Aging and Disease: 1.5 – Aging, Misconceptions

• Aging
• Alzheimer's
• Dementia
• Epigenetics
• microglia
• progeria
• Telomerase

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).

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