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

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