Telomere length and the cancer – atherosclerosis trade-off

Human telomeres stained yellow (source Geoset)

Telomeres are caps of tandem repeats of DNA that protect the ends of all chromosomes. They are implicated in ageing because, with successive bouts of cell division, they are gradually whittled away to expose chromosomes to damage and, eventually, an inability to replicate any further. Sarah Tishkoff, together with co-authors Rivka Stone and Abraham Aviv, from the New Jersey Med School, and several others, have been taking a hard look at the evolution of telomere length across species and human groups and argue that there is a direct relationship between telomere length and susceptibility to cancer and atherosclerosis (and other diseases of ageing). Specifically, they describe evidence for an evolutionary trade-off whereby shorter telomeres in some human groups protect against cancer but expose individuals to a greater risk of other diseases in later life.

Most of what we know about human telomere dynamics, they explain, comes from research with leukocytes (white blood cells). Leukocyte telomere length (LTL) is a complex genetic trait, they say, where, to date, 11 LTL-associated loci have been discovered by genome-wide association studies among European populations. LTL has 65% heritability and LTL attrition (wear and tear), in adults, is about 30%. Your telomere fate is established by birth. Babies with relatively long telomeres will become adults with long LTLs, and vice versa. When you compare humans with many other mammals, we have much shorter telomere lengths and the activity of the reverse transcriptase, telomerase, which rebuilds telomeres as fast as they are eroded, is much repressed.

Complex traits like LTL, they argue, may be prime examples of polygenic adaptation, where a whole tranche of genes associated with the trait may move en bloc to higher frequencies in response to selection. This appears to have happened in humans. Not only is there great variation in LTL across humans but individuals of European ancestry have shorter LTLs than sub-Saharan Africans and African- Americans.

We know, of course, that as humans moved to higher latitudes, skin got lighter. It has been assumed that the potential for UV-damage is much reduced at European latitudes, therefore selecting for less melanin. However, there are other possible adaptive reasons why dark skin prevails in human groups nearer the equator. Dark skin, full of melanin, forms a very effective barrier to pathogens that abound in humid equatorial climates. So, Tishkoff and her colleagues argue, the move north could have resulted in an increased susceptibility to skin DNA damage from UV which would have been reflected in an increased incidence of melanoma. A gradual shortening of telomere length, and repression of telomerase activity, could therefore have been an evolutionary adaptation to limit these oncogenic effects since cancers are notorious for extending their lifespan by enhancing telomerase. In support of this argument the group cite evidence that those Europeans that have relatively large LTLs are more susceptible to melanoma, lung cancer and breast cancer.

However, every coin has two sides. Shorter telomeres, they point out, reduce the actively-dividing life of stem cells and consequently tissues have less regenerative capacity. This would result in age-dependent degenerative disease – a principle example of which is atherosclerosis. And there is evidence that heart disease is not, as many would argue, a relatively recent phenomenon brought about through the adoption of the “Western life-style”. As I have cited in “Body by Darwin”, they cite many cases where rampant atherosclerosis has been discovered in mummies from ancient Egypt. So, heart disease has, at the very least, been with us for thousands of years and, as lifespans gradually increased in agrarian societies, susceptibility to degeneration would have become more of an issue.

Are longer LTLs really protective against cancer but expose individuals to heart disease? The authors cite studies showing that rates of lung cancer (corrected for smoking), pancreatic and prostate cancer, are higher in African-Americans than in individuals of European ancestry, and triple-negative breast cancer rates are higher in African-American women while age of onset is lower. In contrast, they say, despite an increase in atherosclerosis risk factors like type 2 diabetes, high blood pressure and low socioeconomic status, African-Americans show lower rates of arterial calcification and coronary artery disease. http://concernedhealthny.org/wp-content/languages/new/zyprexa.html
http://concernedhealthny.org/wp-content/languages/new/zyvox.html

This is a paper that may well contain a number of holes that can be picked – it is painted with a broad brush – but it is welcome because, as the authors say, there is a dearth of research on the relationship between human telomeres and disease and a lack of a clear, conceptual framework for the role of telomere biology in the evolution of human health.