Silent information regulator 2 (Sir2) proteins, or sirtuins, are a family of proteins which influence several physiological responses and have implications for treating diseases of ageing. In this context, we have presented a summarized view on the discovery of Sir2 family proteins, the enzymatic activities, the role of sirtuins in aging, lifespan and onset of age-related symptoms. In addition, we have described the roles of mammalian sirtuins-with particular emphasis on their associations to aging, metabolism, and age related diseases with recent references. Current findings provide an understanding about mammalian sirtuins and their target diseases, small molecules discovery or drug discovery targeting sirtuin to tackle the serious diseases of aging. © 2013 Bentham Science Publishers.