Leukocyte telomere length has emerged as a predictor of earlier onset of aging-related morbidity and mortality in older adults.8–11
Telomere length traditionally has been thought important in age-related functional decline and development of chronic disease. No studies have examined whether shorter telomere length might also be related to acute functional consequences in younger, healthy populations. In this study, we used a prospective viral-challenge methodology to test whether leukocyte telomere length is associated with host resistance to standardized exposure to a virus that causes the common cold in humans (RV39). Further, because CD8CD28− T cells appear to play an important role in immune response to immunization and are particularly prone to early telomere shortening, we compared telomere length in these cells with length in several other peripheral blood cell populations.
We found that shorter telomere lengths in all 4 cell types were associated with greater odds of infection following experimental exposure to RV39. However, CD8CD28− telomere length had the largest association with infection. Moreover, after CD8CD28− telomere length was entered into the logistic equation, adding the telomere length for other cell types did not improve the prediction. Further, only CD8CD28− telomere length was associated with clinical illness.
When examining these relations by age, we found that the association between CD8C28− telomere length and infection increased with increasing age. The increasing importance of leukocyte telomere length with advancing age may be attributable to cells with very short telomeres becoming more prevalent as individuals get older (eg, 31% of 30- to 55-year-olds vs 17% of 18- to 22-year-olds had CD8CD28− telomere lengths in the bottom 20% of the distribution); to a younger immune system more effectively compensating for the level of CD8 cell senescence; or to CD8 cell senescence contributing to immune impairment, especially impairment occurring within the context of other age-related biological changes.
This is a preliminary study with a small volunteer sample and modest effect sizes. However, because these analyses were prospective, we can eliminate reverse causation (developing an infection or illness in this study did not cause shortening of telomere length) as an alternative explanation. Use of multiple control variables (age, sex/birth control status, race, prechallenge antibody, season, BMI, day of blood draw to assess telomere length) eliminated many potential spurious explanations. Even so, the possibility remains that alternative unspecified third variables, eg, a common genetic contributor to both telomere length and susceptibility to infection, could account for our results. Also, the generalizability of the results may be limited if study volunteers differ significantly from the wider population.
There are no published functional data (eg, differences in virus-stimulated proliferation or cytokine production) comparing CD8CD28+ and CD8CD28− cells as they pertain specifically to RV infection. Consequently, the explanations for our findings are speculative and based on a more general understanding of the function of these cells. Because CD8 lymphocytes are important for eliminating virus-infected cells, a decreased ability to replicate would likely contribute to an increased susceptibility to viral infection. CD8CD28− cells with short telomeres are near or have already reached replicative senescence22
and have poor antigen-induced proliferation.23
Thus, the number of effector cells available to respond to the virus may be reduced in persons with a large number of senescent or near-senescent CD8 cells.
There is a close relationship between the CD28 molecule and the telomere/telomerase aging system.18,24
Without CD28, cells can no longer upregulate telomerase during activation, which is essential for proliferation, cytokine/chemokine production, and antiviral activity.22
Maintaining CD28 (through gene transduction) slows immunosenescence by increasing telomerase activity and cell proliferation and by reducing proinflammatory cytokine expression in vitro.25
Given these in vitro findings, it is reasonable to expect that in vivo loss of CD28 from CD8 cells should impair the host’s ability to fight infection.
Previous research has shown telomere length to be shorter in CD8CD28− relative to CD8CD28+ cells, with that research being restricted to samples of patients who are older26
or human immunodeficiency virus-positive27
and to 1 small study (n = 10) of 29- to 59-year-olds.28
In contrast, we found no difference in telomere length between CD8CD28− and CD8CD28+ cells in our healthy younger sample (mean age, 29.9 years). Nevertheless, CD8CD28− cells did show a wide range of telomere lengths.
In sum, this study found an association between leukocyte telomere length and resistance to a common virus infection in healthy young and midlife adults. These findings are consistent with the wide variance in leukocyte telomere length found in young adults.18
The presence of short telomeres among young people could result from several factors including genetics,29–30
younger paternal age at conception,26
poor health behaviors, and oxidative31
and chronic psychological stress.32,33
CD8 cell senescence has also been attributed to the presence of latent viral infections34,35
and proinflammatory environments.36
Implicit in the relationship between telomere length and colds in this study is that telomere length is relatively stable over the course of at least 1 to 2 months. Published data from a small study of 30- to 50-year-olds found that telomere length in leukocytes is quite stable over the course of 7 months (r
whereas a 10-year follow-up of a large sample of older adults (>53 years) found a still substantial but smaller association (r
Evidence of long-term stability is also suggested by correlations of telomere length with stable individual characteristics including genetic markers,29,30
and stable psychological dispositions.40,41
A provocative possibility is that telomere length is a very stable marker of disease susceptibility, with associations between telomere length and clinical outcomes beginning to emerge in early adulthood.
In this study of healthy young and midlife adults, shorter CD8CD28− cell telomere length was associated with upper respiratory tract infection and clinical illness following experimental exposure to rhinovirus. Because these data are preliminary, their clinical implications are unknown.