Michael Fossel Michael is President of Telocyte

April 5, 2018

Aging and Disease: 2.2 – Cell Senescence, Telomeres

Everyone seems to “know” that telomeres have something to do with aging. The internet even has pop-up ads about foods that lengthen your telomeres, with the unstated assumption that will make your younger, or at least healthier. Inquiry shows, however, that not only do most people have no understanding of the role of telomeres in aging, but neither do most researchers, academics, or clinicians. The result is that many have an unfounded faith in telomeres, while others scoff at the idea that they have any value whatsoever. In fact, both groups are naïve, albeit for different reasons.

The contrarian in me is tempted to assert that “telomeres have nothing to do with aging”, just because people expect me to say that telomeres cause aging, which they don’t. Telomeres play an important role. To say that telomeres have nothing to do with aging is inaccurate, but it’s just as inaccurate to say that telomeres cause aging. To give an analogy, we might say that your entire life is determined by your genes, which is inaccurate, or that genes play no role in your life, which isn’t true either. As with most things, the truth is complicated. Were we to be accurate we might say that telomeres play an important role in the incredibly complex cascade of pathology that we see as aging, indeed a critical and irreplaceable role, but telomeres do not cause aging any more than does any other facet in that intricate web of pathology. Aging is not simply telomeres.

Telomeres have a lot to do with how aging works, but telomeres don’t cause aging.

Causation is a slippery concept, despite the assumption that it’s concrete and well-defined. Causation might apply to billiard balls and the laws of motion, but causation becomes misleading when we apply it to multifactorial events, let alone to complex webs of biological mechanisms. This definitional fuzziness is blithely ignored by both those who ask about causation and those who provide an answer.

To move the discussion to history, for a moment, if I asked for the cause of the American Revolution, there might be a thousand answers that were relevant and appropriate (and not necessarily overlapping). We might focus on taxation, representation, the cultural and geographical distance, any number of specific “flash points”, any of several dozen key players on either side of the Atlantic, etc. Pretending there is “a” cause of the American Revolution presupposes that we already share not only a common framework for the discussion, but common assumptions about what constitutes a cause, and (probably) a great many unexamined prejudices as well. In short, most discussions about causation start with the assumptions that already presuppose a narrow answer. Not a good point to begin understanding.

This is equally true of biological causation. For example, what causes cancer? Is it your genes? Is it down-regulated DNA repair mechanisms? Is it cosmic rays, oxidative damage, or “carcinogens”? It depends on what you are asking. All of these contain an element of truth (and supportive data), but none of them are “the” cause of cancer unless you specify what you are asking and what you want to discuss. If you are a genetic counselor, genes are the focus. If you work for the EPA, carcinogens are the focus. You choose to narrow down your focus but doing so prevents an understanding of the broader question of how cancer occurs and why.

In the case of aging we find the same naiveté. The “cause” of aging depends on your assumptions, why you are asking, and how myopically you look at the process. In short, the question often presupposes the answer. As the Romans once said “Finis origine pendet”. The End hangs on the Beginning, or as too often the case (and using more modern phrasing), garbage in, garbage out. If you already presuppose the answer, then why are you asking? To truly understand how aging works, you need to erase your assumptions, step back, and look at the complexity without blinders or preconceptions. Looking at aging without preconceptions about “the” cause is almost always too much to ask.

There is, however, a more practical approach to understanding aging and the complex cascade of pathology that results from the aging process. Rather than looking for causes, look for effective interventions. If we ignore the deceptive question of causation for a moment and focus on intervention, then telomeres come to the center stage. It’s not that telomeres are in any sense the “cause” of aging, but telomeres are, without doubt, the single most effective point of intervention in the aging process and in age-related diseases.

Telomeres lie at the crossroads – from an interventional perspective – of everything going on in the aging cell. To extend the crossroads analogy, all the roads that lead to aging enter the crossroads of telomeres and all the roads leading toward age-related disease leave that same crossroads. The entire road system – that complex web of pathology that we call aging – consists of myriad highways, county roads, local by-ways, and even walking paths, but almost every one of them, eventually, passes though the same crossroads: the telomere.

Telomeres don’t cause aging and they are not the be-all-and-end-all of the aging process, but they do function as a pivot point, a sine qua non of age-related diseases, and – most importantly of all – the most efficient place to intervene.

Having put telomeres in a more reasonable perspective, what DO they do?

In an odd, but almost accurate sense, you might say that no one really knows. That’s true in two senses. The first sense is that there is simply a great deal that we’ve come to know about telomere mechanisms in the past few decades and there is doubtless a great deal more yet to find out about telomere mechanisms. That first sense, however, is true of everything: there’s a lot we don’t know and anyone who thinks otherwise is probably still in their teen years or has managed to get through life with their eyes (and their minds) closed. The second sense, however, is more specific to telomeres, the aging process, and age-related disease. This second sense is worth exploring, if only to realize the specific gaps in knowledge and how they might impinge on our ability to intervene clinically. This involves how telomeres affect gene expression. What we don’t know (for certain) is the linkage mechanisms, despite discussions about T-loops, sliding sheaths, and all the accompanying data involved over the past two decades. It’s still a bit of a black box. What we do know (for certain), is that telomere shortening changes gene expression (see figure 2.2a), and we do know (for certain) that when we reset telomere lengths we reset gene expression (see figure 2.2b).

We know that this change in gene expression is related to overall shortening and that the change in gene expression is more closely related to the shortest telomere than to the average telomere. We also know that all of this has nothing to do with telomeres “unraveling”. As we discussed before, they don’t unravel. It’s merely a pleasant myth based on the shoelace analogy. Telomeres may function a bit like aglets, but the chromosomal shoelace never unravels. Finally, we know that the absolute length doesn’t determine the changes in gene expression: it’s the relative telomere length that sets the pace of cell aging. Again, this is just the most common misconception, and one that causes inordinate confusion among researchers.

Once telomeres shorten, we know that gene expression changes not only on the same chromosome, but on other chromosomes as well. We know that the changes are progressive and subtle if you only look from one-cell-division-to-the-next (with the associated loss of base pairs). Yet over multiple cell divisions and thousands of base pair losses, these changes in gene expression add up, altering gene expression just enough to have effects upon DNA repair, mitochondrial efficiency, free radical production, lipid membrane competency, protein turnover, and myriad other processes that we associate with aging.

As we will see later in this series, it is this loss of telomere length and the crucial changes that it causes in gene expression that underlies aging and age-related disease, as well as explaining many other diseases, such as the progerias. It also explains why, when telomeres are preserved, cells gain indefinite proliferative potential whether in vitro or in vivo: they are, in common parlance if certainly not in fact, immortal.

Finally, all of this explains why, when we re-extend telomeres, whether in vitro or in vivo, we reset gene expression and not only allow cells to become fully functional again but allow the organism to become functional as well. In short, it explains why and how we may prevent and cure aging and age-related disease.

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: 2.0 – Cell senescence, Perspective

Most of us – when we think of cells at all – seldom appreciate that the idea of a “cell” is a modern idea, not quite two centuries old. One of the tenets of cell theory is that cells are the “basic unit of life”. This makes some sense but note that while the components of cells (mitochondria, for example) can’t live independently but can only survive as part of a cell, it’s also true that most cells don’t do very well independently either but can only survive as part of an organism. Nevertheless, and for good reason, cells are generally thought of at the building block of life, the unit out of which organisms are made. This sort of statement has exceptions (what about viruses?) and qualifications (some muscle “cells” tend to blur together), but overall, cells do function as the “basic unit of life”.

More importantly, most diseases operate at the cellular level or are most easily discussed in cellular terms. Want to understand the immune system? The focus is white blood cells. Want to understand heart attacks? The focus is the dying cardiac muscle cells. Want to understand Alzheimer’s? We tend to focus on dying neurons. In all these cases, other cells are not only involved, but are often the source of the pathology, but regardless of the complexities, qualifications, and exceptions, if you really want to understand a disease these days, you want to look at cells. You may be looking at an organ (such as the liver) or a tissue (such as the surface of a joint), but when push comes to shove, you need to get down into the cells to really understand how a disease works and what might be done about it.

Oddly enough, however, the idea of aging cells somehow never really took off until the middle of the last century. In fact, there was an overriding acceptance of the idea that cells did NOT age. Aging was (here, much hand waving occurred) something that happened between cells and not within them. Organisms certainly aged, while cells did not. This is not surprising when you think of the fact that all organisms derive from single (fertilized) cells that have a germ cell line going back to the origin of life, so while that cell line clearly hadn’t aged, you certainly aged. Voila! Cells don’t age, but you do. There was even a large body of (faulty) data showing that you could keep cells (in this case chicken heart muscle cells) alive and dividing “forever”.

In 1960, however, Len Hayflick pointed out that cells themselves age, and that this aging is related to the number of times the cells divides. Moreover, this rate of cell aging is specific to both species and cell type. While germ cell (think ova and sperm) don’t age, the normal “somatic cells” of an organism show cell aging. By the way, this aging had no relationship to the passage of time but was strictly controlled by the number of cell divisions. In other words, entropy and the passage of years was irrelevant. The only variable that mattered was cell division itself. Entropy only triumphed as cells divided and only in somatic cells. Len had no idea of how cells could count, although he termed this mechanism (whatever it was) the “replicometer” since it measured cell replications.

A decade later, Alexey Olovnikov figured out the mechanism. He pointed out that because of the way chromosomes replicated, every time you replicated a chromosome, you would lose a tiny piece at the end of the chromosome, the telomere. Clearly that wasn’t all there was to it or – since cells and chromosomes have been replicating for billions of years – there wouldn’t be any chromosomes (or life) left on the planet. There had to be something that could replace the missing piece, at least in some cells, such as the germ cell line. That something was telomerase. At least as importantly, however, Alexey pointed out that this was probably the mechanism of Len Hayflick’s “replicometer”: the number of cell divisions was measured in telomere loss.

As it turns out, Len (about cell divisions) and Alexey (about telomeres) were both right. The connection was finally shown in 1990 by Cal Harley and his colleagues, who found that telomere length exactly predicted cell aging and vice versa: if you knew one, you knew the other. At first, this was merely correlation, if a remarkably good one, but it didn’t take more than a few more years to show that telomere loss determined cell aging. Specifically, if you reset the length of the telomere, then you reset cell aging. If, for example, you reset the telomere length in human cells, then those “old” cells now looked and acted exactly like young cells. In short: you could reverse cell aging at will.

This prompted the first book (Reversing Human Aging, 1996) and the first articles in the medical literature (published in JAMA, 1997 & 1998) to suggest that not only did cell aging underlie and explain human aging, but that cell aging could be reversed, and that the clinical potential was unprecedented in the ability to cure and prevent age-related human disease. This was rapidly followed by a set of experiments showing that if you reextended telomeres in aged human cells, you could grow young, healthy human tissues in vitro, specifically in human skin, arterial tissue, and bone. The entire area was extensively reviewed in what is still the only medical textbook on this area (Cells, Aging, and Human Disease; Oxford University Press, 2004). Since then, there have been at least three peer-reviewed publications looking at the use of telomerase activators, each of which showed intriguing and significant (if not dramatic) improvements in many age-related biomarkers (e.g., immune response, insulin response, bone density, etc.).

In a landmark paper (Nature, 2011), DePinho and his group, then at Harvard, showed that telomerase activation in aged mice resulted in impressive (and unprecedented) improvements not only in biomarkers, but (to mention CNS-related findings alone) in brain weight, neural stem cells, and behavior. This was followed by an even more impressive result (EMBO Molecular Medicine, 2012) by Blasco and her group (at the CNIO in Madrid), who showed that the same results could be accomplished using gene therapy to deliver a telomerase gene to aged mice. This result was the more impressive because precisely the same approach can be used in human trials.

Exactly this technique is planned for human Alzheimer’s disease trials next year. But to get there, we need to understand not only the background history, but how cells themselves age, the results of cell aging, and why we can intervene.

Next time: 2.1 Cell senescence, why cells divide


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 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 20, 2018

Aging and Disease: 1.3 – Aging, What it IS

What IS aging?

An explanation of aging must account for all cells, all organisms, and – if we are candid – all of biology and isn’t merely entropy. Prior posts defined our boundaries: what we must include – and exclude. We know that we cannot simply point to entropy, wash our hands of any further discussion, and walk away with our eyes closed. Likewise, an honest explanation can’t simply consider humans and a few common mammals but ignore the entire gamut of Earth’s biology.

So, what IS aging? As a start, we might acknowledge that life has been on Earth for more than four billion years and during that entire time, life has resisted entropy. This serves as an excellent starting point: life might be defined as the ability to maintain itself in the face of entropy. In that case, we might rough out our initial definition: aging is the gradual failure of maintenance in the face of entropy.

We miss the point, however, unless we realize that aging is an active, dynamic process. Aging is not simply a matter of a failure of maintenance in the passive sense. To use an analogy, if entropy were an escalator carrying us downwards, then it is not the only process involved. It is countered by cell maintenance, which is precisely like walking upwards on the same escalator (see Figure 1.3a). Young cells are entirely capable, as are germ cells and many other cells, of indefinitely maintaining their position at the top of the escalator. Entropy and maintenance are equally balanced. Older cells, however, have a subtle (and sometimes not so subtle) imbalance, in which maintenance is less than entropy.

As aging occurs, the problem is not that the escalator (entropy) carries us downwards, but that we are no longer walking upwards (maintenance) at the same rate as the escalator. To view aging as the descending escalator alone is to miss the essential point of biology: life remains on this planet because cells and organisms “walk upwards” and maintain themselves indefinitely in the face of being “carried downwards” by entropy. The process is a dynamic balancing act. To explain aging, it is not enough to cite the escalator, but requires that we explain why maintenance fails, and then only in certain cells and at certain times, while remaining functional in other cells and at other times. Aging is far from universal. A valid explanation of aging must account for why aging occurs in some cases yet does not occur in other cases.


Aging is not the escalator but is a combination of two forces: entropy carrying cells into dysfunction and maintenance ensuring that cells remain functional. Aging occurs only when maintenance is down-regulated. If maintenance is not down-regulated, then the cells and the organism do not age. Aging cells, such as many somatic cells, age because they down-regulate maintenance. “Immortal” cells, such as germ cells, do no age because they do not down-regulate maintenance.

We might try an analogy to see where it takes us, comparing biological aging to “aging” in a car. We could say that aging in a car is not simply what happens as the car undergoes weathering and degradation over time. Rather, car aging would be what happens if we fail to maintain the car on a regular and detailed basis. There are exceptional antique cars that have been in active use longer than most human lifetimes, but they are in excellent shape not because they had better parts (i.e., have the right genes) or were made by a better manufacturer (i.e., are part of the right species), but because they were maintained scrupulously and carefully on an almost daily basis by generations of owners. Such cars are oiled, painted, repaired, realigned, and cared for on an almost daily basis, compared to most cars that are lucky to be cared for annually. The critical difference is not the chronological age of the car nor the amount of wear-and-tear, but the frequency and excellence of their maintenance. Given frequent and excellent maintenance, sufficient to keep up with entropy, a car can last indefinitely, while with sloppy and merely annual maintenance, cars typically last only a few years before “aging” takes them off the road.

In a sense, organisms are no different: the degree of aging is not just a matter of time or entropy, but of the quality and frequency of maintenance. Likewise, aging is not purely a matter of which genes or what species pertain to that organism. Rather, aging is a matter of the rate of repair and recycling within cells, that is, maintenance in the face of entropy.
It’s not the genes, it’s the gene expression.

Let’s use another example, that of water recycling. Every molecule of water that you ingest has been recycled endlessly, but the speed and efficiency of that recycling determines the quantity and quality of the water you drink. Imagine that we plan a trip to Mars. If the average astronaut needs 2 liters per day and 4 astronauts are on a 2.5-year roundtrip to Mars, we might calculate that we need to bring 7 tons of water. But that (incorrectly) assumes no recycling. We can get by on a lot less water, depending on how we recycle. The amount we need to bring with us depends not only on the amount the astronauts use daily, but on the quality and rate of recycling (from urine, for example). The faster the recycling, the less water we need to carry along. The better the quality of our recycling, the longer we can stay healthy.

In a “young” and efficient cell, we recycle molecular pools rapidly and effectively. In an old cell, however, the rate and effectiveness of the recycling decreases. The analogy for our Mars trip would be slower recycling, along with an increasing percent of contaminants that are not being removed in our water recycling unit. The outcome, whether in aging cells or a mission to Mars, is gradually increasing dysfunction. Aging cells no longer function normally (as when they were young cells) and our sickening astronauts no longer function normally either (as when they started out on Earth).
As another example, you oversee a huge office building with multiple daily customers and hundreds of employees. Every night, your cleaning crew comes through, mopping the solid floors, vacuuming the carpets, cleaning the windows, and (when necessary) repainting the walls. Maintenance is frequent and excellent; as a result, the building always looks new (i.e., young). Now let’s radically cut back on your maintenance budget. Instead of daily maintenance, the carpets are vacuumed once every two weeks, the floors are mopped once a month, the windows are cleaned once a year, and repainting occurs once a decade. The resulting problem is not due to the amount of dirt (the entropy), nor the quality of the vacuum, the mop, the washer fluids, or the paint (think of these as the quality of your genes). The problem isn’t the dirt nor is it the cleaning crew, but the rate of maintenance. The outcome is that your building looks dirty and is increasingly incapable of attracting clients or customers – or for that matter, incapable of retaining employees. This parallels the changes in aging cells: the genes (the cleaning products) are excellent and the quality of repair (the cleaning staff) are both excellent, but the frequency of maintenance is too low to maintain the quality of the building. In aging cells, molecular turnover is too slow to keep up with entropic change.

This same analogy could be applied to home repairs, garden weeding, or professional education. The problem is not entropy, but our ability to resist entropy and maintain function. Aging occurs because cell maintenance becomes slower. The quality of gene expression is fine, but molecular turnover (see figure 1.3b) – the “recycling rate” – declines. This effect is subtle but pervasive and the result is increasing dysfunction. This concept – the failure of maintenance to keep up with entropy — is not only central to aging but can account for all of aging and in all organisms, whether at the genetic level, the cellular level, the tissue level, or the clinical outcome – age-related disease.

Aging is a dynamic process, in which entropy begins to gain as maintenance processes become gradually down-regulated.

In subsequent posts, we will explore the detailed mathematics of this change, reviewing the formula and the primary variables, letting us see the remarkable results that occur in terms of denatured molecules and cellular dysfunction. For now, however, let’s look at a few specific clinical examples in human aging, all of which we’ll return to in later posts, when we consider age-related diseases in great detail.

In human skin, between cells, we see changes in collagen and elastin (among dozens of other proteins) as we age. Many people mistakenly assume that these changes are a simple, static accumulation of damage over a lifetime, but these changes are anything but static. These molecules are in dynamic equilibrium, in which the molecules (and their complex structures) are constantly being produced (anabolism) and broken down (catabolism). The overall rate of recycling (the overall metabolism) is high in young skin, with the result that at any given time, most molecules are undamaged and functional (and relatively new). This rate slows with aging, however, with the result that molecules remain longer before being “recycled” and the percentage of damaged and dysfunctional molecules rises, slowly but inexorably. In old skin, molecules “sit around” too long before being recycled. Old skin isn’t old because of damage, but because the rate of maintenance becomes slower and slower. Naïve cosmetic attempts to “replace” skin collagen, elastin, moisture, or other molecules fail because they are transient interventions. By analogy, these cosmetic interventions would be like – in the case of our old, dirty office building – suggesting that we will send in one person, one night, to clean one window pane. Even if you notice a small, transient improvement, the problem isn’t resolved by bringing in one person for a single visit, it requires that we resume having the entire cleaning crew come in every night. Intervening in skin aging is not a matter of providing a few molecules, but of increasing the rate of turnover of all the molecules.

The same problem occurs in aging bones. The problem that lies at the heart of osteoporosis is not “low calcium”, but the rate at which we turnover our bony matrix. Looking solely at calcium as one example, osteoporosis not a static problem (add calcium), but a dynamic problem (increase the rate of calcium turnover). Moving our attention from minerals to cells, young bone is constantly being taken apart (by osteoclasts) and rebuilt (by osteoblasts). The result is continual remodeling (recycling) and repair. Bone turnover is a continual process that slows with age. Young fractures heal quickly and thoroughly. In old bone, however, the rate of remodeling falls steadily, and rebuilding falls slightly behind. The result is that we have decreased matrix, decreased mineralization, decreased bone mass, and an increasing risk of fractures. The fundamental problem underlying osteoporosis is not “a loss of bone mineral density”, but an inability to maintain bony replacement. It’s not the calcium or the phosphorous, but the osteocytes themselves. Loss of bone mineralization is a symptom, not the cause of osteoporosis.

A more tragic and more fatal example is Alzheimer’s disease. Until relatively recently, the leading pathological target was beta amyloid, a molecule which (like tau proteins and other candidates) shows increasing damage and denaturation (plaques in the case of amyloid) in older patients, especially in patients with Alzheimer’s disease. Again, however, amyloid is not a static molecule that is produced, sits around, and slowly denatures over a lifetime. Amyloid is continually produced and continually broken down, but the rate of recycling falls as we age. The result is that the percentage of damaged amyloid (plaque) rises with age, solely because the rate of turnover is slowing down. As we will see, the cells that bind, internalize, and breakdown this molecule become slower as we age. To address Alzheimer’s, we don’t need to remove amyloid or prevent its production, we need to increase the rate of turnover. Beta amyloid plaques are a symptom, not the cause of Alzheimer’s disease.

Wherever we look — an aging cell, an aging tissue, or an aging organism – we see that aging is not a static, linear loss of function due to entropy. Rather, aging is a dynamic process in which the rate of recycling – whether of intracellular enzymes, extracellular proteins, aging cells, or aging tissues – becomes slower as cells senesce. Aging is a programmed failure of maintenance at all biological levels. This is equally true of DNA repair, mitochondrial function, lipid membranes, proteins, and everything else we can measure in an aging system.

We’ve had a glimpse at the core of aging. Let’s explore an overview of how changes in gene expression translate into cell dysfunction, tissue failure, clinical disease, and aging itself.

Next time: Aging, the Overview

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.

February 1, 2018

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

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

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

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

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

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

The proof is in human lives.

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

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

I doubt you’ll be disappointed.


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

January 23, 2018

Aging and Disease: 0.1 – A Prologue

Aging and Disease

0.1 – A Prologue

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

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

It is time to tell the whole story.

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

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

December 31, 2017

Human Nature

Many of you have written to me, expressing surprise about the lack of public reaction (such as media interest) regarding the potential for telomerase therapy to treat age-related diseases. Some of you wonder why people (and particularly the media) “don’t get it”. I’ve had the same thought for a bit more than two decades now, since I published the first book and the first articles on the potential of telomerase therapy. The lack of understanding applies not only to the media, which is neither critical nor surprising, but to many in the investment community and to the pharmacology industry, which is critical if we are to save human lives.

The major reason for that lack of understanding is human nature. Most people have a firmly-held misconception about how aging works and never realize the error. Without thinking about it (which is the fundamental problem), most people think of aging as entropy. In reality, aging is a lot more complicated (as are most things). Aging isn’t the same as entropy; aging is the gradual inability of cell maintenance to keep up with entropy, which is a very different kettle of fish. Aging hinges on the balance between entropy and maintenance. If you think about it, that’s really what biology is all about: maintaining a extremely complex system in the face of entropy. Life is resistance to entropy. Life is continually building, recycling, and maintaining a complex system, that is continually coming apart, thanks to entropy. This is a balance that works quite well generally, which is why life still continues quite splendidly on this planet, a good three and a half billion years after it began. Who says you can’t resist entropy indefinitely?

Nor is aging universal, just because we see it in ourselves, our pets, and the animals we raise. In some organisms (some multi-cellular and some unicellular), aging never occurs. In other organisms (again, some multi-cellular and some unicellular), aging occurs quite predictably as maintenance slows down, allowing entropy to have its way as the organism ages, fails, and dies. While aging is a lot more than just entropy, most people never even begin to consider the facts and sail along with the unexamined assumption that “aging is entropy”.

It’s not that simple. It never is.

Nor are telomeres the “cause” of aging. Telomeres don’t cauase aging, they are just one (very important) part of an enormously complicated cascade of processes that result in age-related pathology and aging itself. Telomeres are important only because they play a key role at the crossroads of this cascade of pathology. Being at the crossroads, telomeres represent the single most effective point of intervention, both clinically and financially. Theye are the only place that we can entirely reset the gradualy deceleration in cell maintenance with a single intervention and it’s the only place that we can leverage our interventions into a strikingly lower cost of health care. Better care, for less cost.

The other problem that keeps people from appreciating the potential of telomerase therapy is inertia, or perhaps inertia and the fear of undermining their own careers. It’s not merely the inertia of never examining our assumptions, but the professional inertia that occurs when we suspect that – should we examine those assumptions – our entire professional lifetime of work may have been not only misdirected, but be seen as valueless, a truly frightening thought and an understandable fear. Human nature being what it is, the result is a stolid inertia from professionals who have spent many decades pursuing a faulty (and incomplete) model of aging and age-related disease. If any of us had spent 40 years of our professional life working for certain global pharmaceutical firms, for example, we would be loathe to give up the assumption that beta amyloid causes Alzheimer’s disease. After all, that model (despite lacking any support) has been the central focus, the raison-d’etre, for everything we have done professionally for several decades. Would any of us be willing to look clearly at reality, knowing that an honest, thoughtful, and careful appraisal of reality might suggest we had wasted those years, along with our personal efforts and dedication? It is asking too much of human nature. In a corporate, rather than a personal sense, this is equally true of drug companies that have invested hundreds of millions of dollars in what has now been proven to be a fruitless endeavor. The endeavor has been aimed at the wrong target, but it’s a lot of years, a lot of money, and a lot of effort, making it difficult to be honest about the prospects, let alone willing to go back to square one and ask if our assumptions were wrong in the first place. Old adages notwithstanding, people and institutions really do “throw good money after bad” and we do it both with a will and stunning consistency.

Yet, there is reason for a realistic optimism. Over the past two decades, there are a growing number of people who look at the data, reexamine their assumptions, and develop a close relationship with the reality of how aging works. That number continues to escalate, and the time when we can take telomerase therapy to an effective clinical trial continues to shrink. We see resources and commitment moving steadily toward a more sophisticated understanding of both Alzheimer’s disease and aging itself. The combination of resources and commitment will soon bring us to a new ability to treat diseases that, until now, have been beyond our understanding, let alone beyond our help.

We have the compassion to save lives; we will soon have the ability.

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