Sci. Aging Knowl. Environ., 22 December 2004
Vol. 2004, Issue 51, p. pe43
[DOI: 10.1126/sageke.2004.51.pe43]

PERSPECTIVES

Telomeres and Human Aging: Facts and Fibs

Abraham Aviv

The author is at the Hypertension Research Center, The Cardiovascular Research Institute, at the University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA. E-mail: avivab{at}umdnj.edu

http://sageke.sciencemag.org/cgi/content/full/2004/51/pe43

Key Words: telomere • white blood cell • biomarker • replicative senescence

Introduction

To what extent can we exploit the swirl of scientific data regarding the mechanisms that determine life span to better understand old age and give the best medical treatment to the aging human? In light of the fuzzy boundary between aging and a host of aging-related diseases, this central quandary both challenges and baffles gerontologists grappling with an onslaught of the elderly in need of medical care. Clinically, we define aging by a singular entity, namely age. A person is as old (aged) as the person's birth certificate. Clearly, this measure of aging is not good enough for medical purposes, given that aging and the rate at which it occurs are biological phenomena, and age is a chronological entity designated by the calendar. As the frequency and severity of aging-related disorders, such as cardiovascular disease, cancer, and dementia, increase with age, should we consider these maladies as distinct expressions of processes that complicate aging? Alternatively, because the etiology of aging is multifactorial, might aging-related disorders epitomize the multiphenotypic manifestation of old age?

Rationale for the Use of White Blood Cell Telomeres in Humans

A biomarker of human aging may help to answer these complex questions (see Miller Perspective). Unfortunately, an ideal biomarker of human aging has not been identified thus far, although white blood cell (WBC) telomere biology appears to provide a better measure of aging than does chronological age (see also Dimri Perspective for a discussion of other potential biomarkers). The rationale for studying WBC telomeres to understand human aging is based on two premises: (i) cell replication, oxidative stress, and inflammation (see Goldschmidt-Clermont Review and McGeer Review) are major determinants in aging (1, 2), and (ii) WBC telomere dynamics records these processes. However, the validity of both contentions has not been systematically tested. Moreover, we must recognize both the advantages and drawbacks of using WBC telomere dynamics to gauge aging in humans.

Telomere Dynamics in Vitro Versus in Vivo

Telomeres are specialized structures at the ends of linear chromosomes that, in the absence of telomerase, become shorter each time the DNA is replicated. Telomeric DNA is highly repetitive; the human telomere sequence, for example, consists of a string of TTAGGG repeats approximately 4 to 18 kilobases long (see "More Than a Sum of Our Cells" and Heist Perspective). In vitro, telomere dynamics provides information about the replicative history of telomerase-negative somatic cells (3-6). There is also evidence that increased oxidative stress (or reduced antioxidative capacity) enhances the loss of telomere repeats per cell division in cultured cells (7, 8). It follows that if somatic cell replication and oxidative stress figure in the biology of aging, telomere dynamics in vivo may provide information over and above age about the magnitudes of these processes. This proposition assumes that telomeres behave in vivo in the same fashion as in vitro, but we don't know whether this is entirely so. The telomere length of proliferative cells is inversely related to the age of the cell donors (9-13). Further, telomeres are longer in postmitotic tissues than in proliferative tissues in adult humans (14, 15). Both observations support the tenet that telomere attrition registers replicative history in vivo. But does telomere dynamics also record the cumulative burden of oxidative stress in vivo? We really don't know.

WBC Telomere Dynamics in Vivo

Most of the information regarding human telomere dynamics in vivo is derived from WBCs, which comprise different subsets whose mean telomere lengths are not equivalent (16). For instance, na�ve cells have longer telomeres than do memory cells (for a discussion of na�ve and memory cells, see "Immunity Challenge"). In addition, telomere length may be modified during WBC passage through the thymus, where these cells exhibit considerable telomerase activity. Variation among individuals and with age in these modalities may therefore confound conclusions regarding the biological meaning of WBC telomere dynamics in vivo. In this regard, the turnover rate of WBCs increases with inflammation, yet certain inflammatory and autoimmune diseases that are not routinely considered as directly related to aging may modify WBC telomere dynamics and thereby further complicate the links between WBC telomeres and aging (17, 18).

Age-adjusted telomere length is highly variable because of inter-individual differences in telomere length at birth (19) and most likely the rate of telomere attrition thereafter. There is also evidence that telomere attrition rate is faster during early childhood than in later life (20). In principle, a person with faster age-dependent telomere erosion may not always have shorter telomeres than his age-matched peer, if the former was born with longer telomeres. Unless performed in large cohorts, cross-sectional evaluation of telomere length may be underpowered to capture the impact of variation in telomere attrition rates on telomere length.

WBC telomere length is equivalent in newborn girls and boys (19); longer in adult women than men (13, 21-23); and highly heritable, with evidence of X-linked inheritance (10, 21-23). [Although (23) originally stated that "age-adjusted TRF (telomere restriction fragment) length in women was shorter than in men," the correct statement is "age-adjusted TRF length in women was longer than in men"; this correction has been submitted to the American Journal of Human Genetics as an erratum.] In addition, a recent report has documented linkage analysis that mapped a locus affecting telomere length to chromosome 12 (23). Thus, telomere length is likely to be a complex trait with X chromosome-dependent and -independent inheritance. Further support for this concept is provided by dyskeratosis congenita: a rare monogenetic disorder with both X-linked and autosomal modes of inheritance (24, 25). The culprit of X-linked dyskeratosis congenita, the most common form of the disorder, appears to be an amino acid substitution in dyskerin (a protein that modifies ribosomal RNA and binds telomerase), leading to shortened telomere length, bone marrow failure, and thus premature demise in affected men (24) (see "Overturned Ends"). It is rather unlikely that the abnormal genes causing dyskeratosis congenita are also responsible for variation in telomere length in the general population. An array of variant genes, interacting with a host of environmental factors, is more likely to regulate telomere length in normal people.

The longer telomeres in women imply a slower rate of telomere attrition in women than men, but this concept has not been examined directly. If telomere attrition is indeed slower in women than in men, does this rate depend on women's menopausal status? What then is the main factor that accounts for the high heritability of telomere length in the general population? Is it telomere length at birth, the rate of telomere attrition during extra-uterine life, or both?

In addition to all these unanswered queries, there lurks the pertinent matter of whether telomere dynamics is not only a proxy for a host of variables engaged in aging but a determinant in human longevity (26) (Fig. 1). In cultured human somatic cells, critically shortened telomeres may halt replication, an eventuality referred to as replicative senescence (4, 6) (see Hornsby Perspective), but can such a phenomenon occur within the human life span? It takes only a small skip in logic to extend in vitro findings to real-life circumstances and thereby hazard the drawing of unsubstantiated conclusions. Although in the elderly, relatively shortened WBC telomere length may forecast premature death (27) (see "When Tips Disappear, the End Is Near"), the causality of this relation is not established. Thus, the putative role of telomere length as the ultimate determinant in human longevity is presently a matter of conjecture and speculation.



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Fig. 1. Is telomere length a determinant in human longevity?

 
Conclusions

Fundamentally, the questions we face in exploring telomere dynamics in humans and not in mice and in vivo and not in vitro are about biological meaning. A body of research has unraveled associations of shortened age-adjusted WBC telomere length with disorders known to diminish human longevity (21, 28-32). In addition, a recent study has reported that psychological stress is associated with accelerated telomere erosion in peripheral mononuclear cells from otherwise healthy women (33). The threads tying these disorders together may be increased oxidative stress and inflammation. However, the importance of these associations will be determined by conclusions based on future large-scale longitudinal clinical studies that must account for environmental and genetic factors, including (i) caloric intake and obesity; (ii) alcohol consumption; (iii) cigarette smoking; (iv) menopausal status; (v) intake of ovarian steroid hormones, anti-inflammatory agents, and vitamins; and (vi) familial predisposition to a host of cardiovascular diseases, including diabetes. The findings of such studies will hopefully establish whether telomere length, telomere attrition rate, or both provide better information than age alone about not only impending mortality but also the morbidity inflicted by age-related diseases.

Whether the coda of human longevity is shaped by telomere dynamics is altogether another matter (Fig. 1). Being a biomarker of aging is not synonymous with being a determinant of longevity. To establish that human life span rides on telomere length, we will need to show unequivocally that, not only in cultured cells but also in the general elderly population, critically shortened telomeres curtail replication of specific cells whose clonal expansion is vital for survival. Without such evidence, which will not be easy to obtain, the roles of telomere dynamics and replicative senescence in human longevity will remain highly speculative and controversial.


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Citation: A. Aviv, Telomeres and Human Aging: Facts and Fibs. Sci. Aging Knowl. Environ. 2004 (51), pe43 (2004).




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