Genetic overexpression of the protein deacetylase Sir2 increases longevity in a variety of lower organisms, and this has prompted a great interest on the effects of its closest mammalian homologue, Sirt1, on aging and cancer. We have generated transgenic mice moderately overexpressing Sirt1 under its own regulatory elements (Sirt1-tg). Old Sirt1-tg mice present lower levels of DNA damage, decreased expression of the aging-associated gene p16Ink4a, a better general health and fewer spontaneous carcinomas and sarcomas. These effects, however, were not sufficiently potent to affect longevity. To further extend these observations, we developed a metabolic syndrome-associated liver cancer model in which wild-type mice develop multiple carcinomas. Sirt1-tg mice show a reduced susceptibility to liver cancer and exhibited improved hepatic protection from both DNA damage and metabolic damage. Together, these results provide direct proof for the anti-aging activity of Sirt1 in mammals and for its tumour suppression activity in aging- and metabolic syndrome-associated cancer.