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SPECIAL ARTICLE |
The Center of Human Development and Aging, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark.
Address correspondence to Abraham Aviv, MD, Room F-464, MSB, The Center of Human Development and Aging, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103. E-mail: avivab{at}umdnj.edu
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Mean leukocyte telomere length may be an indicator of biological age, and as such it appears to provide information over and above chronological age of the risk for developing diseases of aging in humans. Here I propose that the mean leukocyte telomere length is an index of "somatic fitness," a concept that breaks down the artificial boundary between aging and diseases of aging. I also propose that, in exceptionally old humans, ultrashort leukocyte telomeres might be a determinant of life span.
Whether manifested as a specific disease of aging (e.g., coronary heart disease) or a nonspecific deterioration in vitality, the ultimate outcome of a major biological impairment, left unchecked, is death. Thus, a woman who has lived to the ripe old age of 100 has better somatic fitness than has her younger peer who dies from diabetes at the age of 65. But the centenarian hardly avoids the specter of aging-related diseases; her life span (defined here as the individual's age at death from biological causes) is long because she experiences these diseases much later or resists their ultimate outcome longer than the average mortal does (1,2).
Though the same fundamental mechanisms govern aging in all organisms, the variation in life span among species suggests that diverse genetic and environmental factors determine the ultimate demise of individuals from different species. Comparisons of potential life-span determinants between species must hence be interpreted with great caution. For instance, most domesticated mice live roughly 1.5–3 years but have long telomeres, whereas humans (who now may live as many as 10 decades) have short telomeres. Might we conclude, then, that telomeres have little to do with the life span of either species? Certainly not! Selection pressures have probably fashioned telomere length, so that for one species there might be an advantage in having short (or long) telomeres, whereas for another species there might not. From the clinical standpoint, the right question to ask is whether in modern humans, rather than in model organisms, telomere length relates to life span.
Additionally, let's sidestep for a moment the question of causality, namely, whether telomere biology is a determinant in human aging. Although highly important, the answer to this question is irrelevant to the central thesis that, within members of the human species, mean telomere length in leukocytes is an index of somatic fitness. This question will be revisited below with regard to the potential link between telomeres and life span in exceptionally old humans.
Replication of somatic cells is associated with the loss of telomere repeats, a process that takes place both in vitro and in vivo (3–5). In cultured cells, telomere attrition ultimately leads to critically shortened telomeres in a subset of chromosomes. This (telomeric) impasse elicits a DNA damage response that curtails further replication. In vivo, telomere length in replicating somatic cells is inversely correlated with the age of the cell donor. As telomere length in humans is highly variable both in newborns (6) and later in life (7–12), cross-sectional analysis of telomere length is not optimal to track interindividual differences in telomere dynamics over time.
That said, cross-sectional analyses have revealed that shorter mean leukocyte telomere length is linked to diseases of aging, which reduce life span, including coronary heart disease, hypertension, and dementia (7,9,13–16). What's more, shorter mean leukocyte telomere length is associated with obesity, insulin resistance, and cigarette smoking (8,11,12). As telomere length is heritable (8,9,11,17), and obesity and cigarette smoking are largely environmental, acting in combination, genes and the environment may not only shorten leukocyte telomere length but also reduce the human life span.
Cawthon and colleagues (18) observed a lower survival of persons older than 60 years with relatively short mean leukocyte telomere length, but recently, Martin-Ruiz and colleagues (19) could not find a link between mortality and mean telomere length in mononuclear cells of persons older than 85 years. These are not necessarily contradictory observations. For obvious reasons, age-related changes in telomere dynamics in cohorts that include extremely old persons are confounded by selective mortality. Thus, exceptionally old humans are hardly ordinary with respect to their telomere biology and many other factors.
In ordinary individuals, mean leukocyte telomere length may be a surrogate indicator of dysfunctions that cause aging-related diseases and ultimately premature death. If so, in the general population, individuals with shorter mean leukocyte telomere length may tend to die earlier for the simple reason that they express aging-related diseases at a younger age than do their peers. However, exceptionally old persons have survived or have not experienced most of the aging-related maladies that killed their younger peers. In them, telomere length in subsets of leukocytes might have become short enough to curtail clonal expansion, leading to immune senescence and declining ability to fight not only infection but also cancer. In this way leukocyte telomeres become a determinant in mortality and therefore life span of exceptionally old persons. But if cultured cells are any guide, it is not the mean telomere length that brings about replicative senescence; the culprits are the shortest telomeres (20,21). Thus, in and of itself, the mean length of leukocyte telomeres might not provide the optimal measure of interindividual variation in the life span of exceptionally old persons.
The longer life expectancy (22) and mean leukocyte telomeres (7–9) of modern women than men support the premise that mean leukocyte telomere length is an intermediate phenotype of somatic fitness. Because leukocyte telomere attrition is about 20–30 base pairs per year (7,8,12,23), in telomere length equivalence, the sex-related difference in leukocyte telomere length amounts to approximately 7–8 years.
As telomere length is equivalent in newborn boys and girls (6), the sex-related difference in leukocyte telomere length appears to arise from variables that affect telomere attrition during extrauterine life. These variables may include ovarian steroid hormones, particularly estrogen, and selection pressure between two somatic cell types.
Oxidative stress and inflammation figure centrally in several hypotheses of aging and life span (24,25). Oxidative stress accelerates telomere erosion during somatic cell replication (26,27), and inflammation increases leukocyte turnover rate. Thus, the temporal loss of telomere repeats chronicles the individual's life history of both oxidative stress and inflammation. Estrogen, a powerful antioxidant in most tissues (but not in the breast, for instance) and an antiinflammatory agent (28–30), probably attenuates leukocyte telomere erosion in women.
The longer life span of women than men may also originate from innate differences in somatic cell profiles between the two sexes. One of the X chromosomes of each somatic cell of the developing female embryo is stochastically inactivated during the early phases of embryonic life—a process that silences roughly 75% of the genes on the affected chromosome (31,32). Newborn girls, therefore, exhibit a balanced somatic cell mosaicism, in that half of their cells have an active paternal X chromosome and the other half an active maternal X chromosome. These two populations of somatic cells differ in a host of functions by virtue of their dissimilar active X chromosomes. However, somatic cell mosaicism is skewed in elderly women, so that the majority of their somatic cells exhibit either an active paternal or an active maternal X chromosome (33,34). This intriguing and ostensibly epigenetic phenomenon may be explained by selection pressure during the woman's life span. With advancing age, within each woman, cells with superior somatic fitness and presumably longer telomeres, are more likely to survive. A man, in contrast, possesses only one somatic cell type with respect to the X chromosome and is hence disadvantaged as compared with a woman in terms of somatic cell selection.
Altogether, women's augmented antioxidative and antiinflammatory capacity, boosted by the advantage of somatic cell selection, bespeaks a better somatic fitness, expressed in the longer life span and leukocyte telomere length of women than men.
Finally, humans have evolved to become the longest living terrestrial mammal. To attain this status, evolutionary forces must have strengthened humans' ability to fight cancer (35). Cancer is primarily an aging-related disease; the question, then, is "Why is it so infrequent at a younger age?" In no small part, the answer may be the relatively short human telomeres, which are a powerful hurdle to neoplastic transformation. Cancer develops through successive mutations that occur when cell replication runs amok, bypassing cell cycle checkpoints. Short telomeres might hence constitute a fail-safe mechanism to cull potentially cancerous cells. It may not be a coincidence that most cancers demonstrate robust activity of telomerase (36) or have resorted to the alternate (ALT) pathway (37), which employs mechanisms other than telomerase to dodge the telomeric barrier. It follows that the relatively short telomeres in humans may well be an evolutionary tradeoff, expressed by a powerful anticancer capacity at the expense of curtailing a further increase in life span.
In conclusion, mounting evidence supports the premise that, in humans, mean leukocyte telomere length is an index of somatic fitness, which is expressed in life-span duration. Sex, genes, and environment modify leukocyte telomere erosion and also affect the duration of the human life span.
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The author's research on telomeres is supported by National Institutes of Health grants AG021593 and AG020132 and by The Healthcare Foundation of New Jersey.
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Decision Editor: Luigi Ferrucci, MD, PhD
Received December 6, 2005
Accepted February 6, 2006
References
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 J B. Richards, A. M Valdes, J. P Gardner, D. Paximadas, M. Kimura, A. Nessa, X. Lu, G. L Surdulescu, R. Swaminathan, T. D Spector, et al. Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women Am. J. Clinical Nutrition, November 1, 2007; 86(5): 1420 - 1425. [Abstract] [Full Text] [PDF]
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