Skepticism of a Causative Role for Telomeres in Aging
A researcher here takes a skeptical look at telomerase studies, such as those shown to extend life in mice, most likely by boosting stem cell activity. There is a school of thought that suggests the role of telomerase in lengthening telomeres is an important mechanism in the induced longevity attained in these studies, but I think it is correct to be skeptical on this count. Erosion of average telomere length occurs over a life span, but this really does not look like a root cause of degenerative aging. Instead the average length of telomeres in immune cells, where it is commonly measured, appears to be a consequence of some combination of stem cell activity and immune health. In any given tissue, cells with long telomeres are created at some pace by stem cells, telomeres shorten with each cell division, and old cells with short telomeres destroy themselves or become senescent. Stem cell activity declines with age, and it isn't a leap to suggest that this will tend to produce shorter average telomere lengths as the supply of new cells diminishes.
Telomeres are repetitive DNA sequences at the ends of linear chromosomes and serve to maintain chromosome integrity. Additional properties have made telomeres a focus in the biology of aging: (i) telomeres shorten at each cell division due to incomplete replication of their ends; (ii) they are shortened by oxidative damage; and (iii) when telomeres reach a critical length, cells enter a senescent state and cell division ceases. This latter property has been demonstrated in now classic experiments, showing that telomere length predicts the in vitro replicative capacity of human fibroblasts and that over-expressing telomerase - the enzyme that can reverse transcribe telomeric sequence - immortalizes fibroblast cell cultures. These experiments suggest the possible causal involvement of telomeres in the aging process and this hypothesis has increased in popularity since the finding that telomere length predicts human mortality and that, in vivo, human telomeres shorten during aging.It is rarely acknowledged in telomere biology that such associations do not necessarily dictate causality. Of course in principle associations can never show causality, and experimental evidence is a starting point. Such inference is useful interpreting data in terms of biological mechanism and for policy, but can also be harmful when such causality is prematurely inferred or assumed. This can lead to reduced or misfocused research effort to uncover the mechanisms actually responsible for the associations that are reported or false inference of the associated biology. In the biology of aging it is tempting to infer causality from biomarkers of aging because aging mechanisms remain so elusive. It is therefore not surprising that causality of telomere length in aging is often inferred from associations or from the available experimental evidence.
Here I question such causal involvement of telomeres in aging. I review the telomerase knockout and overexpression studies that are often cited and hailed as providing the necessary evidence for the causal involvement of telomere biology in aging. I collated studies on the effects on longevity and conclude that, together; the results are surprisingly mixed and provide weak support. In the cases where lifespan changed as predicted in response to the manipulation of telomerase, the effect on telomere length was either outside the normal range of telomere shortening or telomere elongation was not conclusively demonstrated, thereby limiting any strong conclusions. In addition, the causality hypothesis assumes that there is a critical telomere length at which senescence is induced. This generates the prediction that variance in telomere length decreases with age. In contrast, using meta-analysis of human data, I find no such decline. Inferring the causal involvement of telomeres in aging from current knowledge is therefore speculative and could hinder scientific progress.