Michael Fossel Michael is President of Telocyte

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 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 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 7, 2018

Aging and Disease: 1.1 – Aging, What it Isn’t

Filed under: Aging diseases,Alzheimer's disease,mitochondria — Tags: , , , — webmaster @ 9:29 am

It ain’t what you don’t know that gets you into trouble. It’s what you know for sure that just ain’t so.

– Mark Twain

Twain was right, particularly when it comes to the aging process: there is a lot we think we “know for sure that just ain’t so”. For example, most people (without even thinking about it and with a fair amount of naïve hand-waving) assume that all organisms age and equate aging with entropy. In other words, they think that “aging is just wear-and-tear”. We assume that aging “just happens” and that nothing can be done about it. After all, we all get old, things fall apart, things rust, everything wears out, so what can you expect? But as with Twain’s remark, the trouble is that we are quite sure of ourselves and we what we think is completely obvious, turns out to be completely wrong. We are content to gloss over our faulty assumptions and move to faulty conclusions. It’s bad logic, bad science, and a bad way to intervene in the diseases of aging. Without thinking about it, we conclude that aging is as simple as our preconceptions, which turn out to be erroneous.

Aging isn’t simple and our preconceptions are wrong.

As with most concepts that we don’t examine meticulously, aging is a lot more complex than we realize. Aging isn’t just entropy, it isn’t just wear-and-tear, and it isn’t many things that people blithely believe it to be. Let’s look at a few examples that make us back up and reconsider how aging works. Let’s start with your cells, and then your mitochondria.

We could take any cell in your body, for example a skin cell on the back of your hand. How old is that skin cells? Since we shed perhaps 50 million skin cells every day, there’s a good chance that the cell we are thinking about is only a day or so old, or at least a day or so since the last cell division. But that last division was from a “mother” cell that was there before the cell division resulted in two “daughter” cells. So perhaps our skin cell, counting the age of the “mother” cell is a week or so old? But that “mother” cell, in turn, derived from a dividing cell that was there several weeks ago, backwards ad infinitum to the first cells that formed your body. In fact, every cell in your body is certainly as the whole body, so perhaps that skin cell is a few decades old. You might say that the skin cell has the same age that you see on your driver’s license. Except that your entire body is the result of a cell (ova) from your mother and a cell (sperm) from your father, and each of those cells was already a few decades old (or however old your parents were) when the sperm and ovum became “you” when they joined at fertilization. But, of course, your parent’s germ cells came from their parents, whose germ cells came from their parents, and we can trace that lineage of germ cells back to… Well, all the way back to the origin of life on Earth. So in a very real, very strictly accurate biological sense, every cell in your body is 3.5 billion years old.

But if we assume that aging is just entropy, then we have explain why that line of germ cells (that resulted in your entire body) didn’t undergo any entropy (i.e., didn’t age) for 3.5 billion years and yet your somatic cells are now undergoing entropy (i.e., aging) in your body and have been aging since you were born. Why do somatic cells suffer from entropy, if germ cells don’t? Does entropy only work in certain cells and not in others? Apparently so. And if that’s true, then we can’t just wave our hands and invoke entropy as the entire explanation, can we? We have to explain something more subtle and complicated: why entropy results in aging in some cases (the somatic cells in your body) but not in other cases (the line of 3.5 billion year-old germ cells that led up to you having a body in the first place). How interesting. So much for just invoking the concept of entropy and walking away satisfied.

Entropy almost certainly plays a key role in aging, but we can’t simply leave it at that. We need to think a bit harder. Sometimes entropy wins (your body and most of its cells age in a matter of decades) and sometimes entropy doesn’t appear to win at all (your germ cell line didn’t age for 3.5 billion years). Why sometimes and not other times?

One way that some people have tried to explain this is to invoke mitochondrial damage, but an almost identical problem surfaces in the case of mitochondrial entropy. Given the prevalence of aging explanations based on free radical theory (reactive oxygen species, etc.), mitochondrial dysfunction is an obvious suspect for an explanation of aging. We know that older mitochondria make more free radicals, leak more, and those free radicals aren’t scavenged as well, so perhaps all of aging is a mitochondrial problem? Perhaps entropy simply causes mitochondrial damage and that’s why we age. Perhaps entropy works by aging our mitchondria, right?

Except that mitochondrial entropy can’t explain aging either.

If aging were the result of “aging” mitochondria, damaged by entropy (high internal mitochondrial temperature, free radicals, loose protons and electrons, and a general accumulation of mitochondrial damage over time), then we are still left with an embarrassing conundrum. To understand the problem, let’s ask a simple question: how old are your mitochondria? Mitochondria divide fairly constantly, depending on the cell and its energy demands. In some cells (such as liver cells), with high energy demands, mitochondria are dividing all the time, in others with low energy demands, mitochondria divide much less frequently. On the other hand, since every mitochondria in every cell in your body derived from the mitochondria that were present in you as a fertilized zygote, we might reasonably say that your mitochondria are all the same age as your body, i.e., all of your mitochondria are a few decades old, and as time goes by, your mitochondria simply wear out, right?

Well, no.

Every mitochondria that you had as a fertilized zygote was derived from your mother’s ovum, which supplied all of your original mitochondria, so your mitochondria are as old as you are. Well, as old as you are plus as old as your mother was when you were conceieved. Oh, and plus the age of her mother and her mother and so on, ad infinitum back as far as the very first mitochondrial inclusion in the very first eukaryotes (or so). So every mitochondria in your body is about 1.5 billion years old and they’re doing pretty well for their age. But that means that if we want to blame aging entirely on mitochondrial dysfunction (and mitochondria surely play a major role in aging), we are still left with a conundrum. We have to explain why all of those dividing mitochondria (which were at least 1.5 billion years old) hadn’t aged for 1.5 billion years, and now all of your mitochondria are having significant problems after only a few decades. Why do your mitochondria suddenly start aging when they were doing so well for the last 1.5 billion years? The problem is that your mitochondria really do showing aging changes, but the mitochondra from your mother clearly didn’t until you came along. Worse yet, we have to explain both of these effects (aging and non-aging) simultaneously if we want to explain aging at all. How can we do both? We can’t simply wave our hands (again) and blame entropy unless we can simultanously explain why entropy works sometimes and in some cells (liver cells, for example), but entropy doesn’t work at other times and in other cells (the mitochondria in the germ cell line, for example). Again, why sometimes and not other times?

If entropy were an entirely sufficient explanation, they why does entropy age some cells (and some mitochondria) and not other cells (and other mitochondria)? If we restrict our explanation of aging solely to entropy, then we have a problem. We can’t just say that entropy does cause aging (because sometimes it doesn’t) nor can we say that entropy doesn’t cause aging (because sometimes it does). Entropy plays a role in aging, but not always.Why? What we have to do, if we really want to explain aging, is explain why entropy varies in biological systems. Sometimes entropy wins, sometimes it doesn’t.

Our preconception about entropy – wear-and-tear – as the sole cause for aging is a common misconception and not always noticed. It creates a subtle, but pervasive bias in our thinking about biolgy and aging. Even once we realize that entropy can’t explain all of cell or mitochondrial aging, we still find entropy creeping back into our thinking, but disguised under a different form. We tend to think of Alzheimer’s, for example, as what happens when beta amyloid, tau proteins, or mitochondria undergo entropy and cause neuronal death and clinical disease. We think of skin aging as what happens when collagen and elastin undergo entropy and cause wrinkles and aging skin. Some people blame aging on entropy of the endocrine system, concluding that all of aging comes about because of entropy in a gland or hormonal tissue. The fact that aging can occur in some organisms without endocrine systems (and that replacing hormones doesn’t stop aging) doesn’t change their misconception. But whatever guise it hides under, entropy by itself, cannot explain aging or age-related disease. There are too many odd things to explain, too many exceptions, too many cases where entropy explains one finding, but not another finding. Entropy can explain this cell, but not that cell. Entropy can explain this mitochondria, but not that mitochondria. Entropy simply can’t explain aging in toto. We have to dig a bit further.

Entropy, as an explanation of aging, only works if we close our eyes and ignore most of biology. As we’ll see in the next blog, there is a lot of biology that needs to be accounted for if we are going to explain how aging works. However we try to shoehorn entropy into being the entire explanation, aging cannot be entropy alone. As we will see, entropy does play a crucial role, but we cannot simply cite entropy, wave our hands, and say we understand aging. Aging is not entropy: aging is entropy plus something else, something subtle and complex, but something crucial to a complete understanding of aging.

As we will soon see, aging is entropy in the face of failing maintenance.

 

Next: 1.2 – Aging, What We Need to Explain

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.

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