Telomere Shortening and Organismal Aging

Genomic instability has long been recognized as a common characteristic of both aging and cancer cells. Accumulation of genomic changes such as random point mutations has been proposed as a cause of aging (Dolle et al. 1997). In support of this hypothesis, increasing evidence links human premature aging syndromes and mouse models of premature aging with DNA damage-induced genome dysfunction. Mutant mice unable to repair accumulated DNA damages exhibit symptoms of premature aging and die early (Rudolph et al. 1999, Tyner et al. 2002, Cao et al. 2003, de Boer et al. 2002, Wong et al. 2003), suggesting that proper maintenance of genomic integrity is essential for longevity. Late-generation telomerase null animals display a subset of aging phenotypes, including alopecia, hair greying, a reduced stress response, and decreased longevity (Rudolph et al. 1999). These animals also exhibit elevated genomic instability, manifested as chromosomal fusions and increased cancer incidence. Enhanced sensitivity to genotoxic agents such as ionizing radiation and alkylating agents is also noted in late generation mTerc~'~ mice and derivative cell lines (Wong et al. 2000, Goytisolo et al. 2000, Lee et al. 2001), suggesting that activation of the DNA damage response pathways cooperates with dysfunctional telomeres to further compromise cellular functions in vivo. In support of this notion, inactivating p53 in late-generation mTerc-'- mice rescues many of the associated premature aging phenotypes (Chin et al. 1999).

Although telomeres shorten in aged individuals, and telomere shortening triggers replicative senescence in cultured human cells (Allsopp et al. 1992), the causal contribution of telomere shortening to organismal aging remained unclear until the advent of the telomerase knockout mouse (Rudolph et al. 1999, Herrera et al. 2000). The generation of additional mouse models possessing dysfunctional telom-eres therefore promised to further illuminate the importance of telomere attrition during organismal aging. The ATM kinase plays a critically important role in sensing double-strand DNA breaks and in the coordination of how this signal is relayed to downstream DNA damage checkpoint proteins, in particular p53 (reviewed in Shiloh 2003). Late-generation mTerc~'~ATM~'~ mice experience increased telomere attrition, elevated genomic instability, and generalized proliferation defects across all cellular compartments examined, leading to the onset of premature aging phenotypes and early death (Wong et al. 2003). Interestingly, late-generation mTerc~'~ATM~'~ neuronal stem cells failed to proliferate and differentiate into viable neurons, possibly explaining the neurodegenerative phenotype observed in AT patients. An unexpected finding is the near total suppression of lymphomas in late-generation mTerc~'~ATM~'~ mice (Qi et al. 2003, Wong et al. 2003), in marked contrast to the increased cancer incidence observed in the p53~'~mTerc~'~ mouse (Chin et al. 1999). These contrasting phenotypes could be explained by the fact that p53 can still be constitutively activated in mTerc~'~ATM~'~ mice by dysfunctional telomeres, leading to tumor suppression. Indeed, constitutive activation of a hyper-functional mutant p53 in the mouse germ line has been shown to suppress tumori-genesis while promoting the onset of premature aging phenotypes in mice (Tyner et al. 2002). These results suggest that inappropriate activation of p53 by dysfunctional telomeres in the setting of ATM deficiency may lead to the manifestation of aging phenotypes observed in mTerc~'~ATM~'~ mice. Support for this hypothesis comes from the observation that in late-generation mTerc~'~ mice, dysfunctional telomeres upregulate p53 in diverse cellular compartments including the skin and heart (Gonzalez-Suarez et al. 2000, Leri et al. 2003).

Perhaps the most direct evidence linking telomere dynamics and age-related degenerative conditions in humans comes from the investigations of the human disease, Dyskeratosis congenita (DC) (Dokal 2001; see also Du et al., this volume). DC is a multisystem disorder characterized by a triad of skin abnormalities, including abnormal skin pigmentation, nail dystrophy, and mucosal l eukoplakia. DC patients also experience increased cancer risk and most often succumb to bone marrow failure by the fourth decade of life. These phenotypes bear a striking resemblance to those observed in the mTerc null mouse (Blasco et al. 1997, Lee et al. 1998), and in a satisfying confirmation of the relevance of the telomerase knockout mouse in modeling human telomere biology, the autosomal-dominant form of DC was found to be linked to mutations in genes governing Terc stability (Mitchell et al. 1999) or in the human Terc gene itself (Vulliamy et al. 2001). These mutations result in diminished telomerase activity in critical stem cell compartments, leading to telomere dysfunction, premature bone marrow depletion, and ultimately bone marrow failure. Similar to the generational effects seen in the mTerc null mouse, patients with DC are more severely affected in later generations, most likely due to the inheritance of progressively shorter telomeres (Vulliamy et al. 2004). This disease anticipation, in which the onset of disease occurs at progressively younger ages in subsequent generations, is observed only in siblings inheriting a defective copy of hTerc. These genetic observations strongly implicate critical telomere shortening in successive generations as a mechanism for disease anticipation, and support the notion that a steady increase in the level of telomere dysfunction could contribute to age-related disease processes in normal elderly individuals. Finally, the concordant biological features between the telomerase knockout mouse and DC patients provided a measure of validation that the mouse can serve as a relevant model organism to dissect the complex roles of telomeres in human pathobiology including normal aging, age-related disorders, and inherited premature aging syndromes.

100 Hair Growth Tips

100 Hair Growth Tips

100 Hair Growth Tips EVERY Balding Person Should Know. This Report

Get My Free Ebook

Post a comment