Chronic stress has been associated with decreased telomere length in lymphocytes. The association is robust and has been observed in multiple studies, including one that looked at stress in addition to other risk factors for cardiovascular disease (CVD), so it appears that lymphocyte telomeres are a useful biomarker for some convolution of age and lifetime stress level. The question still remains, however, whether the relationship is correlative or causative. Do stress and other lifestyle factors somehow cause shortened telomeres, or are the two phenomena otherwise-unrelated indications of some common underlying cause?

One of the “trivial” explanations for a causative relationship, usually advanced by critics who aren’t particularly impressed by the initial findings, is that stressed-out or otherwise unhealthy people are more vulnerable to infection than their serene, healthy counterparts. Chronic infection requires increased production of lymphocytes, which overworks the stem cell compartment from which these cells are derived; increased cell divisions leads to decreased telomere length — a perfectly satisfactory explanation for the observation.

If that is true, then chronic infection in the absence of lifestyle risk factors should cause telomere shortening on its own (let’s stipulate for the moment that stress increases susceptibility to disease, an idea supported by my own anecdotal experience of college finals). Ilmonen et al. have demonstrated that this is indeed the case, at least in mouse:

Telomere Attrition Due to Infection

BACKGROUND: Telomeres–the terminal caps of chromosomes–become shorter as individuals age, and there is much interest in determining what causes telomere attrition since this process may play a role in biological aging. The leading hypothesis is that telomere attrition is due to inflammation, exposure to infectious agents, and other types of oxidative stress, which damage telomeres and impair their repair mechanisms. Several lines of evidence support this hypothesis, including observational findings that people exposed to infectious diseases have shorter telomeres. Experimental tests are still needed, however, to distinguish whether infectious diseases actually cause telomere attrition or whether telomere attrition increases susceptibility to infection. Experiments are also needed to determine whether telomere erosion reduces longevity. METHODOLOGY/PRINCIPAL FINDINGS: We experimentally tested whether repeated exposure to an infectious agent, Salmonella enterica, causes telomere attrition in wild-derived house mice (Mus musculus musculus). We repeatedly infected mice with a genetically diverse cocktail of five different S. enterica strains over seven months, and compared changes in telomere length with sham-infected sibling controls. We measured changes in telomere length of white blood cells (WBC) after five infections using a real-time PCR method. Our results show that repeated Salmonella infections cause telomere attrition in WBCs, and particularly for males, which appeared less disease resistant than females. Interestingly, we also found that individuals having long WBC telomeres at early age were relatively disease resistant during later life. Finally, we found evidence that more rapid telomere attrition increases mortality risk, although this trend was not significant. CONCLUSIONS/SIGNIFICANCE: Our results indicate that infectious diseases can cause telomere attrition, and support the idea that telomere length could provide a molecular biomarker for assessing exposure and ability to cope with infectious diseases.

So this part of the “trivial” explanation for the association between stress and telomere shortening holds up under scrutiny, supporting the idea that stress could shorten telomeres secondarily (by causing chronic infection) as opposed to primarily (by some as-yet-unconceived mechanism). In some ways, this diminishes the significance of the stress/telomere connection, since it explains a novel association as a not-very-surprising corollary of two not-very-novel ones.

Nonetheless, the finding is still very important from a biogerontological perspective: To the extent that telomere shortening is a causative force in aging (an idea consistent with correlative data showing an association between critically short telomeres and extreme old age, and bolstered by evidence that telomere length is a heritable determinant of lifespan), this study implies that infection itself contributes to the aging process, at least within the hematopoietic lineage — and that we already have one biomarker, just a PCR away from a peripheral blood sample, to measure the extent of that contribution.

(On a side note: The authors also observed that animals with longer telomeres in early life were more resistant to disease later in life, which is consistent with the idea that one might use telomerase as a means of overcoming immune senescence.)