Questioning Telomere Dynamics as a Predictor of Mortality

Telomeres are caps of repeating DNA sequences at the end of chromosomes. They shorten with each cell division, a little lost when DNA is replicated, and are lengthened by the activity of the enzyme telomerase, which adds additional repeating sequences. When telomeres become very short cells cease to replicate or self-destruct. Thus average telomere length in the cells of any given tissue is a function of how frequently those cells replicate, local levels of telomerase activity, how frequently new cells with long telomeres are created by the stem cell population supporting that tissue, and most likely a range of other factors. Average telomere length tends to decline and the proportion of very short telomeres increase with stress, illness, and advancing age, the latter being effectively just another form of becoming ill.

Telomere length may or may not be an important contributing cause of aging. From where I stand it looks very much like a secondary marker of aging, a consequence of other forms of damage. But researchers have demonstrated extension of life in mice through use of telomerase to extend telomeres - so there is the possibility that in and of itself loss of telomere length is doing further harm.

Measuring telomere length is a business these days. A few young companies have launched to bring to the clinic the laboratory techniques developed for measuring telomere length in blood samples. The hope here is that this has some predictive or diagnostic value, and it certainly seems at first sight that something useful can be found in the data. But straightforward comparisons of telomere length and health do not tend to yield useful results, as illustrated by this and similar studies:

Longitudinal Changes in Leukocyte Telomere Length and Mortality in Humans

Leukocyte telomere length (LTL) ostensibly shortens with age and has been moderately associated with mortality. In humans, these findings have come almost solely from cross-sectional studies. Only recently has LTL shortening within individuals been analyzed in longitudinal studies. Such studies are relevant to establish LTL dynamics as biomarkers of mortality as well as to disentangle the causality of telomeres on aging.

We present a large longitudinal study on LTL and human mortality, where the 10-year change of LTL is analyzed in 1,356 individuals aged 30-70 years. We find age, smoking status, and alcohol consumption to be associated with LTL attrition and confirm a strong association with baseline LTL. The latter association might be an epiphenomenon of regression to the mean. We do not find an association of mortality with either absolute LTL or LTL attrition. This study establishes that certain lifestyle factors influence LTL dynamics. However, it questions the applicability of LTL dynamics as a predictor of mortality.

Other research groups have found that more complex measures, such as looking at the proportion of very short telomeres and changes in that metric over time, can produce better results in animal studies. So there may be ways to slice the data so as to produce a useful outcome.

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