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

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

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