Michael Fossel Michael is President of Telocyte

June 13, 2018

Aging and Disease: 2.6 Cell Senescence, Changes In Molecular Turnover, DNA Repair

Why are we more likely to get cancer as we age?

Not only does the incidence of cancer go up with age, but it goes up exponentially. Why? Moreover, the exponential rise is seen in most species, regardless of their lifespan. It’s not the years, it’s the aging process, regardless of time. Why? The key to these questions lies with the rise of DNA damage as we age. But just as with other kinds of cell damage – free radicals in the mitochondria, for example – the issue is not the rate of damage, but the rate of maintenance. In the case of DNA, however, the key feature to maintenance isn’t the rate molecular turnover, but the rate of DNA repair. DNA is the only molecule that is repaired rather than simply replaced. We replace (i.e., recycle) all other molecules in our cells (and even outside of our cells), but we never replace DNA. Instead, we repair it with great effort and in exquisite detail. DNA carries priceless information in its structure, so rather that just recycling the molecule (breaking it down and building a new molecule), our cells go to enormous lengths (and enormous metabolic cost) to find and repair every single error. Without delving into detail, let’s look at an overview of DNA damage, DNA repair, and the clinical implications for aging cells – and aging people.

DNA damage is continual, as is repair. DNA damage occurs continually due to radiation, oxidation, toxins, viruses, and even spontaneous thermal disruption (even at normal body temperatures) with an incidence estimated at up to 106 hits per cell per day. If unrepaired, the result will not only be a dysfunctional individual cell, but a cell that divides without control, thereby harming (and even killing) the entire organism. Ultimately, uncontrolled cell division is expressed clinically as cancer. Left unrepaired, DNA damage becomes fatal. Clearly DNA repair is critical, and must be both constant and all-but-flawless for any organism to survive.

 

DNA repair is, like most biological concepts, remarkably (almost indescribably) complex. No matter how we discuss it, there will be exceptions, qualifications, and additional intricacies which remain unaddressed in our discussion. We will therefore and of necessity, present a simplified summary of DNA repair, one which presents only a high-level, conceptual view of the cell’s response to a single type of DNA damage (single-base errors), while ignoring other types of DNA damage (e.g., double-strand breaks). With this caveat in mind, we will characterize DNA repair as being handled by four basic families of DNA repair enzymes which have these functions:

  1. Identification: find the damaged DNA base and flag it for removal
  2. Excision: remove the damaged DNA base from the strand
  3. Replacement: insert the correct DNA base into place in the strand
  4. Ligation: link the new DNA base to neighboring bases in the strand

In the aging cell, and correlated with telomere shortening, the expression of all four of these types of DNA repair enzymes are down-regulated. This down regulation is typical of cell senescence and is modulated by the telomere. As the telomere shortens, all four repair processes are down-regulated. DNA repair continues, but at a slower pace. Young cells repair DNA almost instantly, older cells repair DNA but at a more lackadaisical pace. The result is that, at any given moment, older cells are more likely to have unrepaired DNA.

The result is that slower DNA repair – and the rising percentage of (as yet) unrepaired DNA damage – means a higher likelihood that such damage will affect the cell’s ability to control cell division. For example, if the damage occurs to the DNA repair genes themselves or to the genes that are central to the cell cycle braking system (which would otherwise prevent cells with DNA damage from dividing), then the cell may replicate and carry the DNA damage into the daughter cells. The result is a cascade of increasing cell damage and a decreasing ability to control cell division. In short, the stage is set for malignancy, clinical cancer, and death.

We begin to see why cancer rises with age. As cells lose telomere length, DNA repair slows, and the risk of cancer rises. Worse yet, however, each of the steps involved in DNA repair are multiplicative, that is, each step will have an impact on all subsequent steps. So if detection slows and the number of DNA errors doubles, then if excision slows, the number of DNA errors goes up another factor of two, i.e., the DNA errors go up four-fold. When you add in replacement and ligation, the effects multiply one another again, with the result that if we down-regulate all of the steps in DNA repair, the increase goes up exponentially.

Most people assume that cancer rates climb with age because of a longer lifetime means a greater cumulative exposure to carcinogens. In fact, the rate of cancer isn’t correlated with years so much as it is with percent of lifespan. For example, mice have an exponential increase in cancer, just as humans do, despite the fact that the average lifespan of a mouse is about 40 time shorter than the average lifespan of a human. It’s not the years, it’s the rate of DNA repair that determines how fast that exponential curve rises. Ultimately, the deciding factor is not cumulative exposure, but the rate of repair. Mice slow DNA repair over a short lifespan and their rate of cancer goes up exponentially in only two years; humans slow DNA repair over a long lifespan and their rate of cancer goes up exponentially over a much longer lifespan. It’s not a matter of having good DNA repair genes, nor is it a matter of chronology. The deciding factor is neither time nor genes, but gene expression and gene expression is controlled by telomere shortening.

If we take the curves for cancer in mice and humans and overlap them to show not years but lifespans, then the curves become identical. It’s not the years, it’s the rate of repair. If we want to prevent or treat cancer, we shouldn’t be focusing as much on exposure to carcinogens, but on cell senescence. Putting it bluntly, if only slightly simplistically, the reason we get more cancer as we age isn’t a matter of what we were exposed to, but the rate at which we repair the damage that is constantly in play over our lifetimes.

We get cancer because of cell senescence.

 

Next Time: 2.7 Cell Senescence, Changes In Molecular Turnover, Mitochondria

May 15, 2018

Aging and Disease: 2.4 Cell Sensecence, Changes In Molecular Turnover

Effective maintenance is a product of the rate and the quality of the maintenance process. If we look at a car, for example, the long-term condition of the car depends on how often we institute maintenance (once a month or once every few years?) and the quality of the maintenance procedures (do you replace and repair everything or do you simply change the oil?). If we look at a house, the same questions apply: do you maintain it regularly (every few months?) and do you maintain it thoroughly (do you just vacuum the carpets or do you replace and repair the paint, the pipes, the roof, and the windows?). If we look at a garden, again we find the same issues: how often do you maintain it (once a day or once a year?) and how thoroughly do you care for the garden (do you merely mow the lawn or do you weed, fertilize, trim, and replant?).

Cars, houses, and gardens are not immortal and unchanging. To remain viable, they require maintenance: the more frequent the maintenance and the more detailed and careful the maintenance, then the longer-lasting they are. A well-cared for car, house, or garden can – in effect – be “immortal”. If the maintenance is sufficiently frequent and of sufficiently high-quality, then they appear to resist entropy without any apparent change.

The same is true of cells. Whether we look at proteins, lipids, or almost any other molecular pool, we discover that they are in continual equilibrium: they are continually being produced and continually broken down. There is no molecular pool in the body that remains untouched by the years; whether rapidly or slowly, every molecular pool is in the process of being recycled. The one odd exception is our DNA, which isn’t recycled, but repaired in situ. While we repair our DNA, we simply replace everything else. Even in the case of DNA, however, the molecules that do the repairing are themselves being continually replaced.

The result of all of this recycling is that the cells are generally able to functional. To use the analogy of the Red Queen from Alice In Wonderland, our cells run as quickly as they can in order to stay in one place. Moreover, the faster they run (recycle) the more they are able to stay in one place (fully functional). Or, as the French saying has it “plus ça change, plus c’est la même” (the more things change, the more they stay the same).

The problem comes about when we slow the rate of turnover. The slower this “recycling” rate, the more we tend to see damage. This occurs even if the rate of damage is unchanged. The more critical variable is not the rate of damage, but the rate of turnover. Alas, as our telomeres shorten and our cells senesce, this rate of turnover goes down. We still create molecules – the collagen and elastin molecules in our skin for example – and we still destroy molecules. The rate of creation and destruction is perfectly balanced, so the total number of molecules available at any one time remains unchanged, but the rate at which those molecules are turned over falls with cell senescence.

The upshot is that damage accrues.

Let’s take a typical intracellular molecular protein. A young cell might (hypothetically) have a thousand molecules of this protein and might every day destroy 500 of these molecules and create 500 of these molecules, so that every day it might “recyle” 50% of the molecules. The pool size doesn’t change, but the molecules are changed regularly. An old cell, however, might (hypothetically) have the same thousand molecules of this protein, but create only 50 of the molecules and destroy on 50 the molecules, so that every day it might “recycle” only 5% of the molecules. While the number of molecules available to the cell (1000) remains unchanged, the slower turnover means that any time a molecule becomes damaged, it will be replaced much more slowly. In short, the problem isn’t so much the damage per se, as it is the rate at which the cell maintains itself. The “older” the cell (i.e., the more senescent the gene expression), the slower the rate of molecular turnover and the higher the percentage of damaged molecules (see Figure 2.4a).

To invoke another analogy, if the damage is the rate at which your family produces garbage and the turnover rate (the “recyclilng” rate) is the frequency of garbage pickup, then imagine what happens if you go from once-a-week garbage pickup to once-a-year garbage pickup. Conceptually, this is much the same problem that occurs in cells as they senesce. The solution is not to adjust the rate at which you produce garbage, but the rate of garbage pick-up. To take this analogy back to the cell, the solution is not to adjust the rate of damage (through UV, spontaneous racemization, free radicals, etc.), but to adjust the rate of turnover. Young cells have high rates of turnover and low percentages of damaged molecules; old cells have low rates of turnover and high percentages of damaged molecules.

To take this into a clinical venue, this applies to wrinkles in our skin (in which, for example) collagen and elastin turnover are slower), in Alzheimer’s disease (in which, for example, beta amyloid turnover is slower), and in mitochondria (in which, for example, aerobic enzymes and molecules on the lipid bilayers have slower turnover. In every example of aging and age-related disease – with no exception – we can trace the changes to slower molecular turnover.

For those who might like to get a firmer (and more mathematical) grasp on how this works, consider the following equation and its implications (from my textbook, Cells, Aging, and Human Disease; Oxford University Press, 2004):

If the rate of damage (here arbitrarily 1% of molecules/day) and the total number of molecules in the pool (here 100%) remain constant, but the turnover rate varies (r = the percentage of molecules replaced/day), then the percentage of damaged molecules (X) on day (N) will be XN. At equilibrium, XN = XN-1. This can be calculated as the per cent damaged on a particular day, plus the number of damaged molecules remaining from the previous day (XN-1 times M), minus the number of previously damaged molecules replaced during the past day (XN-1 times r), divided by the total percentage of molecules (M) in the cell. At equilibrium:

Equilibrium protein damage:             X = 1 + [X(100 -r)/100]

If the molecular turnover rate (r) is 50%, then:

X = 1 + 0.5X

X = 2

Given a damage rate of 1%, if the turnover rate were 50%, then at equilibrium, 2% of the molecules are damaged on any given day. If the molecular turnover rate (r) is 2%, then:

X = 1 +.98X

X = 50

Given a damage rate of 1%, if the turnover rate were only 2%, then at equilibrium, 50% of available molecules have been damaged (see Fossel; Reversing Human Aging, 1996; p 260). Turnover rates – whether protein, lipid, or other molecules – have a profound effect on the burden of damaged molecules within a cell, i.e., on cell dysfunction.

In the next few blogs, we will see how this process affects: first, the most common intracellular molecules (2.5), then how it affects DNA (2.6), then mitochondrial molecules (2.7), and finally extracellular molecules (2.8)

Next Time: 2.5 Cell Senescence, Changes In Molecular Turnover, Most Molecules

 

April 24, 2018

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

Next time: 2.4 Cell Senescence, Changes in Molecular Turnover

 

April 5, 2018

Aging and Disease: 2.2 – Cell Senescence, Telomeres

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

March 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

 

March 15, 2018

Aging and Disease: 1.5 – Aging, Misconceptions

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

Straw man arguments

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

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

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

Straw man arguments do nothing but prevent progress.

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

Human pathology: which cells cause the disease?

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

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

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

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

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

Cell senescence, genes, and expression

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

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

Misguided approaches to measuring telomeres

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

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

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

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

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

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

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

How does a cell age?

 

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

March 6, 2018

Aging and Disease: 1.4 – Aging, the Overview

How does aging work?

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

Cell Division

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

Telomere Loss

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

Gene Expression

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

Molecular Turnover

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

Cell and Tissue Dysfunction

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

Age-Related Disesase

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

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

Next: 1.5 – Aging, Misconceptions

 

February 13, 2018

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

Our understanding is limited by our vision.

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

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

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

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

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

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

Only then, can we begin understand aging.

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

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

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

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

 

Lets look at these categories in a bit more detail.

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

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

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

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

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

To understand aging, we must understand life.

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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