A Telomere-Centric View of the Biochemistry of Aging

Telomeres are lengths of repeated DNA at the end of chromosomes that in part serve as a sort of clock to limit the life span of some cell types. Telomeres shorten with each cell division, but can be lengthened in longer-lived cells (such as stem cells) by the activity of telomerase. Average telomere length tends to shorten in white blood cells with ill health and aging, but this is somewhat dynamic: go out and exercise more and your average telomere length will increase, for example. Looking at the average length is a smeared-out measure of numerous low-level processes in our biology, such as telomerase activity, the pace at which stem cells are generating new cells with long telomeres, rate of cell division, and so on and so forth.

For some years now there has been a contingent of researchers focused on telomeres: producing better ways to measure them, or more ambitiously trying to construct therapies that lengthen telomeres using telomerase. It seems to me that most research indicates shortening telomere length to be a secondary marker of aging, and thus not a helpful target to either slow or reverse aging, but there exist studies in which mouse life span was extended by upregulating the activity of telomerase. This may, however, be one of those areas of biology in which mice are in fact significantly different from people, or it may be the case that telomerase has other effects independent of lengthening telomeres, such as acting to reduce levels of mitochondrial damage.

Why is that telomere lengths are such good predictors of longevity, but too much telomerase can be bad for you? The answer is probably that telomere lengths measured in the white blood cells reflect a broad range of factors, such as our genetic makeup but also the history of a cell. Some of us may be lucky because we are genetically endowed with a slightly higher telomerase activity or longer telomeres, but the environment also plays a major role in regulating telomeres. If our cells are exposed to a lot of stress and injury - even at a young age - then they are forced to divide more often and shorten their telomeres. The telomere length measurements which predict health and longevity are snapshots taken at a certain point in time and cannot distinguish between inherited traits which confer the gift of longer telomeres to some and the lack of environmental stressors which may have allowed cells to maintain long telomeres.

What are the stressors which can affect cellular aging and shortening of telomeres? Oxidative stress, the excess production of reactive oxygen species oxidizes proteins, disrupting their structure and function to the extent that oxidized proteins become either useless or even harmful. Inflammatory stress refers to excessive inflammation which transcends the normal inflammatory response of cells from which they can recover. Prolonged inflammation, for example, can cause cells to activate a cell-death program. Recent studies in mice have shown that activation of inflammation pathways in the brain can suppress cognitive function, muscle strength and overall longevity. Stressors are often interconnected. Prolonged elevation of stress hormones or prolonged inflammation can increase oxidative stress. The higher the level of these stressors, the more prematurely cells will age. This means that the body of a person in their 30s or 40s exposed to high levels of inflammation or oxidative stress may already numerous cells showing signs of aging.

How do these stressors lead to premature aging? Shortening of telomeres could be one answer. If cells are chronically inflamed due to autoimmune diseases or inflammation-associated diseases such as obesity and atherosclerosis then they have to be continuously replaced by cell division which shortens telomeres. However, telomere shortening is not the only route to cell aging. Aging research groups have uncovered multiple additional pathways which can accelerate the premature aging of cells without necessarily requiring the shortening of telomeres. Inflammation or oxidative stress can activate certain aging pathways such as the aging regulator p16INK4a. An inflammatory cytokine can convert highly regenerative blood vessel progenitor cells into aged cells which no longer replicate by activating p16INK4a, and that this occurs without affecting telomere length. Researchers have uncovered an important vicious cycle: Once cells begin aging, they themselves release inflammatory proteins which in turn can activate aging in neighboring cells, thus setting a self-reinforcing cascade of aging in motion.

Where does this interaction of telomere-dependent and telomere-independent aging pathways as well as the influence of known (and many unknown) stressors leave us? The molecular understanding of cellular aging is progressing steadily, but the complexity of cellular aging and the even more complex question of how organs such as the brain and heart age requires a lot more work. There will be no single molecular switch which can reverse or halt aging and triple our lifespan, but most aging researchers do not have this as their goal. Understanding specific aging pathways, as well as the genes and stressors which activate them, will allow us to prevent and treat age-related diseases as well as one day be able to provide personalized advice to individuals on how to maximize their "healthspan".

Link: http://blogs.scientificamerican.com/guest-blog/2014/07/05/aging-too-much-telomerase-can-be-as-bad-as-too-little/


Is it not likely that telomere shortening is the mechanism the body uses to induce apoptosis to get rid of damaged cells and to replace them with new cells freshly grown from the stem cells? Its not the telomere shortening itself thats causing the aging, but the underlying aging process that is damaging the cells that then requires the body to use telomere shorting to get rid of and replacing them with new cells. This seems plausible to me.

Posted by: Abelard Lindsey at July 7th, 2014 11:28 AM

Left unsaid is the mechanism of telomere shortening. When DNA polymerase attaches to a chromosome to duplicate it, polymerase covers up a few DNA bases of the telomere. It cannot duplicate the bases it covers; so the telomere becomes shorter each time the cell duplicates. However, it is probable that telomerase is active in the stem cells, and keeps the stem cells' telomeres from shortening, as opposed to the somatic cells whose telomeres shorten with each cell division.

Posted by: Jerry Collins at July 9th, 2016 1:07 PM

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