Michael Fossel Michael is President of Telocyte

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 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 6, 2018

Aging and Disease: 1.4 – Aging, the Overview

How does aging work?

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

Cell Division

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

Telomere Loss

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

Gene Expression

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

Molecular Turnover

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

Cell and Tissue Dysfunction

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

Age-Related Disesase

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

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

Next: 1.5 – Aging, Misconceptions

 

February 20, 2018

Aging and Disease: 1.3 – Aging, What it IS

What IS aging?

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

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

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

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

 

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

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

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

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

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

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

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

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

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

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

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

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

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

Next time: Aging, the Overview

February 13, 2018

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

Our understanding is limited by our vision.

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

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

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

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

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

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

Only then, can we begin understand aging.

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

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

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

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

 

Lets look at these categories in a bit more detail.

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

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

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

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

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

To understand aging, we must understand life.

February 7, 2018

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

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

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

– Mark Twain

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

Aging isn’t simple and our preconceptions are wrong.

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

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

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

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

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

Except that mitochondrial entropy can’t explain aging either.

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

Well, no.

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

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

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

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

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

 

Next: 1.2 – Aging, What We Need to Explain

January 23, 2018

Aging and Disease: 0.1 – A Prologue

Aging and Disease

0.1 – A Prologue

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

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

It is time to tell the whole story.

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

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

December 1, 2017

Big Pharma: Still Looking for the Horse

About a century ago, in a small American town, the first automobile chugged to a stop in front of the general store, where a local man stared at the apparition in disbelief, then asked “where’s your horse?” A long explanation followed, involving internal combustion, pistons, gasoline, and driveshafts. The local listened politely but with growing frustration, then broke in on the explanation. “Look”, he said, “I get all that, but what I still want to know is ‘where is your horse?’”

About three hours ago, in a teleconference with a major global pharmaceutical company, I was invited to talk about telomerase therapy and why it might work for Alzheimer’s, since it doesn’t actually lower beta amyloid levels. I explained about senescent gene expression, dynamic protein pools whose recycling rates slow significantly, causing a secondary increase in amyloid plaques, tau tangles, and mitochondrial dysfunction. The pharmaceutical executive listened (not so politely) with growing frustration, then broke in on the explanation. “Look”, she said, “I get all that, but what I still want to know is how does telomerase lower beta amyloid levels?”

In short, she wanted to know where I had hidden the horse.

The global pharmaceutical company that invited me to talk with them had, earlier this year, given up on its experimental Alzheimer’s drug that aimed at lowering beta amyloid levels, since it had no effect on the clinical course. None. They have so far wasted several years and several hundred million dollars chasing after amyloid levels, and now (as judged by our conversation) they still intent on wasting more time and money chasing amyloid levels. We offered them a chance to ignore amyloid levels and simply correct the underlying problem. While not changing the amyloid levels, we can clean up the beta amyloid plaques, as well as the tau tangles, the mitochondrial dysfunction, and all the other biomarkers of Alzheimer’s. More importantly, we can almost certainly improve the clinical course and largely reverse the cognitive decline. In short, we have a new car in town.

As with so many other big pharmaceutical companies, this company is so focused on biomarkers that they can’t focus on what those markers imply in terms of the dynamic pathology and the altered protein turnover that underlies age-related disease, including Alzheimer’s disease. And we wonder why all the drug trials continue to fail. The executive who asked about amyloid levels is intelligent and experienced, but wedded to an outmoded model that has thus far shown no financial reward and – worse yet – no clinical validity. It doesn’t work. Yet this executive met with me as part of a group seeking innovative approaches to treating Alzheimer’s disease.

Their vision is that they are looking for innovation.

The reality is that they are still looking for the horse.

September 20, 2017

Genes and Aging

Several of you have asked why I don’t update this blog more often. My priority is to take effective interventions for age-related diseases to FDA phase 1 human trials, rather than blogging about the process. Each week, Outlook reminds me to update the blog, but there are many tasks that need doing if we are going to get to human trials, which remains our primary target.

In working on age-related disease, however, I am reminded that we can do very little unless we understand aging. Most of us assume we already understand what we mean by aging, but our assumptions prevent us from a more fundamental and valid understanding of the aging process. In short, our unexamined assumptions get in the way of effective solutions. To give an analogy, if we start with the assumption that the Earth is the center of the solar system, then no matter how carefully we calculate the orbits of the planets, we will fail. If we start with the assumption that the plague results from evil spirits rather than Yersinia pestis, then no matter how many exorcisms we invoke, we will fail. We don’t fail because of any lack of effort, we fail because of misdirected effort.

Our assumptions define the limits of our abilities.

When we look at aging, too often we take only a narrow view. Humans age, as do all the mammals and birds (livestock and pets come to mind) that have played common roles in human culture and human history. When most people think of aging, they seldom consider trees, hydra, yeast, bacteria, or individual cells (whatever the species). Worse, even when we do look at these, we never question our quotidian assumptions. We carry our complacent assumptions along with us, a ponderous baggage, dragging us down, restricting our ability to move ahead toward a more sophisticated (and accurate) understanding. If we looked carefully, we would see that not all cells age and not all organisms age. Moreover, of those that age, not all organisms age at the same rate and, within an organism, not all cells age at the same rate. In short, neither the rate of aging, nor aging itself is universal. As examples, dogs age faster than humans and, among humans, progeric children age faster than normal humans. The same is true when we consider cells: somatic cells age faster than stem cells, while germ cells (sperm and ova) don’t age at all. So much for aging being universal.

The key question isn’t “why do all things age?”, but rather “why does aging occur in some cases and not in others, and at widely different rates when it occurs at all?” The answer certainly isn’t hormones, heartbeats, entropy, mitochondria, or free radicals, for none of these can explain the enormous disparity in what ages and what doesn’t, nor why cells age at different rates. Nor is aging genetic in any simplistic sense. While genes play a prominent role in how we age, there are no “aging genes”. Aging is not a “genetic disease”, but rather a matter of epigenetics – it’s not which genes you have, but how those genes are expressed and how their expression changes over time, particularly over the life of the organism or over multiple cell divisions in the life of a cell. In a sense, you age not because of entropy, but because your cells downregulate the ability to maintain themselves in the face of that entropy. Cell senescence effects a broad change in gene expression that results in a gradual failure to deal with DNA repair, mitochondrial repair, free radical damage, and molecular turnover in general. Aging isn’t a matter of damage, it’s a matter of no longer repairing the damage.

All of this wouldn’t matter – it’s mere words and theory – were it not for our ability to intervene in age-related disease. Once we understand how aging works, once we look carefully at our assumptions and reconsider them, our more accurate and fundamental understanding allows suggests how we might cure age-related disease, to finally treat the diseases we have so long thought beyond our ability. It is our ability to see with fresh eyes, to look at all organisms and all cells without preconceptions, that permits us to finally do something about Alzheimer’s and other age-related disease.

Only an open mind will allow us to save lives.

 

December 13, 2016

Telomeres: The Purloined Letter of Aging

     “What is only complex is mistaken (a not unusual error) for what is profound.”

                                                Edgar Allen Poe

 Edgar Allen Poe is still well-known for his poetry, he is less well-known for his detective stories. Some 170 years ago, his Parisian amateur detective, Dupin, was the conceptual forerunner for Sherlock Holmes, who made his London debut almost half a century later. Poe also made a series of observations that echo, even today, as we try to understand aging, age-related disease, and how we can cure them.

Poe’s detective pointed out that even intelligent, meticulous investigators are often oblivious to the obvious. The same can even be true of modern scientific investigators, who may focus so closely on their hard-won facts that the relationships between those facts – and their implications – are often overlooked. In aging research, for example, many investigators focus so intensely on genes, proteins, and small-molecular therapies, that they can miss the broader picture and miss an effective approach to curing the diseases of aging. Putting it simply, too often we focus our intellect, our education, and our strenuous effort on the “nouns”, but we entirely miss the “verbs”. We know the data, we fail to see what it means.

The intellect, the education, the dedication, and the funding are enormous, but our focus is off-target and the results, as expected, are futile. Truth, Poe tells us, is frequently overlooked, regardless of how intense our investigation. In describing such a case (in Poe’s case a policeman, in our case a scientist), Poe put it this way:

“… he erred continually by the very intensity of his investigations. He impaired his vision by holding the object too close. He might see, perhaps, one or two points with unusual clearness, but in so doing he, necessarily, lost sight of the matter as a whole. Thus there is such a thing as being too profound. Truth is not always in a well. In fact, as regards the more important knowledge, I do believe that she is invariably superficial.”

 As Poe suggest, we seek truth in the depth of a well in a valley, while truth is usually sitting in plain sight on the (easily visualized) mountain tops surrounding that valley. Such is the case with aging. It’s not that the truth is simple, for aging is far more complex than most of us give it credit for, but the truth is not found in the narrow details so much as it found in the overview of those details. The truth really is on the mountain tops, not in the bottom of a well, even when that well includes reams of data. It’s not the amount of data that is crucial, but the implications of that data. To give an example from clinical medicine, I may know everything about a patient’s fever, their hypotension, their abnormal white count, and their vomiting, but the numbers alone aren’t nearly as important as the realization that the patient has Ebola. Curing an Ebola infection cannot be relegated to lowering a fever, increasing the IV fluid, removing white cells, and given an anti-emetic. It’s not the individual therapies that cure Ebola, it’s the realization that you’re dealing with a viral infection and the use of a more general – and more effective – therapy, whether an antiviral or an immunization.

There is a parallel in understanding aging.

Treating the diseases of aging is not a matter of using individual therapies, but a matter of understanding the more profound relationships that change in aging cells. Until we do so, we will continue to fail when we try monoclonal antibodies for beta amyloid – as Eli Lilly finally realized with its Solanezumab trials – or merely attack tau proteins, mitochondrial changes, inflammation, or other targets. In each case, we have mistaken a plethora of data for a profundity of data. Only when we realize the actual complexity, the dynamic biological relationships, the profound effects of epigenetic changes, the role of telomeres as a therapeutic target, and that the fundamental pathology of aging and age-related diseases is rooted in cell senescence, only then will we — to our own vast and naïve surprise — discover that we can cure most of the diseases that still plague humankind.

 

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