even if I could prove a clinical intervention appeared to result in all of the circulating LTL’s getting longer, that doesn’t prove anything about the mean telomere lengths in the body as a whole. We certainly can’t claim that we have improved the immune function or “reversed aging” in lymphocytes. Such conclusions are not only invalid, they are naïve to the point of embarrassment.

If we really want to show that telomerase therapy can lower mortality or cure age-related disease, then we need to look at mortality and disease, not lymphocytes.

 

April 28, 2015

Telocyte Begins

Things are slowly beginning to move ahead on our project to cure Alzheimer’s disease. It’s clear that not only is the role of microglia slowly becoming accepted, but there are more and more investors who see an opportunity to help move biotech and medicine from the old paradigm (BAPP and Tau cause disease) to the new paradigm (cell senescence triggers a far more complex cascade than we had once thought). One example of this shift is the recent review by Boccardi et al (Boccardi V, Pelini L, Ercolani S, Ruggiero C, Mecocci P. From cell senescence to Alzheimer’s disease: the role of telomere shortening. Ageing Research Reviews 22:1-8, 2015).

On a personal note, we now have investors pushing us to move ahead with our Telocyte project and we have a commitment from one of the leading research organizations in the world to form a collaborative effort. Our intent is to move ahead with the remaining animal trials necessary to get an IND, then commence FDA-sponsored human trials. Those of you who are interested in either helping our effort or being on a registry of potential patients with early Alzheimer’s may contact me.

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?

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