Telomeres and Premature Aging

Among the first mouse models to show multiple signs of accelerated aging was the telomerase knockout mouse. These mice completely lack telomerase activity owing to a germ-line disruption in the gene encoding the essential telomerase RNA component, mTR (147). Interestingly, mTR-/- mice are asymptomatic for the first three to four generations. Subsequent generations, however, are shorter lived and prematurely develop hair loss and graying, ulcerative skin lesions, delayed wound healing, reduced fertility, reduced stress resistance, and increased cancer. As noted earlier, mice have telomeres that are much longer than humans. It is notable, then, that the reduced longevity and fitness of mTR-/- mice were not manifest until the mouse telomeres had substantially shortened to lengths more typical of those found in aged human tissues. Thus, this model demonstrates a critical role for telomere function not only in suppressing cancer, but also in ensuring many other aspects of organismal fitness.

The reduced-longevity and premature-aging phenotypes of mTR-/- mice are even more pronounced when combined with a deficiency in WRN (Chapter 3), the gene that is defective in the human premature-aging disorder, Werner syndrome (WS) (148). WRN encodes a DNA exonuclease/helicase that participates in several processes important for genomic stability, including telomere maintenance (149). Humans with WS develop multiple aging phenotypes (e.g., wrinkled skin, thin gray hair, cataracts, osteoporosis, type II diabetes, cancer)

shortly after puberty, and generally die in the fifth or sixth decade of life. By contrast, WRN-/- mice are largely asymptomatic. However, when crossed to mTR-/- mice and allowed to propagate for three to four generations, WRN-/-mTR-/- double mutants rapidly develop many of the symptoms seen in WS

(150). In addition, cells from the double-mutant mice, like cells from WS patients, undergo rapid senescence in culture. This mouse model, then, suggests that many of the progeroid symptoms in WS are a consequence of improper telomere maintenance. Further, it supports the idea that cellular senescence can cause or contribute to some aging phenotypes and diseases.

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