Michael Fossel Michael is President of Telocyte

April 24, 2018

Aging and Disease: 2.3 – Cell senescence, Changes in Gene Expression

Changes in gene expression underlie aging and age-related diseases. There is all-but-universal (and equally unwarranted) assumption that both aging and age-related diseases are genetic. We see articles on “aging genes” and “genes that cause Alzheimer’s disease” (or genes that cause heart disease, osteoarthritis, etc.). The reality is that both aging and age-related diseases are not genetic, they are epigenetic.

To get at the difference, albeit in a slightly different context, consider the difference between a skin cell and a nerve cell. These cells have the same genes, but very different gene expression. The difference between a skin cell and a nerve cell is not genetic, but epigenetic. Same genes, different gene expression.

The same is true of aging cells. The difference between a typical young cell and a typical old cell is not genes, but gene expression. The two cells – for example, a young skin cell and an old skin cell – have the same genes, but very different patterns of gene expression. What makes a cell “old” is not gene damage or altered genes, but alterations in the way those genes are expressed. To use the analogy of a symphony orchestra, both young cells and old cells have the same orchestral instruments (violins, oboes, etc.), but they’re playing slightly different scores (Mozart instead of Bach, as it were). Old cells aren’t old because their “instruments” (the genes) are “out of tune”, but they are old because they play a different tune.

This alteration in gene expression underlies all age-related diseases. The reason we have heart disease, dementia, osteoarthritis, osteoporosis, or other hallmarks of aging (including things like wrinkles, that aren’t actually diseases at all), is because certain cells have an altered pattern of gene expression. Same genes, different gene expression.

A growing number of papers have pin-pointed specific changes in gene expression that are present in old cells and old tissues, but they focus narrowly on such changes as “the” important change, then explore how they might address that single, specific change. They see a single “tree” (of a change of expression in single gene) but lack the ability to see the larger “forest” (encompassing the gamut of changes in expression in hundreds of genes). Too often, they view each change as a “cause” of aging, not realizing that each single change is an effect, caused in turn by a more fundamental process: the shortening of the telomere. In fact, there are literally hundreds (perhaps thousands) of such changes, all of which are not, by themselves, causes of disease or aging, but are the results of changes in telomere length. Aging – and age-related diseases – are not the result of one gene, nor the result of the change of expression in one gene, but rather the result of wholesale and subtle changes of expression in many genes, acting in concert. To harp back to the orchestra: the problem is the orchestral score, not the orchestral instrument.

Nor are do such epigenetic changes stop there. As the telomere influences the expression of a few local genes, these in turn influence the expression of more distant genes, which in turn influence genes on other chromosomes. Moreover, there are interactional effects between such genes: gene a1 may affect three other genes, but such “downstream” genes may well be influenced by other genes as well.

Views of aging (or disease) that focus only on one particular gene or gene product (any of the various “x’s” at the bottom of figure 2.3a) miss the complexity of the process. As examples of this, we see human trials that, in the case of Alzheimer’s disease for example, focus narrowly upon particular gene products, such as beta amyloid (or genes, such as APOE4), then express confusion and surprise when carefully thought out interventions (aimed only at beta amyloid) fail to have any impact on the progressive course of the disease. These trials my employ an effective intervention for one particular gene or gene product, but they ignore the expression of other genes and ignore the complex interactions of multiple genes, all of which are undergoing changes in gene expression as the cells age.

Such human trials remove one tree and then wonder why the forest is still there.

Moreover, as we will see, even when you restrict your focus to a particular gene, the problem is not the product itself, but the rate at which it turns over. To stretch our tree and forest analogy, even if you restrict your view to one particular tree, you find that it keeps regrowing. The question isn’t “can you cut the tree”, but “how often you need to recut the tree?” Beta amyloid, for example, is continually being turned over. Simply lowering the amount of amyloid (“cutting the tree”) won’t work – as many human trials aimed at amyloid have shown – because amyloid is a dynamic pool (a “tree that keeps regrowing”).

The problem comes back to the telomere. Not only isn’t it enough to focus on a single gene, a single protein, or a molecule, but even if you use a broader view and look at all the changes in gene expression – modulated by changes in telomere length – you must realize that every single gene, protein, or molecule is dynamic. Alzheimer’s, for example, is not JUST a matter of beta amyloid, but a matter of dynamic turnover in the amyloid pool. To account for the broad changes, you need to account for ALL the gene changes and account for the turnover rates as gene expression changes.

Trying to treat disease is much like trying to treat hundreds of dynamic processes all at once. You can try aiming at all the processes with hundreds of drugs, you can even try to find a drug that will increase the turnover rates of all these hundreds of processes with hundreds of drugs, one-by-one and with interactive side effects. The actual processes that encompass these age-related changes in gene expression are stunningly complex, encompassing DNA methylation, histone tails and other histone modifications, nucleosome positioning, micro RNA’s (miRNA’s), repressor proteins, i-motif DNA “knots”, and probably dozens of other “tools” of our epigenetic landscape, but the details of these processes lie well beyond our current discussion.

The upshot is plain, however. We could focus one-by-one on each of thousands of individual genes, we could focus one-by-one on each of dozens of different regulatory processes, and for each of these thousand genes or dozen processes attempt to develop (one-by-one!) effective interventions, then hope to combine all of these interventions (while hoping there are not interactive side effects) and use them to treat age-related disease by giving thousands of small molecule drugs.

Or, we can simply reset gene expression by addressing the change in telomere lengths.


Next time: 2.4 Cell Senescence, Changes in Molecular Turnover


March 27, 2018

Aging and Disease: 2.1 – Cell senescence, Why Cells Divide

Why do some people age faster than others? We’ve all seen people – high school reunions come to mind – who have the same chronological age, but different biological ages: with the same “age”, one person looks ten years older (or younger) than another. If aging is related to cell senescence and cell senescence depends on cell division, then why do some people’s cells divide more than other people’s cells? Why don’t people age at the same rate?

Why does he look old, but she doesn’t, even at the same “age”?

And why do our own organs and tissues age at different rates? We’ve all seen people whose skin looks old, but they have no evidence of osteoarthritis or dementia; equally, we’ve seen other people with terrible osteoarthritis, but no heart disease or dementia. Not only do we age at different rates when we compare different people, but our tissues sometimes age at different rates even within the same person. If aging is related to cell senescence and cell senescence depends on cell division, then why do people vary internally, having some cells (in one tissue) divide more frequently than other cells (in another tissue)? Why don’t all of our tissues age in parallel?

Why does he have bad knees, but she has a bad heart, even at the same “age”?

The easy – and naïve – answer is to say the magic word “genes” and nod knowingly.

The real – and more complex – answer demands a lot more thought. It requires that we reexamine both the data and our assumptions. It requires, in a word, that we think about what’s really going on. Part of this complex answer begins easily. We notice that people who were exposed to too much sun (and too many sun burns), for example, have skin that ages faster than people who avoided sun damage to their skin, and this is true even with identical genes, as in identical twins. We have discussed the fact that aging is not simple a matter of genes, but it’s a balance between damage and maintenance. “It’s not the years, it’s the miles.” Indeed, the degree to which we pile damage onto our tissues shows a good correlation to how fast those tissues show aging and age-related disease. Most of us know this without really thinking about it. For example, we automatically assume that smoking causes COPD, “bad” diets increase your risk of heart attacks, and so forth. These assumptions are now part of our cultural baggage and (true or not) have attained the status of medical wisdom. In fact, to a large extent these are supported by a fair amount of good evidence, although it’s always a bit more complex than the current culturally accepted facts would have you believe. For example, it may or may not (depending on the decade we’re talking about) be accepted that dietary cholesterol has a direct impact on the cholesterol deposits in your coronary arteries, but the evidence that dietary intake (unspecified for the moment, but not just cholesterol) has a long-term impact on coronary artery disease is fairly good.

In short, your behavior (diet, exercise, stress, etc.) can accelerate or decelerate not only your overall rate of aging, but the rate of aging (and age-related disease) in a number of specific tissues. To give a few more examples, people engaged in high-impact activities (think basketball) have a higher incidence of osteoarthritis of the knees than do people engaged in low-impact activities (think yoga). People who get repeated head injuries (think pugilists and American football players) have a higher incidence of Alzheimer’s and other dementias. In both of these cases – osteoarthritis and dementia – those at high risk not only have a higher incidence of the age-related disease in old age, but they get the specific age-related disease at a younger age than do those at lower risk. They are both more likely to get the disease and more likely to get it earlier. What this tells us is not surprising: aging is related to what you do behaviorally, not just who you are genetically. In short, it’s not just your genes.

Genes do, of course, play a fundamental role but they do it in complex relationship with the damage that accrues over a lifetime. If you really want to avoid osteoarthritis, you not only want to have parents who never had osteoarthritis, but you want to avoid repetitive high-impacts to your joints. If you really want to avoid dementia, you not only want a double allele of APOE-2 (instead of two APOE-4 alleles), but you want to avoid boxing or playing football. But then if these sorts of behavior cause age-related disease, and cell senescence underlies age-related disease, what is the relationship?

The key relationship is the rate of cell division. If your cells are forced to divide more frequently, you force them to senesce faster. If, for example, you damage your knees (forcing your chondrocytes to divide and replace the damaged cells) then you will accelerate aging in your knees (as those cells divide, lose telomeres, and change gene expression). The more you damage your knee joints, the more rapidly your chondrocytes divide, and the more rapidly you develop osteoarthritis. If you damage your head (forcing glial cells to divide and replace the damaged cells), then you will accelerate aging in your brain (as those cells divide, lose telomeres, and change gene expression). The more you damage your brain, the more rapidly your glial cells divide, and the more rapidly you develop dementia.

The details, the pathology, the reality of these age-related diseases are wildly more complex than this cursory review suggests, but the basic theme is valid. Given equivalent genes, people who engage in a lifestyle that increases cell turnover will increase their rate of aging. Likewise, your particular lifestyle may increase cell turnover preferentially in one organ or tissue and that will accelerate the rate at which that organ or tissue develops age-related disease.

Any cell in your body (in any tissue) has a baseline “rate of cell division” (i.e., rate of tissue aging). Skin cells, gastrointestinal lining cells, and hematopoietic stem cells divide frequently, while neurons, muscle cells, etc. divide very infrequently in the adult (an in some cases, not at all). Anything that accelerates cell division, accelerates aging. Anytime you increase the rate of damage to a tissue, you increase the rate of cell division (i.e., the rate of tissue aging) and the result is increased aging and increased age-related disease. The same is true between individuals. We each (based on our own genetics) have what you might think of as a “baseline rate of aging” for our body. If you take care of yourself, you still age inexorably, but relatively slowly. If you engage in a high-risk lifestyle, you will age not only inexorably, but relatively quickly.

Aging is caused by cell senescence and cell senescence is cause by cell division, but while you need your cells to divide in order to survive, the relative rate of cell division is, to an extent, controlled by your lifestyle. Cells divide because you’re alive, but the way you live has an impact on how fact those cells divide and how fast you age.

So, let’s answer our initial question. We have been making the case that aging occurs because cells divide, shortening telomeres, which changes gene expression, which results in dysfunctional cells, dysfunctional tissues, and tissue aging (and disease). This is true, but it begs the question of “if cell division causes aging, then what causes cell division?”

The answer is that cell division is both a natural result of being you (your genes, your personality, your culture, and the simple fact that you are alive and some of your cells MUST divide to keep you alive) and the result of what you do to yourself. You have a baseline rate of cell division (and hence aging). If you have a high-risk lifestyle, you age faster; if you have a low-risk lifestyle, you age a bit more slowly. You can increase or decrease your rate of aging – to a degree – depending on what you do. There is (so far) nothing you can do to STOP aging, but can certainly make it a bit slower, or a lot faster.

Next time: 2.2 Cell senescence, Telomeres

March 20, 2018

Aging and Disease: An Index

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

0.1 Prologue

1.0 Aging, our purpose, our perspective

1.1 Aging, what is isn’t

1.2 Aging, what we have to explain

1.3 Aging, what it is

1.4 Aging, the overview

1.5 Aging, misconceptions

2.0 Cell senescence, perspective

2.1 Why cells divide

2.2 Telomeres

2.3 Changes in gene expression

2.4 Changes in molecular turnover

2.5 Changes in molecular turnover, most molecules

2.6 Changes in molecular turnover, DNA repair

2.7 Changes in molecular turnover, Mitochondria

2.8 Changes in molecular turnover, extra-cellular molecules

2.9 Cell senescence and tissue aging

3.0 Aging disease

3.1 Cancer

3.2 Direct and indirect aging

3.3 Skin

3.4 Immune system

3.5 Osteoarthritis

3.6 Osteoporosis

3.7 Arterial (vascular) disease

3.8 CNS disease

3.9 CNS: Parkinson’s disease

3.10 CNS: Alzheimer’s disease

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

4.1 What doesn’t work, killing senescent cells

4.2 What works, lowering risks

4.3 What works, resetting gene expression

5.0 Telomerase in the Clinic

March 15, 2018

Aging and Disease: 1.5 – Aging, Misconceptions

Misconceptions regarding the current model of aging are rampant and they tend to fall into one of several categories. These include Straw man arguments, unfamiliarity with how age-related human pathology occurs, simplistic views cell senescence, genes, and expression, or misguided approaches to measuring telomeres (usually in the wrong cells).

Straw man arguments

          The Earth can’t possibly be round, or you’d fall off the other side.

This sort of argument attacks a position by attacking the wrong target, then claiming victory. The approach is called a “straw man argument”. Rather than facing an actual opponent (or making a logical argument), you build a man out of straw (or offer up a faulty premise), attack it and beat it (or disprove the faulty premise), then claim that you have beaten your opponent (or proven your entire argument). Straw man arguments are safer and easier but they’re dishonest and they don’t lead to clinical progress.

Several centuries ago, some clerics argued that if Copernicus was right about the sun being the center of the solar system, then he must be denying the existence of God (the straw man) and the truth of the Bible (another straw man). Never mind the astronomical data: critics focused on the religious straw man. A century ago, some people argued that humans could never fly because humans are heavier than air. You couldn’t deny the straw man (we really are heavier than air), but it didn’t affect validity of flying machines. Even the Wright brothers would be shocked senseless by the weight of the modern commercial jet. History is replete with “disproof’s” that misrepresent or make wildly erroneous straw man arguments about new thoughts, new theories, and new technologies.

Straw man arguments do nothing but prevent progress.

The telomerase theory of aging has frequently been criticized using straw man arguments. The most common example is suggesting that telomere length (instead of change in length) is important to aging, then demolishing the straw man. Cellular aging – as marked by changes in gene expression – is not modulated by telomere length but is modulated by changes in telomere length. Telomere length per se is a straw man. The fact that some young mice have 150kbp telomeres (but a 2-year lifespan) while some young humans have 15kbp telomerase (but 80-year lifespans) is irrelevant: it’s a straw man. Cell aging is determined by the gradual changes in gene expression and these are determined by relative telomere loss, not by absolute telomere length. To say that some species have longer telomeres and shorter lifespans while other species have shorter telomeres and longer lifespans is interesting but misses the point. Telomere length (the straw man) has nothing to do with lifespan or cell aging. The key factor isn’t length, but the change in length of the telomeres and – more directly – how the changing length of telomeres changes the pattern of gene expression. To focus on telomere length creates a wild goose chase. The key feature is not the telomere (and certainly not the absolute telomere length), but the patterns of gene expression as modulated by the changes in telomere length over time.

Human pathology: which cells cause the disease?

A more egregious error occurs when the straw man is due to a stunning naiveté regarding age-related pathology. In this case the error lies in misunderstanding clinical medicine rather than in misunderstanding telomere biology. This type of straw man argument has surfaced repeatedly online, in articles, and (sadly) even in academic discussions. The two most typical (and most egregious) examples aim at heart disease and dementia. The most typical false statements are:

  1. Cell aging can’t explain heart disease, since heart cells don’t divide.
  2. Cell aging can’t explain dementia, since neurons don’t divide.

These statements, as is often the case, tell us far more about the critic than they tell us about the target of the criticism. In these two examples, we discover that the critics have no understanding of the clinical pathology underlying either heart disease or dementia. The two statements are not only straw man arguments but display an extraordinary lack of clinical knowledge. While it’s true that heart cells and neurons generally don’t divide, that fact has nothing to do with the actual disease process nor the role of cell aging.

Classical “heart” disease (i.e., myocardial infarction, angina, etc.) doesn’t begin in the heart muscle (whose cells rarely divide), but in the endothelial cells that line the coronary arteries (whose cells divide regularly). The observation that heart cells don’t divide is (more or less) accurate but has nothing to do with heart disease being caused by cell aging. Heart muscle cells are the innocent bystanders. The vascular endothelial cells are where the pathology begins. To blame heart disease on heart muscle cells is like blaming the murder victim rather than the murderer. Heart cells are the victim, not the perpetrator. We might have equally (and just as foolishly) said that “cholesterol can’t explain heart disease, since heart cells don’t accumulate cholesterol.” The latter is true, but it’s hardly relevant. Cholesterol’s role (like that of cell aging) lies in the vascular lining cells, not in the heart muscle cells. Whether we are talking about cell aging or cholesterol deposits, the heart cells are the innocent bystanders and it’s the coronary arteries that are the problem. Cell aging accurately explains everything we know of human “heart disease”, as well as age-related vascular disease generally (e.g., strokes, aneurysms, peripheral vascular disease, congestive heart failure, etc.). The straw man arguments are disingenuous and largely based on a willful (a woeful) ignorance of human age-related disease.

Much the same is true for dementia. Neurons don’t divide (much, if at all, in the adult human), but glial cells (such as microglia) both divide and have been implicated in the basic pathology that underlies Alzheimer’s and many other dementias. We know, for example, that Alzheimer’s patients have shorter telomeres than do age-matched patients without Alzheimer’s. In short, cell aging explains dementia logically and accurately, while the lack of neuronal cell division has nothing to do with the argument (or the disease). In this context, such Straw man arguments display the distressing naiveté of those using them.

Cell senescence, genes, and expression

Cell senescence is often regarded as all-or-nothing: a cell is either young or old, but never anything in-between. Over the past half century, this error has often resulted in people speaking past one another, never recognizing that they have different definitions of “cell senescence”. While it’s true that there is an endpoint (a senescent cell that is incapable of division or much else), short of that extreme, cell senescence remains a relative matter. This is not only seen in the physiology (how well does the cell function?) but in terms of gene expression. Like cell senescence, gene expression is not all-or-nothing. It’s true that a particular gene at a particular time is either being transcribed or not, but if we look at the rate of gene expression over any reasonable time duration (e.g., an hour, a day, or a week), we see that the rate of gene expression looks more like a continuum. You might say that it’s “analog” rather than “digital”. More importantly, that rate of gene expression can be seen to change not only over time, but as an integral part of cell senescence. In “older” cells, while we find that the genes and gene transcription process is perfectly normal (i.e., the same quality of genes and gene transcription as a “young” cell), we find that the rate of gene expression is now quite different. Putting it simply, the rate of gene expression slows down as a cell segues from a young cell to a senescent cell. Thinking of cell senescence and gene expression as all-or-nothing is a troublesome error but is not the only error when it comes to genes and aging.

Perhaps the most rampant error lies in thinking of “aging genes”. A century ago, it wasn’t unusual to hear people talk about genes for any number of things: intelligence, beauty, compassion, etc. While there are genes that play a role in these (and myriad other characteristics), the relationship between intelligence and genes has proven to be remarkably complex, requiring input from epigenetics, environment, diet, and other factors. Even if we restrict ourselves to genes alone, there are probably hundreds of genes that play a role in determining intelligence. Moreover, these same genes also play dozens of roles at once, including roles in immunity, endocrine development, motor function, memory, and cells throughout the body and in every tissue. So are these genes really “intelligence” genes? To think of them that way is merely to expose both our ignorance and our naiveté. These are systems genes; they play dozens (hundreds?) of interacting roles in virtually every part of the body. Much the same can be said for “aging” genes. Short of a few genes that characterize some of the progerias (for example, the lamin-A gene in H-G progeria), there are no aging genes. To look at your gene scan and point to an “aging gene” is exactly like the early phrenologists who looked at your skull and pointed to a “bump of combativeness” or a “bump of sublimity”. There are no such bumps and there are no such “aging genes”. There are certainly genes that play a role (or much more likely, play multiple roles) in the aging process. Unquestionably, there are innumerable genes that increase (or decrease) your risk of age-related diseases or that increase (or decrease) the probable length of your lifespan, but there are no specific “aging genes”, unless you’d like to go to the other extreme and acknowledge that all genes are aging genes, as in some sense, they are.

Misguided approaches to measuring telomeres

About once every two weeks, I receive a research article that goes something like this. The authors measured the telomeres of several dozen volunteers, then performed an intervention (changed the diet, taught them meditation, increased their daily exercise, etc.), then measured the telomeres again in six months, and found that the telomeres had lengthened. They conclude that the intervention lengthens telomeres (and, by implication, reverses aging). While they might be right, the data prove certainly don’t justify their conclusions. If they are right, they are right despite poor design, poor analysis, poor thinking, and a very shaky knowledge of cells. There are several problems these types of study, starting with the fact that almost every one of these studies only measures telomere lengths in white blood cells, which are easy to obtain, but not particularly useful (nor are they valid or reliable, as we’ll see). A typical study of this type is summarized in Figure 1.5a.

The first problem is that even if they truly lengthened the telomeres in those white blood cells (and see below), most of us die of aging cells in our arteries or aging cells in our brains (not to mention the problems we have with our joints, our bones, our kidneys, etc.). Measuring the telomeres in white cells tells us precisely nothing about these more important cells and tissues. It’s much like using hair color (how gray is your hair?) to assess your risk for having a heart attack or Alzheimer’s disease. White cells are the wrong cells to look at. They may be easy to get, but they don’t get you anywhere.

The second problem is that white cells are a dynamic population and they respond to almost any stress by dividing (and shortening their telomeres). Once the stress is gone, the white cells get replaced by “younger” white cells (with longer telomeres) from the stem cells in your bone marrow. So, you might say that if you only measure your white cell telomeres, then you will appear older as a result of any stress and you will appear younger again once the stress goes away. For example, you will appear to have older white cells if you have an infection, if you just had a loved one die, if you lost your job, or if you are malnourished. The opposite is equally true: your white cells will appear younger if your stress resolves, since your white cells will then be replaced with “younger” cells from the stem cell compartment in your bone marrow. Note that if we actually measured your bone marrow cells (and not the circulating white cells), you would find that your hematopoietic stem cells are slowly aging almost regardless of what you do. Whether we cure your infection, improve your diet, make you exercise regularly, or have you meditate, makes little difference to your marrow cells. Almost any clinical intervention might affect your circulating white cells, but there is no evidence that any intervention can make your stem cells younger (or can increase their telomeres). To focus on the white cell telomeres is an illusion. This is not to say that these various interventions aren’t useful and may not improve your health, but there is no evidence that any of these interventions make you any younger. For that matter, there may be evidence that these interventions change the particular white cells you sample (so the new sample has longer telomeres), but there is no evidence that these interventions lengthen telomeres, let alone make you any younger.

To give you an analogy, imagine that you are trying to make people younger in a large country (the US, for example), so you measure the average age in a particular block of a major city (Boston, for example), then you perform an intervention (an urban renewal program, for example) over several decades (between 1950 and 2018, for example), then measure the average age of people living in that same block. The average age may well be lower in 2018 than it was in 1950, but that does NOT mean that you have made anyone get younger and it certainly doesn’t mean that the rest of the country is now younger. The population has changed: some people moved out, some moved in and those that moved in tended to be younger.

The same thing happens when you measure white cell telomeres: the old white cells are gone, and new white cells have “moved into the block”. To conclude that you have made the white cells (let alone the whole body) younger is silly, to say nothing of entirely unsupported by the data. This is not to say that the various interventions purported to affect telomeres and/or aging (meditation, vegetarian diets, exercise, or in one case, living in zero gravity) may not have physical benefits (or that they might actually affect telomeres or aging), but that not a single one of these various interventions has valid data to answer those questions. Measuring peripheral white cell telomere lengths is not only fraught with errors, but (at least as far as most current research goes) has approximately the same validity as casting a horoscope.

Finally, most telomere measurements are done by average length, which is relatively cheap but not particularly relevant. Tissue function is highly dependent upon the oldest (not the average) cells in the tissue and cell function is highly dependent upon the shortest (not the average) telomere in the cells. Measuring the average telomere may be cheap and easy, but it’s like trying to figure out the risk of terrorism in a city by measuring the average person. The average person isn’t a terrorist, but that’s not the point. It’s the extremes that determine the overall risk of terrorism in a community. It only takes a few terrorists to result in disaster and, in your tissues, it only takes a few senescent cells to result in disease. Within the cells, it only takes a few short telomeres to result in a dysfunctional cell. The upshot is that when we measure telomere lengths, the measurement that is most often used is the measurement that doesn’t tell you what you know. The result is that most studies measure the wrong thing and then, with perfect confidence, draw the entirely unwarranted conclusions. No wonder the literature is misleading.

Understanding aging – and understanding cell aging – is replete with pitfalls and misconceptions that are all-too-common, even in the research literature. Leaving these caveats aside for now, however, let’s delve directly into the aging process itself, starting with the cell.

How does a cell age?


Next time: Aging and Disease: 2.0 – Cell senescence, Perspective

March 6, 2018

Aging and Disease: 1.4 – Aging, the Overview

How does aging work?

So far, in the prologue (section 0) and the section 1 posts, we have discussed a perspective, what aging isn’t (and is), and what we need to explain in any accurate model of aging. In this post, I provide an overview of how the aging process occurs, from cell division to cell disease, followed by a post on the common misconceptions about this model, which will complete section 1. Section 2 is a series of posts that provide a detailed discussion of cell aging, section 3 explores age-related disease, and section 4 maps out the potential clinical interventions in aging and age-related disease. In this post, however, I provide an outline or map of the entire aging process. This will shoehorn much of what we know about cellular aging and age-relaed disease into a single post, giving you an overview of how aging works.

Cell Division

Aging begins when cells divide. Before moving beyond this, however, we need to ask ourselves why cells divide in the first place. The impetus for cell division is itself a driving force for aging, and the rate and number of cell divisions will control the rate of aging. IF cell division “causes” aging, then what causes cell division? As with any comprehensive examination of causation, we immediately discover that if A causes B, there is always something (often ignored) that must have caused A in turn. In short, causation (and this is equally true of aging) is a cascade of causation that can be pushed back as far as you have to patience to push the question. In the case of cell division, the next upstream “cause” is often environmental and is related to daily living itself. For example, we loose skin cells because we continually slough them off and we therefore need our cells to divide and replace the cells that we lose. As with most tissues, the rate of cell division is strongly modulated by what we do (or what we’re exposed to). If we undergo repeated trauma or environmental stress, then we lose more cells (and consequently have more frequent cell divisions) than we would otherwise. In the knee joint, for example, cell division in the joint surface will be faster in those who undergo repetitive trauma (e.g., basketball players) than in those who engage in low-impact activities (e.g., yoga). In the arteries, cell divisions along the inner arterial surface will be faster in those suffering from hypertension than in those with lower blood pressure (and lower rheological stress). Not all cells divide regularly. While some cells rarely divide in the adult (muscle cells, neurons, etc.), those that do divide regularly – such as skin, endothelial cells in the vascular system, glial cells in the brain, chondrocytes in the joints, osteocytes in the bone, etc. – will vary their rate of division in response to trauma, toxic insults, malnutrition, infections, inflammation, and a host of other largely environmental factors. Putting it simply, in any particular tissue you look at, the rate of cellular aging depends on what you do to that tissue and those cells. Repeated sunburns induce more rapid skin aging, hypertension induces more rapid arterial aging, close head injuries induce more rapid brain aging, and joint impacts induce more rapid joint aging. In all of these cases, the clinical outcome is the acceleration of tissue-specific age-related disease. So while we might accurately say that aging begins when cells divide, we might equally go up one level and say that aging begins in whatever prompts cell division. Any procees that accelerates cell loss, accelerated cell division, and thus accelerates aging and age-related disease.

Telomere Loss

Cell division has limits (as Len Haylfick pointed out in the 1960’s) and tee limits on cell division are, in turn, determined by telomere loss (as Cal Harley and his colleagues pointed out in the 1990’s). Telomeres, the last several thousand base pairs at the end of nuclear chromosomes (as opposed to mitochondrial chromosomes), act as a clock, setting the pace and the limits of cell division. In fact, they determine cell aging. Telomeres are longer in young cells and shorter in old cells. Of course, it’s never quite that simple. Some cells (such as germ cells) actively replace lost telomere length regardless of chronological age, while others (such as neurons and muscle cells) divide rarely and never shorten their telomeres as the adult tissues age. Most of your body’s cells, those that routinely divide, show continued cell division over the decades of your adult life and show a orrelated shortening of their telomeres. Note (as we will in the next blog post) that it is not the absolute telomere length that is the operative variable, but the relative telomere loss that determines cell aging. Nor, in many ways, does even the relative telomere length matter, were it not for what telomeres control “downstream”: gene expression.

Gene Expression

As telomeres shorten, they have a subtle, but pervasive effect upon gene expression throughout the chromosomes and hence upon cell function. In general, we can accurately simplify most of this process as a “turning down” of gene expression. The process is not all-or-nothing, but is a step-by-step, continuum. Gene expression changes gradually, slowly, and by percent. The change is analogous to adjustments in an “volume control” rather the use of an on/off switch. Where once the expression of a particular gene resulted in a vast number of proteins in a given time interval, we now see 99% of that amount are now produced in that time interval. The difference may be one percent, it may be less, but this small deceleration in the rate of gene expression becomes more significant as the telomere shortens over time. Whereas the young cell might produce (and degrade) a pool of proteins using a high rate of molecular “recycling”, this recycling rate slows with continued cell division and telomere shortening, until older cells have a dramatically slower rate of molecular recycling. While you might suspect that a slightly slower rate of turnover wouldn’t make much difference, this is actually the single key concept in aging and age-related disease, both at the cellular and the tissue levels. We might, with accuracy and validity, say that aging is not caused by telomere loss, but that aging is caused by changes in gene expression and, even more accurately, that aging is caused by the slowing of molecular turnover.

Molecular Turnover

To understand molecular turnover is to understand aging. As we will see later in this series (including a mathematical treatment with examples), the predominant effect of slower molecular turnover is to increase the percentage of denatured or ineffective molecules. Examples would include oxidized, cross-linked, or otherwise disordered molecules due to free radicals, spontaneous thermal isomerization, or other disruptive, entropic processes. The cell’s response to such molecular disruption is not to repair damaged molecules, but to replace such molecules with new ones. This replacement process, molecular turnover, is continual and occurs regardless of whether the molecules are damaged or not. The sole exception to the use of replacement rather than repair is that of DNA, which is continuall being repaired. But even the enzymes responsible for DNA repair are themselves being continually replaced and not repaired. There are no stable molecular pools, intracellular or extracellular: all molecular pools are in dynamic equilibrium, undergoing continual turnover, albeit at varying and different rates. Some molecules are replaced rapidly (such as the aerobic enzymes within the mitochondria), others more slowly (such as collagen in the skin), but all molecular pools are in a condition of dynamic equilibrium. More importantly, if we are to understand aging, the rate of molecular turnover slows in every case as cells senesce and the result is a rise in the proportion of damage molecules. To use one example, beta amyloid microaggregates in the brain (in Alzheimer’s disease) occur not simply result because damage accrues over time (entropy). Amyloid microaggregates begin to form when the rate of glial cell turnover of beta amyloid molecules (the binding, internalization, degradation, and replacement of these molecules) becomes slower over time and is no longer keeping pace with the rate of molecular damage (maintenance versus entropy). The result is that beta amyloid molecular damage occurs faster than molecular turnover, and the the histological consequence is the advent of beta amyloid plaques. The same principle – the slowing of molecular turnover with cell aging – applies to DNA repair and the result in an exponential rise in cancer, as we will see in later sections. This general problem of slower molecular turnover applies equally within aging skin, where wrinkles and other facets of skin aging are not the result of entropy, but result from the failure of maintenance (e.g., turnover of collagen and elastin) to keep up with entropy. The incremental and gradual slowing of molecular turnover or molecular recycling is the single most central concept in aging. Aging isn’t caused by damage, but by the failure of maintenance to keep up with that damage. Aging results from insufficient molecular turnover.

Cell and Tissue Dysfunction

The slower molecular turnover and it’s outcome – an increase in dysfunctional molecules – results in a failure within and between cells. Within the cell, we see slower DNA repair, leakier mitocondrial membranes, an increase in the ratio of ROS/ATP production (creating more free radicals and less energy), decreasinly effective free radical scavengers, and a general decrease in the rate of replacement of those molecules that are damage, whether by free radicals or otherwise. For the cell itself, the outcome is a gradual loss of function and an increase in unrepaired DNA. With respect to free radicals, for example, it’s not that free radical damage causes aging, but that cellular aging causes free radical damage. As our cells age (and molecular turnover slows), our mitochondria produce more free radicals (since the aerobic enzyemes aren’t as frequently replace), the mitochondrial membranes leak more free radicals (since the lipid molecules in the mitochondrial aren’t as frequently replaced), free radicals are more common in the cytoplasm (since free radical scavenger molecules are as frequently replaced), and consequent damage becomes more common (since damaged molecules aren’t as frequently replaced). Free radicals do not cause aging: they are merely an important by-product of the aging process. As in cells, so in tissues: just as molecular turnover slows and results in cellular dysfunction, so do do we see dysfunction at higher levels: tissue, structural anatomy, and organ systems. Slowing of molecular turnover expresses itself in dysfunctional cells, an increase in carcinogenesis, and ultimately in clinical disease.

Age-Related Disesase

At the clinical level, the changes in cell and tissue function result in disease and other age-related changes. Wrinkles, for example, may not be a disease, but they result from exactly the same cellular processes outlined above. In each case, however, we see age-related changes or age-related diseases are the result of underlying “upstream” processes that follow a cascade of pathology from cell division, to telomere shortening, to epigenetic changes, to a slowing of molecular turnover, to growing cellular dysfunction. As glial cells “slow down” (in their handling of amyloid, but also in regard to mitochondrial efficiency and a host of other subtle dysfunctions), the result is Alzheimer’s and the other human dementias. As vascular endothelial cells senesce, the result is coronary artery disease, as well as heart attacks, strokes, aneursyms, peripheral vascular disease, and a dozen other age-related diseases and syndromes. As chondrocytes senesce, the result is ostoarthritis. As osteocytes senesce, the result is osteopororis. Nor are these the only manifestations. We see cell senescence in renal podocytes, in dermal and epidermal cells of the skin, in fibroblasts within the lung, and in essentially every tissue that manifests age-related changes. Age related disease and age-related changes are, at the clinical level, the predictable and ultimate outcomes of cellular aging.

The above model is accurate, consistent, and predictively valid, yet there have been a number of crucial misconceptions that have remained common in the literature, making it difficult for many people to grasp the model correctly. Next time, we will explore these errors before moving into the details of aging and disease.

Next: 1.5 – Aging, Misconceptions


February 13, 2018

Aging and Disease: 1.2 – Aging, What We Have to Explain

Our understanding is limited by our vision.

If we look locally, our understanding is merely local; if we look globally, our understanding becomes more global; and if we look at our entire universe, then our understanding will be universal. When we attempt to understand our world, we often start with what we know best: our own, local, provincial view of the world around us, and this limits our understanding, particularly of the wider world beyond our local horizon.

Trying to explain the shape of our world, I look at the ground around me and – perhaps not surprisingly – conclude that the world is probably flat. After all, it looks flat locally. Trying to understand the heavens, I look up at the sky around me and – perhaps not surprisingly – conclude that the sun circles the earth. After all, the sun appears to circle over me locally. Trying to understand our physical reality, I look at everyday objects and – perhaps not surprisingly – conclude that “classical physics” accounts for my universe. After all, classical physics accounts for typical objects that are around me locally. As long as we merely look around, look up, and look at quotidian objects, these explanations appear sufficient.

But it is only when we look beyond our purely local neighborhood – when we move beyond our provincial viewpoint, when we give up our simple preconceptions – that can we begin to understand reality. Taking a broader view, we discover that the Earth is round, that the sun is the center of our local star system, and that quantum and relativity physics are a minimum starting point in trying to account for our physical universe.

To truly understand requires that we step back from our parochial, day-to-day, common way of seeing world and open our minds to a much wider view of reality. We need to look at the broader view, the larger universe, the unexpected, the uncommon, or in the case of modern physics, the extremely small and the extremely fast. Time, mass, energy, and other concepts may become oddly elusive and surprisingly complicated, but our new understanding, once achieved, is a lot closer to reality than the simple ideas we get from restricting our vision to the mere commonplace of Newtonian physics. This is true of for branch of science, and for human knowledge generally.

The wider we cast our intellectual nets, the more accurately we understand our world.

To understand aging demands a wide net. If our knowledge of aging is restricted to watching our friends and neighbors age, then our resulting view of aging is necessarily naïve and charmingly unrealistic. If we expand our horizons slightly, to include dogs, cats, livestock, and other mammals, then we have a marginally better view of aging. But even if we realize that different species age at different rates, our understanding is only marginally less naive. To truly understand aging, we need to look at all of biology. We need to look at all species (not just common mammals), all diseases (e.g., the progerias and age-related diseases in all animals), all types of organisms (e.g., multicellular and unicellular organims, since some multicellular organisms don’t age and some unicellular organisms do age), all types of cell within organisms (since somatic cells age, germ cells don’t, and stem cells appear to lie in between the two extremes), and all the cellular components of cells. In short, to understand aging – both what aging is and what aging isn’t – we need to look at all life, all cells, and all biological processes.

Only then, can we begin understand aging.

To open our minds and examine the entire spectrum of aging – so that we can begin to understand what aging is and how to frame a consistent concept of “aging” in the first place – let’s contrast the small sample we would examine in the narrowest, common view of aging with the huge set of biological phenomena we must examine if we want to gain comprehensive and accurate view of aging, a view that allows us to truly understand aging.

The narrow view, the most common stance in considering aging, examines aging as we encounter it in normal humans (such as people we know or people we see in the media) and in normal animals (generally pets, such as dogs and cats, and for some people, domesticated animals, such as horses, cattle, pigs, goats, etc.). This narrow view leaves out almost all species found on our planet. This sample is insufficient to make any accurate statements about the aging process, with the result that most people believe that “everything ages”, “aging is just wear and tear”, and “nothing can be done about aging”. Given the narrow set of data, none of these conclusions are surpring, but then it’s equally unsurprising that all of these conclusion are mistaken.

A broad view has a lot more to take into consideration (see Figure 1), which is (admittedly) an awful lot of work. The categories that we need to include may help us see how broad an accurate and comprehensive view has to be. We need to examine and compare aging:

  1. Among all different organisms,
  2. Within each type of organism,
  3. Among all different cell types, and
  4. Within each type of cell.


Lets look at these categories in a bit more detail.

When we look at different organisms, we can’t stop at humans (or even just mammals). We have to account for aging (and non-aging) in all multicellular organisms, including plants, lobsters, hydra, naked rats, bats, and everything else. And not only do we need to look at all multicellular organisms, we also need to account for aging (and non-aging) in all unicellular organisms, including bacteria, yeast, amoebae, and everything else. In short, we need to consider every species.

When we look within organisms, we need to account for all age-related diseases (and any lack of age-related diseases or age-related changes) within organisms. Diseases will include all human (a species that is only one tiny example, but that happens to be dear to all of us) age-related diseases, such as Alzheimer’s disease and all the other CNS age-related diseases, arterial aging (including coronary artery disease, strokes, aneurysms, peripheral vascular disease, cogestive heart failure, etc.), ostoarthritis, osteoporosis, immune system aging, skin aging, renal aging, etc. But we can’t stop there by any means. In addition to age-related diseases within an organism, we need to look at aging changes (and non-aging) whether they are seen as diseaeses or not, for example graying hair, wrinkles, endocrine changes, myastenia, and hundreds of other systemic changes in the aging organism.

When we look at different cells, we need to account for the fact that some cells (e.g., the germ cell lines, including ova and sperm) within multicellular organisms don’t age, while other cells in those same organims (e.g., most somatic cells) do age, and some cells (e.g., stem cells) appear to be intermediate between germ and somatic cells in their aging changes.

When we look within cells, we need to account for a wild assortment of age-related changes in the cells that age, while accounting for the fact that other cells may show no such changes, even in the same species and the same organism. In cells that age – cells that senesce – we need to account for telomere shortening, changes in gene expression, methylation (and other epigenetic changes), a decline in DNA repair (including all four “families” of repair enzymes), mitochondrial changes (including the efficacy of aerobic metabolism enzymes deriving from the nucleus, leakier mitochondrial lipid membranes, increases in ROS production per unit of ATP, etc.), decreased turnover of proteins (enzymatic, structural, and other proteins), decreased turnover of other intracellular and extracellular molecules (lipids, sugars, proteins, and mixed types of molecules, such as glycoproteins, etc.), increased accumulation of denatured molecules, etc. The list is almost innumerable and still growing annually.

If we are truly to understand aging, we cannot look merely at aging humans and a few aging mammals, then close our minds and wave our hands about “wear and tear”. If we are to understand aging accurately and with sophistication, then we must not only look at a broader picture, but the entire picture. In short, to understand aging, we must stand back all the way in both time and space, and look at all of biology.

To understand aging, we must understand life.

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.

October 4, 2017

The End Hangs on the Beginning

A major stumbling block in our understanding of age-related disease, such as Alzheimer’s, is a propensity to focus on large numbers of genes, proteins, etc., without asking what lies “upstream” that results in the associations between such genes (etc.) and the disease. While some would tout the advantages of using Artificial Intelligence to attack the problem, the problem with AI is that (like most scientists) it focuses on finding solutions only once the problem has been defined ahead of time. If, for example, we define Alzheimer’s as a genetic disease, then we will find genes, but will never reassess our unexamined assumption that AD is genetic. If we assume that it’s genetic, then we only look at genes. If we assume it’s due to proteins, then we only look at proteins. If we assume that it’s environmental, then we only look at the environment. Data analysis and AI, no matter how powerful, is limited by our assumptions. We tend to use large data analysis (and AI) in the same mode: without ever realizing we have narrowed our search, we assume that a disease is genetic and then accumulate and analyze huge amounts of data on gene associations. While AI can do this more efficiently than human scientists, the answers will always remain futile if we have the wrong question. Once we make assumptions as to the cause, we only look where our assumptions direct us. If we look in the wrong place, then money and effort won’t correct our unexamined assumptions and certainly won’t result in cures.

It’s like asking “which demons caused plague in Europe in the middle ages”? If we assume that the plague was caused by demons, then we will never (no matter how hard-working the researcher, how large the data set we crunch, or how powerful the AI we use) discover that the plague was caused by a bacteria (Yersinia pestis). If you look for demons, you don’t find bacteria. If you look for genes, you don’t find senescent changes in gene expression. The ability to find answers is not merely limited by how hard we work or how large the data sample, but severely and unavoidably limited by how we phrase our questions. We will never get anywhere if we start off in the wrong direction.

To quote the Latin phrase, “Finis origine pendet“. The end hangs on the beginning.

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.


April 12, 2017

We Already Know It Works

Oddly enough, many investors don’t realize how far we are down the road to a cure.

In fact, most people don’t understand why such studies are done and – more to the point – why Telocyte is doing one. Just to clarify: we’re not doing an animal study to prove efficacy. We already know it’s effective in animals.

The reason we do an animal study is because the FDA, quite reasonably, requires an animal safety study in order to assess risks and side effects. Most people assume that animal studies are done to show that a potential therapy works in animals, so that it might work in humans as well. In fact, however, once you have shown that a therapy works in animals, as we have already, then before you can go on to human trials, you first need to do an animal safety study.

Animal studies are done to assess safety, not to assess efficacy.

For an initial human trial, the main question for the FDA isn’t efficacy, but safety. Sensibly, the FDA requires that the safety data be done carefully and credibly, to meet their careful standards. We know telomerase gene therapy works, but we still need to prove (to the FDA’s satisfaction) that telomerase gene therapy is safe enough to justify giving our therapy to human patients. So the question isn’t “Do we have a potential intervention for Alzheimer’s?” (which we do), but rather “Do we know what the risks are once we give it?” We’re fairly certain that we know those risk, but we need to document them rigorously.

In getting our therapy to human trials, you might say that there are three stages:

  1. Animal studies that show efficacy (already done by our collaborators).
  2. Animal studies that show safety (an FDA requirement).
  3. Human trials before release for general use (an FDA requirement).

Telocyte already has good data on the first stage: we know that telomerase is remarkably effective in reversing the behavioral decline seen in aging animals and that the same result will likely occur in aging human patients. In short, we are already confident that we can prevent and at least partially reverse Alzheimer’s disease. The FDA doesn’t need us to demonstrate efficacy: we already have good data on efficacy. What the FDA wants from us is more (and more detailed) data on the probable safety, which we’re about to provide.

While we are now ready to start on the FDA animal safety trial. Doing our FDA animal study isn’t a way of showing that telomerase gene therapy works – which is already clear from animal studies – but a detailed look at side effects, preparatory to our having permission to begin human trials next year.

Telomerase therapy works.

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