Across Large Populations, Telomere Length Falters as a Biomarker of Aging in the Oldest Cohorts

Telomeres are the repeated DNA sequences found at the ends of chromosomes. A little of that length is lost with each cell division, and this serves as a part of the mechanism that limits the number of times a somatic cell can divide. Stem cells employ telomerase to maintain long telomeres through the asymmetric divisions needed to supply tissues with new daughter somatic cells equipped with long telomeres. This split of responsibilities between many restricted cells and a few privileged cells is the primary strategy by which multicellular organisms keep the risk of cancer low enough for evolutionary success.

Given this arrangement, average telomere length in any given tissue is a blurred measure of how fast cells divide and how frequently new cells are delivered by the supporting stem cell population. Over large populations of people, shorter telomere length tends to correlate with greater age, most likely because stem cell activity declines with age. Unfortunately, it is the case that telomere length as presently measured - in leukocytes from a blood sample - is quite dynamic in response to day to day environmental circumstance, and is thus only poorly correlated to aging for any given individual. Telomere measurement services are readily available, but there really isn't all that much that can be deduced from the result. It isn't actionable. If measured again next week or next month, or with a passing infection versus without, then the number will likely be significantly different.

Further, for every study population in which the correlation with aging is affirmed, there is another in which the telomere length data stubbornly refuses to do the expected thing. The study here produces both of these outcomes, confirming the correlation in younger people, but also finding that the relationship falters for individuals older than 80 years of age. All in all telomere length just isn't a very useful measure of aging. It is not robust enough, and its individual variability means that the numbers are next to useless when it comes to guiding medical decisions.

Telomere Length and All-Cause Mortality: A Meta-analysis

Telomere attrition has been widely reported to be associated with increased morbidity and mortality of various age-related diseases. In 2003 was reported for the first time that telomere shortening contributed to all-cause mortality based on a study of 143 unrelated Utah residents aged 60-97 years. More recently, other researchers used the largest study so far (n = 64,637) to demonstrate that short telomeres were associated with a higher risk of all-cause mortality. Although several other studies reported an association of telomere length (TL) with all-cause mortality, there is a substantial variability among the findings of these studies due to the different TL measurement techniques and the varying age, sex, and ethnicity of the study participants. To this end, we aimed to perform a meta-analysis of the association of TL with all-cause mortality, taking advantage of both previously published results from cohort studies of the general population and un-published original data from the Swedish Twin Registry (STR).

We found that shorter leukocyte TL was associated with an increased risk of all-cause mortality, although some between-study heterogeneity was observed. The magnitude of the association of TL and all-cause mortality was similar for the youngest groups (younger than 75 years and 75-80 years), but weaker for the oldest old (over 80 years). The results of our STR cohorts were similar in effect sizes compared to several earlier studies, but slightly weaker than those reported by others.

Women have on average longer telomeres and life expectancy compared to men of the same age. Our STR study further confirmed the sex difference in TL. Several plausible biological mechanisms have been proposed to explain the phenomenon. First, estrogen may stimulate the production of telomerase and may be protective against reactive oxygen species damage. In addition, estrogens have been shown to stimulate the phosphointositol 3-kinase/Akt pathway, which contributes to enhanced telomerase activity. Second, the heterogametic sex hypothesis suggests that shorter telomeres in men may arise if the unguarded X chromosome in men contains inferior telomere maintenance alleles. Third, men have a faster rate of telomere attrition than women although there is no difference of TL at birth. The longer telomeres may on the other hand be a reason for the overall lower risk of age-related diseases and consequently longer lifespan of women compared to men.