Telomeres and Organismal Aging

Despite the finding that telomere length and telomere shortening rates define the replicative potential of telomerase-negative cells in tissue culture experiments, the in vivo evidence for telomere involvement in human aging is mostly limited to correlations. One informative study suggests that the telomeric restriction fragments isolated from DNA from human sperm cells are significantly longer than such fragments isolated from corresponding replicating cells in vivo (Cooke and Smith 1986). Telomeres in kidney samples from young individuals were found to be significantly longer than telomeres in kidney samples from older individuals (Melk et al. 2000). In a different study, the number of senescent skin fibroblasts in baboons increased exponentially with age, thus linking telomere dysfunction and organismal aging (Herbig et al. 2006). Numerous such correlations have been documented, and they show that telomeres shorten with age, and suggest that telomere shortening is one of the underlying causes of aging in humans.

The targeted deletion of the RNA template of telomerase (TERC) in mice (Blasco et al. 1997) provided an opportunity to study the effects of telomere shortening at the organismal level (Rudolph et al. 1999). An aging population of generation 3 TERC knockout mice displayed an increased incidence of hair graying, hair loss, and skin lesions over time. These observations correlated inversely with telomere length in the animals, suggesting a link between the two. The aged generation 3 TERC-/- animals displayed decreased bodyweight, suffered from an impaired stress response, and a decreased wound healing capacity. Although the mice did not suffer from the full spectrum of age-related pathophysiological symptoms of aging, a critical role of telomeres for the overall fitness and well-being of aging organisms could be demonstrated (Rudolph et al. 1999; see also Chang, this volume).

Recently, it has become increasingly clear that telomere function plays a major role in a variety of human disease syndromes. Classical Dyskeratosis Congenita (DC), a heritable disorder, is characterized by bone marrow failure, frequently resulting in premature mortality. The gene for autosomal-dominant DC localizes to chromosome 3q, the same chromosomal location to which the gene for the RNA subunit of telomerase has been mapped. Mutational analysis of TERC in DC families led to the conclusion that this disease is due to mutations in the telomerase template RNA (Vulliamy et al. 2001; see also Du et al., this volume). The observation that DC patients have very short telomeres (Marciniak and Guarente 2001, Marciniak et al. 2000) suggests that DC arises from diminished telomerase activity. Insufficient telomere elongation accelerates telomere shortening (Mitchell et al.

1999), and cells in highly proliferative tissues are lost, which is consistent with the pathology of the disease. The observation that both the catalytic subunit of telom-erase and the RNA template limit telomere elongation (Hao et al. 2005, Liu et al.

2000) suggests that heterozygous mice, missing one allele for either one of these genes, are valid animal models for DC. Indeed, interbreeding of mice heterozygous for TERC with a strain carrying very short telomeres leads to animals suffering from organ failure similar to DC patients (Hao et al. 2005).

Werner Syndrome (WS) is a premature aging disease, in which the patients appear much older than their chronological age, and exhibit many of the clinical signs and symptoms of normal aging at an early stage in life, including an increased incidence of cancer. The WRN gene, mutated in the syndrome, is a member of the RecQ helicase family. Primary cells from WS patients display increased rates of chromosomal aberrations and undergo senescence prematurely, a phenotype reversed by forced telomerase expression (Opresko et al. 2003, Wyllie et al. 2000; see Davis and Kipling, this volume). The involvement of telomerase in the WRN phenotype has been confirmed by the finding that deleting both WRN and telomerase mimics human WRN pathogenesis in mice (Chang et al. 2004). However, accelerated telomere shortening rates in cells lacking WRN cannot explain the slow growth phenotypes of WS cells or the pathological symptoms of WS patients, since no real correlation between the lack of WRN and accelerated telomere erosion has been found (Baird et al. 2004, Schulz et al. 1996, Tahara et al. 1997). However, it has been suggested that individual telomeres are lost at low frequencies from WS cell chromosomes (Crabbe et al. 2004). This telomere loss phenotype is restricted to the telomeric strand synthesized by the lagging-strand replication machinery and depends on the helicase activity of

WRN, leading to a model wherein WRN is required for the efficient replication of the telomeric G strand. Telomerase-based elongation of the critically short telomeres in WS cells is able to suppress the accumulation of genome instability, raising the possibility that telomere loss is linked to the increased incidence of cancer in the syndrome (Crabbe et al. 2007).

While the link between telomeres and replicative aging has now been firmly established (de Lange 1998), little is known about the role played by telomeres during the aging process of differentiated cells and postmitotic organisms. Caenorhabditis elegans is an optimal model system to study organismal aging, since this nematode, after passing through its different developmental stages, consists of differentiated cells only. Surprisingly, overexpression of the telomere-binding protein HRP-1 in the worm not only led to elongation of telomeres, but also to an increased life span (Joeng et al. 2004), raising the possibility that telomere length also affects differentiated cells, and in turn, the aging of postmitotic organisms. However, this debate has not been settled yet, since the life span of clonal wild-type nematode strains and of inbred mouse strains is independent of their highly variable telomere length (Hemann and Greider 2000, Raices et al. 2005).

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