Genetic studies of human progeric syndromes have furthered our understanding of the molecular mechanisms of the aging process. Mutations in Wrn causes Werner Syndrome (WS), a disease characterized by premature aging, elevated genomic instability and cancer. WS fibroblasts prematurely senescence due to telomere shortening, suggesting the possibility that telomere dysfunction collaborates with Wm loss to generate WS. Telomeres function to prevent chromosomal ends from being recognized as double-strand DNA breaks and confer genome stability. It has been postulated that telomere shortening serves as a molecular clock that eventually signals replicative senescence. WS cells senescence while still possessing long telomeres, suggesting that they may be hypersensitive to telomere shortening. This hypothesis is supported by the observation that the senescence phenotype observed in WS cells can be rescued by overexpression of telomerase, suggesting that one consequence of the WS defect is the acceleration of normal telomere-based senescence. Mice lacking WRN do not display obvious aging phenotypes, and I hypothesize that manifestation of the WS phenotype requires the presence of critically short telomeres. Mouse telomeres are normally too long for the required telomere attrition to take place during the aging process. ? ? To test experimentally the hypothesis that manifestation of the WS phenotype in WRN-/- mice requires critical telomere shortening, telomere lengths were shortened genetically via successive intercrossings of WRN-/- mTERC-/- mice. Compound mutant mice with short dysfunctional telomeres exhibited early onset of aging phenotypes, including alopecia, cataract formation and glucose intolerance and died prematurely. These exciting results suggest that our mouse model recapitulates features of WS observed in human patients. Our immediate goal is to characterize additional aging phenotypes in these mice and to correlate the onset of premature aging with genomic instability induced by telomere dysfunction. These studies should establish a role for WRN function in mammalian telomere biology and lend support to the notion that telomeres play a causative role in mammalian aging. ? ?
