Michael Fossel Michael is President of Telocyte

July 31, 2018

3.0 Aging Disease

Aging causes disease.

To many people, the relationship is even closer: aging is a disease. The latter view is controversial. Most biologists and physicians would view aging as a “natural process” and contend that “normal aging” is independent of disease. Aging, in this view is not a disease, although it certainly causes disease. They often distinguish between, for example, “normal” brain aging and abnormal brain aging, such as Alzheimer’s, Parkinson’s, Frontotemporal dementia, vascular dementia, and other dementias.

The academic position that “aging is not a disease” is understandable, but ironically inconsistent with normal human behavior. The same academics who argue that “aging is not a disease” are seen to dye their gray hair, undergo Botox treatments or plastic surgery for wrinkles, buy “anti-aging” skin creams, and do everything they can to avoid aging… Judging from behavior (as opposed to academic argument), humans act as though aging were a disease. We go to a great deal of trouble to avoid a “natural process”. So is aging a disease? There is no objective answer. We argue that aging is not a disease, while acting as though it is.

Nor does the argument that “aging is a natural process” validate the position. Aging may be quite natural, but we avidly avoid many “natural processes” because of the risk of death, pain, disability, or fear. Labor pains and neonatal mortality, infections and epidemics, starvation and malnutrition, broken bones and head injuries, and almost everything that modern medicine works to prevent, cure, or treat is a natural process. Simply because a process is natural does not mean that we accept, condone, or value the outcome of such natural processes. Polio infection, smallpox, and tetanus are all natural processes, but these are also diseases, diseases that we put a lot of global effort into eradicating or preventing.

To argue that infection, trauma, genetic disease, or cancer are natural processes is rational, but misses the point and merely results in clinical nonsense. Yes, these are all natural, but are they desirable? No. Precisely the same can be said of both aging and age-related diseases. Natural yes, desirable no.

Arguments about whether or not aging is a disease lose contact with our daily reality. Rather than dispute semantics consider the practical questions: can we do anything about aging and age-related diseases? Most people find both aging and age-related disease to be uncomfortable and worth avoiding – if possible. One of my 94 year-old patients was asked if she would take a pill to reverse aging. “No, I’d rather let nature take it’s course”. I asked about the scar on her sternum: “Quadruple bypass surgery.” I inquired about her swollen knuckles: “Arthritis and ibuprofen isn’t helping any more.” Why had she come to the hospital? “I have pneumonia and I need to be admitted to the… Oh, wait, I see what you’re driving at. I’d take the pill!” In the abstract aging is fine, but the reality becomes a different matter.

If we are to intervene in age-related disease, we need to intervene in the aging process itself. Beneath every age-related disease lies a more fundamental “disease”, that of aging. It is the very genetic and cellular processes that we have addressed in our previous blog posts that trigger age-related diseases, regardless of cell-type, tissue, or organ. Whether we are looking at dementia, arterial disease, joint changes, or weakening bone, in every case we can trace the clinical disease to the changes occurring deep within cells. The gradual changes in epigenetic pattern and the consequent changes in cell functions underlie all age-related problems.

The underlying, common problem in age-related disease is the shortening of telomeres with consequent gradual, but pervasive changes in the pattern of gene expression. These epigenetic changes are reflected in a significant degradation of cell function, particularly in the rate of turnover of molecular pools (internally and externally), the slowing of DNA repair, the decrease in mitochondrial efficiency, and the increase in the rate of molecular damage. In addition, cell aging impinges upon the function of neighboring cells in each tissue, even if such neighboring cells are not as far along on the cell aging spectrum. Although the underlying problem is the same (telomere shortening, epigenetic changes, cell dysfunction), the outcome varies between tissues. In the brain, the aging of glial cells results in neuronal dysfunction and is expressed clinically as one of several dementias. In the case of vascular endothelial cells, the outcome is arteriosclerotic pathology, and is expressed as myocardial infarction, stroke, aneurysm, peripheral vascular disease, heart failure, and other syndromes. In joints, we see osteoarthritis. In bone, we see osteoporosis. No organ is spared. Skin, lungs, kidneys, the immune system, the endocrine organs – all tissues and organs demonstrate age-related changes, loss of function, and diseases peculiar to themselves.

In every case, however, age-related diseases, regardless of cell type, tissue, or organ, share the same etiology: cell senescence orchestrated by shifts in telomere length. In the next several posts, we will explore the diseases of aging, then move on to interventions to prevent and cure the diseases of aging.

Next time: 3.1 Aging Disease, Cancer

July 16, 2018

Aging and Disease: 2.9 Cell Senescence And Tissue Aging

The human body represents a “system” in the engineering sense: all parts (cells, tissues, organs) are interdependent. To understand how the body functions (and how it ages), we may appropriately study individual cells, but we must also study the interactions between cells. We may start by looking at small communities of cells (local, homogenous tissues), but we must then move onwards, looking at how cells, tissues, and organs interact. To give an example, in studying the blood vessels, we can study cells that make up the inner vessel wall (e.g., vascular endothelial cells), we can study other cells in the local tissue (both endothelial and subendothelial cells), or we can enlarge our view to look at how these cells affect more distant tissues (e.g.,the myocardium). We might start by ignoring the interactions with other cells, but if we want to understand most age-related diseases, then we must consider the more distant effects as well.

Initially, we will focus on the cells within a typical tissue. In fact, we will start by simplifying so far as to pretend that a tissue has only one type of cell: an unlikely example in actual practice, but useful as a didactic concept, if only by allowing us to understand what actually happens to a tissue as its cells age.

One overarching concept requires emphasis: failing cells result in failing tissues.

Groups of cells do not fail because of some enigmatic gestalt phenomenon, groups of cells fail because changes in individual cells have effects upon the cells around them, as well as more distant tissues. No cell operates independently, even within a “homogenous” tissue. When cells fail, they not only become dysfunctional by themselves, but they actively interfere with the function of other neighboring cells. To use an analogy, if we have a group of people working together in an organization, then aging is a process in which the organization fails not solely because some individuals refuse to do their job, but because those individuals actively interfere with others around them. To take this analogy back into the biological world, age-related disease occurs because the aging of any particular cell can have multiple effects:

  1. Aging cells no longer do their jobs within the tissue.
  2. Aging cells directly interfere with function of other cells within the tissue.
  3. Aging cells indirectly interfere with the function of more distant tissues.

You might think of a single aging cell as a “sin of omission”, in that the cell no longer performs its normal function; however any aging cell is also a “sin of commission” because it actively interferes with the normal function of other cells as well. To give an example, aging glial cells become dysfunctional in their ability to recycle amyloid molecules, but they also excrete proinflammatory cytokines (and other factors) and thereby interfere with the normal function of surrounding cells that are not senescent. This latter process is generically referred to as SASP (“senescence associated secretory phenotype”) and is typical of most aging tissues.

Aging is not a uniform process, either between tissues or within tissues. In any tissue, not all cells are the same functional “age”. Even in a fairly homogenous tissue, cells age at different rates, have different telomere lengths, and (as a result) differing patterns of senescent gene expression. If we were to measure telomere lengths in aging tissues, we’d find that some tissues have a narrow spread of telomere lengths and others tissues have a large spread, but none of them have all the same telomere lengths. The cells within a tissue have different rates of aging (and different trajectories as well). To see this graphically, see figure 2.9a (adapted from my textbook, Cells, Aging, and Human Disease, Oxford University Press, 2004).

Notice that there are two sorts of variability here: the degree to which any individual cell is “senescent” and the timing of that senescence. As we have noted already, senescence is not an all-or-nothing event, but rather it is a spectrum of dysfunction, due to relative telomere loss and the degree to which the pattern of gene expression has changed. Moreover, some cells move toward senescence quickly, some more slowly, and some with varying trajectories, as shown in figure 2.9a. The result is that if we look at senescence in any given tissue, we see a range of dysfunction. It is not true that all of the cells suddenly flip from normal to senescent, nor is it true that some cells suddenly flip from normal to senescent. In reality, each cell varies in both its degree of senescence and in the rate (or trajectory) of that gradual change. To see this graphically, see figure 2.9b (also adapted from Cells, Aging, and Human Disease).

Cells are part of an extremely complex biological community. Aging cells not only fail to contribute, but can actively and directly impede other cells in that local tissue, as well as having indirect effects in distant tissues. If for example, we look at vascular endothelial cells in the coronary arteries, as some of these cells become senescent, they not only fail to act as adequate “linings” to the artery, they also trigger inflammatory changes in the underlying (subendothelial) cells, Moreover, this local pathology within the coronary artery can result in decreased blood flow (chronically as the vessel narrows and acutely if a thrombus breaks free and “corks” more distant vessels, causing ischemia). In the community of cells that comprise the heart and its coronary arteries, endothelial cell senescence results in a dysfunctional vessel surface (local cells), an atherosclerotic local mass within the vessel wall (the neighboring cells), and, for example, a myocardial infarction in cardiac muscle cells (the more distant cells, that are mere “innocent bystanders”). Cells may be senesce locally, but their senesce may have a dramatic impact on distant cells and the outcome may be fatal for the entire organism. No cell is independent and this is all the more true of age-related disease.

Later in this set of blogs, we will make the distinction between direct and indirect pathology. Direct pathology occurs when one type of senescing cell (for example, the chondrocytes of your knee) directly result in age-related disease in that same tissue (for example, osteoarthritis in that same knee). Indirect pathology occurs when one type of senescing cell (for example, the endothelial cells in your coronary arteries) indirectly result in age-related disease in a different tissue (for example, myocardial infarction when the artery fails).Before exploring these more typical forms of aging and age-related disease however, we will look at another, related type of disease that, while still related to cell senescence and aging, has characteristics all its own: cancer.

First, however, let’s consider age-related disease as a whole.

 

Next Time: 3.0 Aging Disease

July 4, 2018

Aging and Disease: 2.8 Cell Senescence, Changes In Molecular Turnover, Extracellular Molecules

The human body contains perhaps a bit short of 40 trillion cells, which is an impressive number, yet a large part of our body – a quarter to a third, depending how you measure it – isn’t intracellular, but extracellular. This includes not only the fluids within the blood and lymphatic spaces, but the space that lies between our cells, even in “solid” tissue. This extracellular space is just as critical – and as it turns out, just as dynamic – as our intracellular space.

The extracellular space has cells within it, for example the fibroblasts in our dermis, the lymphocytes wandering about in our lymphatic system, and the red and white (and other) cells circulating in our blood streams, but if we ignore all of these cells for a moment, we find that the extracellular space is still a complex place. It is replete with important molecules, including electrolytes and proteins (and many others), and these molecules are continually being “recycled”, much as the intracellular molecules are.

The extracellular space is not a quiet place and certainly not a place where protein molecules can quietly “retire” for a few decades. To the contrary, the molecules come and go, subject to continual degradation and replacement. Aging doesn’t occur simply because molecules “sit around and fall apart”. Aging occurs because molecules aren’t turned over as quickly as we age.

Looking solely at human skin – and then solely at a few of the dozens of important molecules that play a role – we find two well-known molecules that are worth focusing on: collagen and elastin. We will simplify our discussion by looking just at the skin, just at collagen and elastin, and just at both proteins generically, intentionally ignoring the multiple subtypes of both collagen and elastin. We will also simplify our discussion by ignoring the water, electrolytes, immune proteins, enzymes, hormones, and various other structural proteins (keratin, muscle, bony matrix, fibronectin, laminins, etc.) that we might discuss.

Let’s focus on what happens to the collagen and elastin in our skin as we age.

Both collagen and elastin are familiar to most of us, as well as to anyone who has ever watched advertisements for skin care products. Collagen is a long, chain-like protein that provides strength and some cushioning throughout the body, including the skin. It is collagen that keeps your skin from pulling apart, providing resistance to stress. In addition to skin, collagen is also found in cartilage, tendons, bones, ligaments, and just about everywhere else. Elastin is – as the name suggests – and elastic molecule that allows skin (and other tissues) to return to its original position when it has been deformed. You might think of collagen as chain that has strength and elastin as a rubber band that stretches. Collagen prevents too much deformation, while elastin pulls skin back after slight deformations.

As we age, both of these fail. Collagen breaks and our skin becomes more fragile and prone to damage from slight impacts or friction. Elastin breaks and our skin sags and no longer “bounces back”. As both of these fail over time, we form wrinkles, although these are only one of the obvious cosmetic changes that occur. Skin loses both strength (collagen) and elasticity (elastin) over time. Why?

Whether you are six or sixty, your collagen and elastin molecules are steadily breaking down and failing. The difference is not the rate of damage, but the rate of turnover. This is the rate at which molecules – such as collagen and elastin — are recycled and replaced. In young skin, collagen turnover can be as high as 10% per day, but the rate of turnover falls steadily with chronological age, or more specifically, with cell aging. As cells are lost and replaced by cell division, the telomeres shorten, gene expression changes, and molecular turnover slows down. The older your cells, the slower the rate at which they replace damaged extracellular proteins, whether collagen, elastin, or any other protein (such as beta amyloid in the elderly patient with Alzheimer’s disease). No wonder our skin becomes fragile, loses elasticity, and develops wrinkles.
Despite the advertising world, none of these changes are amenable to moisturizers, protein injections, serums, creams, or a host of other “miracle anti-aging products” that tout the ability to erase wrinkles, rejuvenate skin, and restore lost beauty.

There is, however, one intervention that would be effective: to reset gene expression and upregulate molecular turnover, so that key molecules, such as collagen and elastin, are more rapidly turned over, with the result that damaged molecules no longer accumulate, but are replaced more quickly. The key to extracellular aging isn’t the damage, but the rate of turnover. The practical implication is that whether we are talking about collagen, elastin, beta amyloid, or dozens of other types of extracellular protein, we can effectively intervene by resetting gene expression. Whether we are looking at skin, joints, bone, or brains, the potential is an innovative and effective intervention for age-related problems.

Next Time: 2.9 Cell Senescence And Tissue Aging

June 20, 2018

Aging and Disease: 2.7 Cell Senescence, Changes In Molecular Turnover, Mitochondria

Filed under: mitochondria,senescent cells,Telomeres — Tags: , , — webmaster @ 9:28 am

Many people assume that mitochondria (and free radicals) lie at the heart of aging or that they are “the cause” of aging. Despite having a central role in aging, the assumption that mitochondria cause aging is both simplistic and – not to put too fine a point on it – is totally at odds with both logic and evidence.

Mitochondria do not cause aging.

This is not to say that mitochondria don’t play a central role in aging cells, but playing a central role is not the same as being the cause nor the same as an overarching explanation for aging, let alone an explanation for age-related disease. By analogy, fevers and elevated white blood cell counts (leukocytoses) play a central role in the clinical presentation of many viral infections, but they neither cause nor explain any viral infection. To describe the presentation of a viral infection, you should include the clinical symptoms and signs, including fevers and high white counts, but while they are an integral part of the process of infection, they don’t cause infection. With that in mind, let’s consider mitochondria, starting with a high-level perspective and then looking at the way mitochondria change in aging cells. In so doing, we will see how mitochondrial aging plays a role in cell aging, but we will also see that mitochondrial aging is secondary to changes within the nucleus, and specifically to changes in gene expression as modulated by telomere shortening.

Previously, we pointed out that every cell in your body is – biologically speaking – several billion years old, yet those cells only show evidence of aging during the several decades of a typical human lifespan. We each inherit a line of cells that didn’t age for billions of years, and yet begin aging during the several decades after birth. The same is true for mitochondria. Every mitochondria in the human body is at least 1.5 billion years old, the time at which the first mitochondria and eukaryotic cell joined forces. If you suggest that all aging is due to aging mitochondria, then you are immediately brought up short by the biological provenance of mitochondria. You end up forced to admit that mitochondria didn’t age for 1.5 billion years and yet (as with your cells themselves) begin aging during the decades after birth.

You inherit mitochondria that have never aged and that then age rapidly during your lifespan. If mitochondria cause aging, then why didn’t they age for the past 1.5 billion years? Why suddenly now? In short, if you want to explain aging by pointing to mitochondria, then you are going to have to back up a step and explain mitochondrial aging itself.

To put it bluntly: if mitochondrial aging causes human aging, then what causes mitochondrial aging?

As we’re just seen, you can’t very well blame “wear and tear”, since your mitochondria are all 1.5 billion years old and they did perfectly well until you came along. If mitochondria play a key role (and they do), you still have to ask why mitochondria sometimes do age and sometimes don’t, or why mitochondria didn’t age for billions of years, but then suddenly age after conception. We can’t simply ignore the question, wave our hands, and blame “free radical damage”.

Yet it is clear that mitochondria show changes during cell aging. There are two clear changes in metabolism: they become less efficient at creating energy (ATP) and they become more likely to produce free radicals (ROS). Putting it graphically, we see that as telomeres shorten, as gene expression changes, and as cells progress toward senescence, we find that the mitochondria show a decrease in ATP production and an increase in ROS production. Putting it differently, the ratio of ATP/ROS goes down with age. As our cells age, they get sloppier, taking more effort to produce usable cellular energy, while simultaneously creating more damaging ROS as they do so. To be specific, young cells typically produce about 1-4% ROS for every mole of ATP, but this percentage increases as our cells senesce. Nor, as we will see, is ROS production the only problem.

To understand why mitochondria lose efficiency, and why it is the result of telomere shortening, we need to understand a bit about mitochondria and their dependence upon the nucleus. It’s true that the mitochondria have their own 37 genes and that these code for 13 proteins that are critical to aerobic metabolism, but it is equally true that most mitochondrial enzymes are imported from the nucleus. Likewise, while the rate of mitochondrial DNA damage is 3 to 20-fold higher than that of nuclear DNA damage (due to the high concentration of mitochondrial ROS, the lack of protective histones, the lack of introns, and less effective mitochondrial DNA repair), mitochondrial DNA repair, replication, and transcription, as well as mitochondrial maintenance generally (including membrane maintenance) are entirely dependent upon the nuclear DNA. Moreover, most of the aerobic enzymes (including those required for the citric acid cycle) have components that are coded for in nuclear genes. In other words, mitochondrial function is almost entirely dependent upon gene expression in the nucleus, which is modulated by telomere shortening. The mitochondria and mitochondrial energy metabolism (including both ATP and ROS production) are completely at the mercy of nuclear gene expression, and are not independent. Aging occurs because changes in nuclear gene expression result in mitochondrial dysfunction, not the other way around.

Looking at this visually, almost all the enzymes required for normal mitochondrial function are based in the nucleus, not in the mitochondria. The mitochondria, far from being an island unto itself, is entirely dependent upon nuclear DNA, the rates of nuclear gene expression, and telomere modulation of that gene expression.

We have already pointed out that, as cells age, the mitochondria become less adept at producing energy, as well as increasingly prone to producing ROS. By implication, these two changes in energy metabolism are both the result of changes in gene expression within the nucleus, but these are far from the only changes that occur with cell aging. A young, fully functional cell has four processes which address the dangers of ROS. These four processes are:

 

  1. Production:           ROS are produced within the mitochondria
  2. Sequestration:     Membranes restrict ROS within the mitochondria
  3. Trapping:             Scavenger molecules “capture” ROS outside the mitochondria
  4. Repair:                 DNA repair and molecular turnover deal with ROS damage

 

The bulk (perhaps 93%) of ROS are produced within the mitochondria. In young cells, the rate of production is relatively low and even those ROS that are produced are generally kept within the mitochondrial membranes. As cells age (and as telomeres shorten and gene expression alters), the enzymes required for efficient energy production are turned over less rapidly, are less available, and are more likely to be denatured: the outcome is that the rate of ROS production climbs. Moreover, a similar problem is occurring within the membranes that wall off the mitochondria: the enzymes responsible for cell membrane molecules – mostly lipid molecules – are also down regulated, with the result that membrane molecular turnover slows, the percent of damaged (oxidized) lipids increases, and the membranes are increasingly porous, allowing ROS leakage to increase. Adding to the membrane problem is that membrane leakage also rises in the nuclear membranes, so the rate of DNA damage rises even as the rate of DNA repair begins to fall. In short, as telomeres shorten and gene expression changes, the mitochondria not only produce more ROS, but are more likely to leak ROS into the cytoplasm and the nucleus.

In the young cell, such ROS are rapidly trapped by multiple mechanisms, including SOD (superoxide dismutase), catalase, and other enzymes coded for in the nucleus (as well as trapping due to dietary scavenger agents, such as urate, tocopherols, etc.). As cells age, however, these scavenger enzymes are recycled more slowly and at any given time the older cell has an increasing percentage of dysfunctional ROS scavenger molecules. Worse yet, the rate of DNA repair declines, as does the rate of recycling of damaged molecules generally.

The result of these four processes is the “perfect storm”, a multiplicative set of four effects causing an exponential increase in overall cell damage.

  1. Mitochondrial ROS production increases,
  2. Mitochondrial and nuclear membrane leakage increases,
  3. ROS damage increases as scavenger efficiency declines, and
  4. Cellular responses to damage (molecular recycling and DNA repair) decline.

It is little wonder that antioxidants have little practical effect upon cell aging or age-related diseases. An increase in dietary anti-oxidants shows almost no effect upon the third of these four effects (scavenging) and no effect whatsoever upon the other three effects (production, leakage, or recycling/repair of damage.

As cells age, there are critical changes within the mitochondria as well as in the cell’s ability to respond to the increasingly dysfunctional mitochondria. However, all of these changes – in production, sequestration, scavenging, and repair – are the result of changes occurring within the nucleus. Much of what happens in cell aging can be seen in the increasing dysfunction of the mitochondria, but all of these changes are secondary to changes within the nucleus.

Specifically, it is telomere shortening and its effect upon gene expression within the nucleus that results in mitochondrial aging. Mitochondrial changes are a key part of the tragedy that plays out on the stage of cellular aging, but that tragedy is directed by the nuclear chromosomes – and by our telomeres.

Next Time: 2.8 Cell Senescence, Changes In Molecular Turnover, Extra-Cellular Molecules

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 27, 2018

Aging and Disease: 2.1 – Cell senescence, Why Cells Divide

Why do some people age faster than others? We’ve all seen people – high school reunions come to mind – who have the same chronological age, but different biological ages: with the same “age”, one person looks ten years older (or younger) than another. If aging is related to cell senescence and cell senescence depends on cell division, then why do some people’s cells divide more than other people’s cells? Why don’t people age at the same rate?

Why does he look old, but she doesn’t, even at the same “age”?

And why do our own organs and tissues age at different rates? We’ve all seen people whose skin looks old, but they have no evidence of osteoarthritis or dementia; equally, we’ve seen other people with terrible osteoarthritis, but no heart disease or dementia. Not only do we age at different rates when we compare different people, but our tissues sometimes age at different rates even within the same person. If aging is related to cell senescence and cell senescence depends on cell division, then why do people vary internally, having some cells (in one tissue) divide more frequently than other cells (in another tissue)? Why don’t all of our tissues age in parallel?

Why does he have bad knees, but she has a bad heart, even at the same “age”?

The easy – and naïve – answer is to say the magic word “genes” and nod knowingly.

The real – and more complex – answer demands a lot more thought. It requires that we reexamine both the data and our assumptions. It requires, in a word, that we think about what’s really going on. Part of this complex answer begins easily. We notice that people who were exposed to too much sun (and too many sun burns), for example, have skin that ages faster than people who avoided sun damage to their skin, and this is true even with identical genes, as in identical twins. We have discussed the fact that aging is not simple a matter of genes, but it’s a balance between damage and maintenance. “It’s not the years, it’s the miles.” Indeed, the degree to which we pile damage onto our tissues shows a good correlation to how fast those tissues show aging and age-related disease. Most of us know this without really thinking about it. For example, we automatically assume that smoking causes COPD, “bad” diets increase your risk of heart attacks, and so forth. These assumptions are now part of our cultural baggage and (true or not) have attained the status of medical wisdom. In fact, to a large extent these are supported by a fair amount of good evidence, although it’s always a bit more complex than the current culturally accepted facts would have you believe. For example, it may or may not (depending on the decade we’re talking about) be accepted that dietary cholesterol has a direct impact on the cholesterol deposits in your coronary arteries, but the evidence that dietary intake (unspecified for the moment, but not just cholesterol) has a long-term impact on coronary artery disease is fairly good.

In short, your behavior (diet, exercise, stress, etc.) can accelerate or decelerate not only your overall rate of aging, but the rate of aging (and age-related disease) in a number of specific tissues. To give a few more examples, people engaged in high-impact activities (think basketball) have a higher incidence of osteoarthritis of the knees than do people engaged in low-impact activities (think yoga). People who get repeated head injuries (think pugilists and American football players) have a higher incidence of Alzheimer’s and other dementias. In both of these cases – osteoarthritis and dementia – those at high risk not only have a higher incidence of the age-related disease in old age, but they get the specific age-related disease at a younger age than do those at lower risk. They are both more likely to get the disease and more likely to get it earlier. What this tells us is not surprising: aging is related to what you do behaviorally, not just who you are genetically. In short, it’s not just your genes.

Genes do, of course, play a fundamental role but they do it in complex relationship with the damage that accrues over a lifetime. If you really want to avoid osteoarthritis, you not only want to have parents who never had osteoarthritis, but you want to avoid repetitive high-impacts to your joints. If you really want to avoid dementia, you not only want a double allele of APOE-2 (instead of two APOE-4 alleles), but you want to avoid boxing or playing football. But then if these sorts of behavior cause age-related disease, and cell senescence underlies age-related disease, what is the relationship?

The key relationship is the rate of cell division. If your cells are forced to divide more frequently, you force them to senesce faster. If, for example, you damage your knees (forcing your chondrocytes to divide and replace the damaged cells) then you will accelerate aging in your knees (as those cells divide, lose telomeres, and change gene expression). The more you damage your knee joints, the more rapidly your chondrocytes divide, and the more rapidly you develop osteoarthritis. If you damage your head (forcing glial cells to divide and replace the damaged cells), then you will accelerate aging in your brain (as those cells divide, lose telomeres, and change gene expression). The more you damage your brain, the more rapidly your glial cells divide, and the more rapidly you develop dementia.

The details, the pathology, the reality of these age-related diseases are wildly more complex than this cursory review suggests, but the basic theme is valid. Given equivalent genes, people who engage in a lifestyle that increases cell turnover will increase their rate of aging. Likewise, your particular lifestyle may increase cell turnover preferentially in one organ or tissue and that will accelerate the rate at which that organ or tissue develops age-related disease.

Any cell in your body (in any tissue) has a baseline “rate of cell division” (i.e., rate of tissue aging). Skin cells, gastrointestinal lining cells, and hematopoietic stem cells divide frequently, while neurons, muscle cells, etc. divide very infrequently in the adult (an in some cases, not at all). Anything that accelerates cell division, accelerates aging. Anytime you increase the rate of damage to a tissue, you increase the rate of cell division (i.e., the rate of tissue aging) and the result is increased aging and increased age-related disease. The same is true between individuals. We each (based on our own genetics) have what you might think of as a “baseline rate of aging” for our body. If you take care of yourself, you still age inexorably, but relatively slowly. If you engage in a high-risk lifestyle, you will age not only inexorably, but relatively quickly.

Aging is caused by cell senescence and cell senescence is cause by cell division, but while you need your cells to divide in order to survive, the relative rate of cell division is, to an extent, controlled by your lifestyle. Cells divide because you’re alive, but the way you live has an impact on how fact those cells divide and how fast you age.

So, let’s answer our initial question. We have been making the case that aging occurs because cells divide, shortening telomeres, which changes gene expression, which results in dysfunctional cells, dysfunctional tissues, and tissue aging (and disease). This is true, but it begs the question of “if cell division causes aging, then what causes cell division?”

The answer is that cell division is both a natural result of being you (your genes, your personality, your culture, and the simple fact that you are alive and some of your cells MUST divide to keep you alive) and the result of what you do to yourself. You have a baseline rate of cell division (and hence aging). If you have a high-risk lifestyle, you age faster; if you have a low-risk lifestyle, you age a bit more slowly. You can increase or decrease your rate of aging – to a degree – depending on what you do. There is (so far) nothing you can do to STOP aging, but can certainly make it a bit slower, or a lot faster.

Next time: 2.2 Cell senescence, Telomeres

March 20, 2018

Aging and Disease: 2.0 – Cell senescence, Perspective

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

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

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

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

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

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

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

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

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

Next time: 2.1 Cell senescence, why cells divide

 

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