Michael Fossel Michael is President of Telocyte

December 1, 2017

Big Pharma: Still Looking for the Horse

About a century ago, in a small American town, the first automobile chugged to a stop in front of the general store, where a local man stared at the apparition in disbelief, then asked “where’s your horse?” A long explanation followed, involving internal combustion, pistons, gasoline, and driveshafts. The local listened politely but with growing frustration, then broke in on the explanation. “Look”, he said, “I get all that, but what I still want to know is ‘where is your horse?’”

About three hours ago, in a teleconference with a major global pharmaceutical company, I was invited to talk about telomerase therapy and why it might work for Alzheimer’s, since it doesn’t actually lower beta amyloid levels. I explained about senescent gene expression, dynamic protein pools whose recycling rates slow significantly, causing a secondary increase in amyloid plaques, tau tangles, and mitochondrial dysfunction. The pharmaceutical executive listened (not so politely) with growing frustration, then broke in on the explanation. “Look”, she said, “I get all that, but what I still want to know is how does telomerase lower beta amyloid levels?”

In short, she wanted to know where I had hidden the horse.

The global pharmaceutical company that invited me to talk with them had, earlier this year, given up on its experimental Alzheimer’s drug that aimed at lowering beta amyloid levels, since it had no effect on the clinical course. None. They have so far wasted several years and several hundred million dollars chasing after amyloid levels, and now (as judged by our conversation) they still intent on wasting more time and money chasing amyloid levels. We offered them a chance to ignore amyloid levels and simply correct the underlying problem. While not changing the amyloid levels, we can clean up the beta amyloid plaques, as well as the tau tangles, the mitochondrial dysfunction, and all the other biomarkers of Alzheimer’s. More importantly, we can almost certainly improve the clinical course and largely reverse the cognitive decline. In short, we have a new car in town.

As with so many other big pharmaceutical companies, this company is so focused on biomarkers that they can’t focus on what those markers imply in terms of the dynamic pathology and the altered protein turnover that underlies age-related disease, including Alzheimer’s disease. And we wonder why all the drug trials continue to fail. The executive who asked about amyloid levels is intelligent and experienced, but wedded to an outmoded model that has thus far shown no financial reward and – worse yet – no clinical validity. It doesn’t work. Yet this executive met with me as part of a group seeking innovative approaches to treating Alzheimer’s disease.

Their vision is that they are looking for innovation.

The reality is that they are still looking for the horse.

September 20, 2017

Genes and Aging

Several of you have asked why I don’t update this blog more often. My priority is to take effective interventions for age-related diseases to FDA phase 1 human trials, rather than blogging about the process. Each week, Outlook reminds me to update the blog, but there are many tasks that need doing if we are going to get to human trials, which remains our primary target.

In working on age-related disease, however, I am reminded that we can do very little unless we understand aging. Most of us assume we already understand what we mean by aging, but our assumptions prevent us from a more fundamental and valid understanding of the aging process. In short, our unexamined assumptions get in the way of effective solutions. To give an analogy, if we start with the assumption that the Earth is the center of the solar system, then no matter how carefully we calculate the orbits of the planets, we will fail. If we start with the assumption that the plague results from evil spirits rather than Yersinia pestis, then no matter how many exorcisms we invoke, we will fail. We don’t fail because of any lack of effort, we fail because of misdirected effort.

Our assumptions define the limits of our abilities.

When we look at aging, too often we take only a narrow view. Humans age, as do all the mammals and birds (livestock and pets come to mind) that have played common roles in human culture and human history. When most people think of aging, they seldom consider trees, hydra, yeast, bacteria, or individual cells (whatever the species). Worse, even when we do look at these, we never question our quotidian assumptions. We carry our complacent assumptions along with us, a ponderous baggage, dragging us down, restricting our ability to move ahead toward a more sophisticated (and accurate) understanding. If we looked carefully, we would see that not all cells age and not all organisms age. Moreover, of those that age, not all organisms age at the same rate and, within an organism, not all cells age at the same rate. In short, neither the rate of aging, nor aging itself is universal. As examples, dogs age faster than humans and, among humans, progeric children age faster than normal humans. The same is true when we consider cells: somatic cells age faster than stem cells, while germ cells (sperm and ova) don’t age at all. So much for aging being universal.

The key question isn’t “why do all things age?”, but rather “why does aging occur in some cases and not in others, and at widely different rates when it occurs at all?” The answer certainly isn’t hormones, heartbeats, entropy, mitochondria, or free radicals, for none of these can explain the enormous disparity in what ages and what doesn’t, nor why cells age at different rates. Nor is aging genetic in any simplistic sense. While genes play a prominent role in how we age, there are no “aging genes”. Aging is not a “genetic disease”, but rather a matter of epigenetics – it’s not which genes you have, but how those genes are expressed and how their expression changes over time, particularly over the life of the organism or over multiple cell divisions in the life of a cell. In a sense, you age not because of entropy, but because your cells downregulate the ability to maintain themselves in the face of that entropy. Cell senescence effects a broad change in gene expression that results in a gradual failure to deal with DNA repair, mitochondrial repair, free radical damage, and molecular turnover in general. Aging isn’t a matter of damage, it’s a matter of no longer repairing the damage.

All of this wouldn’t matter – it’s mere words and theory – were it not for our ability to intervene in age-related disease. Once we understand how aging works, once we look carefully at our assumptions and reconsider them, our more accurate and fundamental understanding allows suggests how we might cure age-related disease, to finally treat the diseases we have so long thought beyond our ability. It is our ability to see with fresh eyes, to look at all organisms and all cells without preconceptions, that permits us to finally do something about Alzheimer’s and other age-related disease.

Only an open mind will allow us to save lives.

 

December 13, 2016

Telomeres: The Purloined Letter of Aging

     “What is only complex is mistaken (a not unusual error) for what is profound.”

                                                Edgar Allen Poe

 Edgar Allen Poe is still well-known for his poetry, he is less well-known for his detective stories. Some 170 years ago, his Parisian amateur detective, Dupin, was the conceptual forerunner for Sherlock Holmes, who made his London debut almost half a century later. Poe also made a series of observations that echo, even today, as we try to understand aging, age-related disease, and how we can cure them.

Poe’s detective pointed out that even intelligent, meticulous investigators are often oblivious to the obvious. The same can even be true of modern scientific investigators, who may focus so closely on their hard-won facts that the relationships between those facts – and their implications – are often overlooked. In aging research, for example, many investigators focus so intensely on genes, proteins, and small-molecular therapies, that they can miss the broader picture and miss an effective approach to curing the diseases of aging. Putting it simply, too often we focus our intellect, our education, and our strenuous effort on the “nouns”, but we entirely miss the “verbs”. We know the data, we fail to see what it means.

The intellect, the education, the dedication, and the funding are enormous, but our focus is off-target and the results, as expected, are futile. Truth, Poe tells us, is frequently overlooked, regardless of how intense our investigation. In describing such a case (in Poe’s case a policeman, in our case a scientist), Poe put it this way:

“… he erred continually by the very intensity of his investigations. He impaired his vision by holding the object too close. He might see, perhaps, one or two points with unusual clearness, but in so doing he, necessarily, lost sight of the matter as a whole. Thus there is such a thing as being too profound. Truth is not always in a well. In fact, as regards the more important knowledge, I do believe that she is invariably superficial.”

 As Poe suggest, we seek truth in the depth of a well in a valley, while truth is usually sitting in plain sight on the (easily visualized) mountain tops surrounding that valley. Such is the case with aging. It’s not that the truth is simple, for aging is far more complex than most of us give it credit for, but the truth is not found in the narrow details so much as it found in the overview of those details. The truth really is on the mountain tops, not in the bottom of a well, even when that well includes reams of data. It’s not the amount of data that is crucial, but the implications of that data. To give an example from clinical medicine, I may know everything about a patient’s fever, their hypotension, their abnormal white count, and their vomiting, but the numbers alone aren’t nearly as important as the realization that the patient has Ebola. Curing an Ebola infection cannot be relegated to lowering a fever, increasing the IV fluid, removing white cells, and given an anti-emetic. It’s not the individual therapies that cure Ebola, it’s the realization that you’re dealing with a viral infection and the use of a more general – and more effective – therapy, whether an antiviral or an immunization.

There is a parallel in understanding aging.

Treating the diseases of aging is not a matter of using individual therapies, but a matter of understanding the more profound relationships that change in aging cells. Until we do so, we will continue to fail when we try monoclonal antibodies for beta amyloid – as Eli Lilly finally realized with its Solanezumab trials – or merely attack tau proteins, mitochondrial changes, inflammation, or other targets. In each case, we have mistaken a plethora of data for a profundity of data. Only when we realize the actual complexity, the dynamic biological relationships, the profound effects of epigenetic changes, the role of telomeres as a therapeutic target, and that the fundamental pathology of aging and age-related diseases is rooted in cell senescence, only then will we — to our own vast and naïve surprise — discover that we can cure most of the diseases that still plague humankind.

 

November 15, 2016

Close to a Cure

We are now within two years of a cure for Alzheimer’s disease.

What a brash and disruptive claim! What hubris! Yet events are coming together, underlining a new and far more complete understanding of the disease, illuminating the cause, supporting the ability to intervene, safely and effectively. We finally see a way to intervene in the basic pathology, underlining the potential to both prevent and cure Alzheimer’s disease.

But why has it taken so long? Why was Alzheimer’s disease first defined 110 years ago, and yet remains totally beyond our ability to intervene even now? Why have all other approaches, whether those of big pharma or those of biotech, failed utterly? Why has not a single clinical trial shown any ability to change the progress of this frightening disease? Why is Alzheimer’s disease not only called “the disease that steals human souls”, but also called the “graveyard of companies”? Why has every single approach (which has at most shown only an effect on biomarkers, such as beta amyloid), still failed to show any change in the cognitive decline in patients with this disease? Why have we failed universally, until now?

Because every approach has concentrated on effects, not on causes.

Currently, most approaches target beta amyloid, many target tau proteins, and some target mitochondrial function, inflammation, free radicals, and other processes, but no one targets these problems as a single, unified, overarching process. Alzheimer’s isn’t caused by any one of these disparate processes, but by a broader, more complex process that results in every one of these individual problems. Beta amyloid isn’t a cause, but a biomarker. Equally, tau proteins, phosphodiesterase levels, APOE4, presenilins, and a host of other markers are effects, not causes. The actual cause lies upstream and constitutes the root cause of the dozens of separate effects that are the futile downstream targets of every current FDA trial aimed at Alzheimer’s disease. Understanding this, we will be targeting the “upstream” problem, rather than the dozens of processes that others target individually and without success. Our animal studies support the ability to effectively intervene in human disease: when we say that we are about to cure Alzheimer’s disease, we base claim that on a clear and consistent theoretical model, supported by equally clear and consistent data.

Within the next few months, we will begin our FDA toxicity study, preparatory to obtaining an IND that will permit us to begin our FDA human trial. Our toxicity study will take 6 months and will meet FDA requirements for human safety data. Our first human trial is planned to begin one year from now and is intended to show not only safety, but a clear efficacy. We will include a dozen human volunteers, each with (not just early, but) moderate Alzheimer’s disease and our human trial will last 6 months, including a single treatment and multiple measurements of behavior, laboratory tests, and brain scans. We expect to show unambiguous cognitive improvement within that six-month period. We are confident that we cannot merely slow, not merely stop, but reverse much of the cognitive decline in our twelve patients. We intend to demonstrate an ability to cure Alzheimer’s disease clearly and credibly.

Curing Alzheimer’s requires investments of money, time, and thought. The toxicity study costs 1 million dollars; the human trial costs 2.5 million dollars. Telocyte has half a million dollars committed to this effort and at least one group of investors with a firm interest in taking us all the way through the human trials. We are close and we grow closer each day.

After 110 years, we are about to cure Alzheimer’s.

October 18, 2016

The Carpets of Alzheimer’s Disease

Why do Alzheimer’s interventions always fail?

Whether you ask investors or pharmaceutical companies, it has become axiomatic that Alzheimer’s “has been a graveyard for many a company”, regardless of what they try. But in a fundamental way, all past and all current companies – whether big pharma or small biotech – try the same approach. The problem is that while they work hard at the details, they never examine their premises. They uniformly fail to appreciate the conceptual complexity involved in the pathology of Alzheimer’s. They clearly see the technical complexity, but ignore the deeper complexity. They see the specific molecule and the specific gene, but they ignore the ongoing processes that drive Alzheimer’s. Focusing on a simplistic interpretation of the pathology, they apply themselves – if with admirable dedication and financing – to the specific details, such a beta amyloid deposition.

But WHY do we have beta amyloid deposits? Why do tau proteins tangle, why do mitochondria get sloppy, and why does inflammation occur in the first place? Focusing on outcomes, rather than basic processes explains why all prior efforts have failed to affect the course of the disease, let alone offer a cure for Alzheimer’s.

Let’s use an analogy: think of a maintenance service. Any big organization, (university, pharmaceutical firm, group law practice, or hospital) has a maintenance budget. Routine maintenance ensures that – in the offices, clinics, or laboratories – carpets are vacuumed, walls are repainted, windows are cleaned, floors are mopped, and all the little details are taken care of on a regular basis. These are the details that make a place appear clean and well-cared for, providing a pleasant and healthy location. In most offices (as in our cells), we are often unaware of the maintenance, but quite aware of the end result: an agreeable location to work or visit. In any good workplace, as in our cells, maintenance is efficient and ongoing.

That’s true in young cells, but what happens in old cells?

Imagine what happens to a building if we cut its maintenance budget by 90%. Carpets begin to show dirt, windows become less clear, walls develop nicks and marks, and floors grow grimy and sticky. This is precisely what happens in old cells: we cut back on the maintenance and the result is that cells becomes less functional, because without continual maintenance, damage gradually accumulates. In the nervous system, beta amyloid, tau proteins, and a host of other things “sit around” without being recycled efficiently and quickly. Maintenance is poor and our cells accumulate damage.

All previous Alzheimer’s research has ignored the cut back in maintenance and focused on only a single facet, such as beta amyloid. You might say that they focused only on the dirty carpet and ignored the walls, the windows, and the floors. Even then, they have focused only on the “dirt”, and ignored the cut back in maintenance. Imagine an organization that has cut its maintenance budget. Realizing that they have a problem, they call in an outside specialist to focus exclusively on the loose dirt in the carpet, while ignoring the carpet stains, ignoring the window, walls, and floors, and then only coming in once. What happens? The carpets look better for a few days, but the office still becomes increasingly grungy and unpleasant. In the same way, if we use monoclonal antibodies (the outside specialist) to focus on beta amyloid plaque, the plaques may improve temporarily, but the Alzheimer’s disease continues and it is definitely unpleasant. Various companies have focused on various parts of the problem – the floors, the walls, the windows, or the carpets – but none of them have fixed the maintenance, so the fundamental problem continues. You can put a lot of effort and money into treating only small parts of Alzheimer’s, or you can understand the complex and dynamic nature of cell maintenance. Ironically, once you understand the complexity, the solution becomes simple.

The best solution is to reset cell maintenance to that of younger cells. Neurons and glial cells can again function normally, maintaining themselves and the cells around them. The outcome should be not another “graveyard for companies”, but life beyond Alzheimer’s .

 

February 16, 2016

Unexamined Assumptions

The problem with curing Alzheimer’s is, as with so much of our understanding of aging and age-related diseases, that we make unexamined assumptions. Let me admit that many of our unexamined assumptions are either useful or reasonable. I assume that the sun will come up again tomorrow morning and that’s a useful and reasonable assumption. Useful, in that it allows me to plan my future, reasonable in that the sun has been coming up every morning for quite a while and is therefore likely to do so tomorrow as well. Certain unexamined assumptions are equally justifiable in dealing with Alzheimer’s disease. In the strictly poetic sense, Alzheimer’s certainly is the disease that “steals our souls”, yet no physician or researcher would actually make the assumption that the mind is some vague ethereal quantity that can be stolen by demons, let alone go on to promulgate a theory of Alzheimer’s pathology based on this assumption.

Yet we make exactly that same error, using an unexamined assumption, when we blithely assume that aging is simply the accumulation of damage and, pari passu, that Alzheimer’s disease is simply the accumulation of damaged molecules, be they amyloid, tau tangles, or altered mitochondrial enzymes. This unexamined assumption lies behind almost innumerable multi-million dollar FDA trials, academic papers, and clinical interventions. We assume, without even realizing we have made the assumption, that Alzheimer’s is merely the accumulation of damaged molecules.

We make the same unexamined assumption in looking at other age-related diseases and in the broader field of aging itself. We delve into the details of advanced glycation end-products (AGE), lipofuscin, cross-linking, and other molecular pools showing “accumulative damage”, all the time never realizing that we are making the same fallacy. We are working with completely unexamined (and erroneous) assumptions about how aging works. We naively assume that aging occurs – and age-related diseases follow – merely because things “rust” over time. We age because “molecules fall apart.”

 

Yet the data and logic both say differently. Let me give you a useful analogy: the cell phone. Consider a large pool (several thousand) of people who own cell phones. We know that if we examine any SINGLE cell phone, the best predictor of failure is how long it has been since production. If, however, we want to predict the percentage of failures in any large pool of owners, the best predictor is not time-since-production, but length-of-contract, that is, how often does it get turned over and replaced? Imagine two large pools of cell phone owners. In group A, the cell phones are replaced annually, with a failure rate (at equilibrium) of approximately 1%. In group B, the cell phones are replaced every ten years, with a failure rate (at equilibrium) of approximately 80%. In both groups, the rate of failure of any individual phone is the same. Furthermore, the rate of failure is only marginally related to the “genes”, i.e., whether the phone is an Apple iPhone, an Android, or some other type (a different “allele”). As the turnover rate (contract length to replacement) lengthens, the percent of failed cell phones climbs dramatically, regardless of the failure rate of any individual cell phone. In a pool of cell phones, “aging” is not a matter of passively accumulated damage, but of how actively we replace them.

The same is occurring in molecular pools in biological systems. The key predictor of “denatured” or dysfunctional molecules (e.g., AGE, beta amyloid microaggregates, cross-linking, elastin failure, collagen stiffening, etc) is not the rate of damage but the rate of turnover. In the case of cell aging, when we reset gene expression (reset telomere length) we reset the turnover rates (anabolism and catabolism rates) of all molecular pools to those typical of “young” cells. The outcome is that molecule pool turnover is more than sufficient to deal with typical rates of damage.

Without realizing it, most of us make the mistake of thinking of molecular pools as static and damage as purely accumulative. The reality is that such pools are dynamic and the key dependent variable (as with cell phones) is not the passive rate of damage, but the active rate of turnover.

Unless we understand – and examine – our assumptions, we can never expect to cure age-related diseases. Once we start down the wrong path, all the logic and data in the world can’t make up for the fact that we are looking in the wrong place. It’s time we stopped blaming “demons” and starting thinking carefully.

December 7, 2015

21st Century Science: Isn’t It About Time?

The other day I was asked about the role of denaturation of a particular protein in aging. It was a typical question that pretty much sums up the problem we have had in understanding (and doing anything about) aging during the past century. The problem is the question hides a flawed premise. It presupposes that molecules simply sit around and accrue damage. Put another way, the problem is that we look at molecules as part of as static pool rather than looking at the dynamic turnover that is the hallmark of metabolism.

Imagine a 1930 Duesenberg that has been lovingly cared for and is in pristine condition, even though it rolled off the assembly line 85 years ago. Compare this to my two-year-old car that already has a few rust spots. Was the Duesenberg better made than my car, that is, did it come with “better genes”? Was the Duesenberg exposed to less damage than my car, that is, did it have “fewer free radicals, less denaturing of its proteins, or a smaller rate of cross-linking”? No. The difference between that “ageless” Duesenberg and my own “aging” car is not the quality of the production line nor the exposure to sun, snow, salt, and dirt. The difference lies exclusively in the dynamics of its care. That Duesenberg was polished, aligned, oiled, repainted, repaired, and “recycled” on a regular basis. My own car is “aging faster” because I don’t care for it as frequently or as carefully as did the owners of that Duesenberg, and therein lies the entire difference between young organisms and old ones.

In aging organisms, it’s neither the genes nor the damage, but the slowing rate of recycling and repair that results in old cells, old tissues, old organisms, and age-related diseases.

Bizarrely and ironically, most people still look at biological systems and ignore the fact that they are alive, that they are dynamic, that they are constantly in flux. We look at a particular molecule – whether beta amyloid, collagen, GDF-11, or a thousand others – and we ignore the fact that these molecules are constantly being created, broken down, and replaced, but instead, we blindly focus on the damage itself. It’s true that as an organism ages any given pool of molecules shows an increase in damage – such as the aggregates of beta amyloid in early plaque formation – but the key is not the damage, the key is the slowing of the metabolic turnover. An accumulation of damage is not static and passively accumulative; it occurs because the rate of turnover falls as a result of changes in the pattern of gene expression. Whether we look at tau proteins, elastin, or any other molecular pool you want to look at, the key to the problem lies not in any particular gene nor in any particular source of damage. The key lies in the rate at which both anabolism and catabolism are replacing those molecules.

We don’t age because we accumulate damage, we accumulate damage because aging permits damage to accumulate.

A doctrinaire attention to “aging genes” and a catalog of one’s favorite sources of molecular damage will never result in cures to age-related disease. The key to intervention lies in the rate of molecular turnover, which responds to changing patterns of gene expression. Those who focus on genes and damage, to the exclusion of molecular turnover and gene expression, are perhaps some of our most highly-educated and intelligent minds of the 20th century…

…but it’s now the 21st century.

It’s time we caught up.

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 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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