Sirt1's systemic protective roles and its promise as a target in antiaging medicine

Silent information regulator 2 (Sir2/Sirt1), a member of the sirtuin family of class III histone deacetylases, has been implicated extensively in lifespan extension and is a prominent drug target in antiaging medicine. The mammalian Sirtl has multiple targets, which include histones, transcription factors, and other molecules that collectively modulate energy metabolism, stress response, and cell/tissue survival. Several of Sirtl's substrates regulate key metabolic processes, and Sirtl activation may underlie the lifespan prolonging effect of caloric restriction. Recent studies have also identified multifaceted protective roles for Sirtl against cellular senescence and stress in the neural, cardiovascular, and renal systems. Sirtl's activity in multiple tissues may decline with aging, and sustaining or reactivating this activity seems invariably beneficial. Several studies also point towards a general tumor suppressive role for Sirtl at least in the context of certain human cancers. Development of Sirtl-based therapeutic interventions against systemic aging and aging-associated diseases will benefit from a thorough understanding of underlying pathological mechanisms of diseases as well as metabolic connections between different tissues and organs. (Translational Research 2011;157:276-284)