Mutational inactivation of the Wrn helicase gene causes Werner Syndrome (WS), an autosomal recessive disease characterized by premature aging, elevated genomic instability and increased cancer incidence. The capacity of enforced telomerase expression to rescue premature senescence of cultured human WS cells and the lack of a phenotype in Wrn deficient mice with long telomeres have implicated telomere attrition in WS pathogenesis. Here, we show that the varied and complex in vivo and cellular phenotypes of WS are precipitated upon exhaustion of telomere reserves in mice. In late generation mice doubly null for Wrn and the telomerase RNA component (Terc), telomere dysfunction elicits a classical WS premature aging syndrome typified by premature death, hair graying, alopecia, osteoporosis, type II diabetes, and cataracts. In addition, loss of Wrn promotes the activation of telomerase-independent mechanisms of telomere length maintenance and cooperates with p53 loss to initiate cancer. Our data establish that the delayed manifestation of the complex pleiotropic phenotypes of Wrn deficiency relates to critical telomere shortening.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]