Michael Fossel Michael is President of Telocyte

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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