The Werner and Bloom syndromes are caused by loss-of-function mutations in WRN and BLM, respectively, which encode the RecQ family DNA helicases WRN and BLM, respectively. Persons with Werner syndrome displays premature aging of the skin, vasculature, reproductive system, and bone, and those with Bloom syndrome display more limited features of aging, including premature menopause; both syndromes involve genome instability and increased cancer. The proteins participate in recombinational repair of stalled replication forks or DNA breaks, but the precise functions of the proteins that prevent rapid aging are unknown. Accumulating evidence points to telomeres as targets of WRN and BLM, but the importance in vivo of the proteins in telomere biology has not been tested. We show that Wrn and Blm mutations each accentuate pathology in later-generation mice lacking the telomerase RNA template Terc, including acceleration of phenotypes characteristic of latest-generation Terc mutants. Furthermore, pathology not observed in Terc mutants but similar to that observed in Werner syndrome and Bloom syndrome, such as bone loss, was observed. The pathology was accompanied by enhanced telomere dysfunction, including end-to-end chromosome fusions and greater loss of telomere repeat DNA compared with Terc mutants. These findings indicate that telomere dysfunction may contribute to the pathogenesis of Werner syndrome and Bloom syndrome.Clues to aging mechanisms have come from segmental progeroid disorders, genetic diseases that hasten certain features of aging. Chief among these is Werner syndrome, characterized by premature aging of the skin, vasculature, and bone and elevated rates of certain cancers, particularly sarcomas (12, 37). A related disease is Bloom syndrome, characterized by limited features of aging, including premature menopause, and by short stature and elevated rates of most cancers (10). Werner syndrome and Bloom syndrome are caused by loss-offunction mutations in WRN and BLM, respectively, which encode 3Ј-5Ј DNA helicases of the RecQ family (11, 60). The WRN protein also includes a 3Ј-5Ј exonuclease domain not shared with BLM (20,47). Based on the genome instability in Werner and Bloom syndromes, cell biological studies, biochemical studies of the purified proteins, and genetic studies of RecQ homologues in yeasts and Escherichia coli, it is widely accepted that the proteins function in the recombinational repair of stalled replication forks or double-strand breaks (25,35,36). Furthermore, there is evidence that WRN and BLM function in S-phase checkpoint and apoptotic responses to DNA damage (25, 35). Several observations indicate that the proteins also play important roles in telomere maintenance (36). Although the maintenance of DNA stability throughout the genome by WRN and BLM presumably contributes substantially to their anticancer activities, it is not yet known what particular functions of the proteins are most important for preventing rapid aging.Evidence pointing to telomere functions for the WRN and BLM ...