The family of protein deacetylases represented by yeast Sir2 has been the focus of intense investigation because of the longevity activity of Sir2 in yeast, worms and flies. Research in mammals has mainly focused on SIRT1, the closest homologue of Sir2. Emerging evidence from mouse models is yielding a sharper picture, in which SIRT1 is a potent protector from ageing-associated pathologies, such as diabetes, liver steatosis, cardiovascular disease, neurodegeneration and, importantly, various types of cancer.