Sir2/Sirt1, a mediator of longevity in several animal models, is a member of the sirtuin family of type III histone deacetylases. Its non-histone substrates include a group of regulatory molecules that modulate energy metabolism, such as peroxisome proliferator-activated receptor-gamma (PPAR gamma), and its transcriptional coactivator, PPAR gamma coactivator-1 alpha (PGC-1 alpha). Sirt1's activity on these substrates May underlie its connection with the metabolic changes brought about by caloric restriction (CR). Recent studies have elucidated new substrates for Sirt1 that are involved in metabolic regulation, and have further delineated Sirt1's functional associations with other metabolic regulators like AMP-activated kinase (AMPK) Perplexingly, manipulations that either increase or decrease Sirt1 activity have both been associated with a beneficial effect in animal models of ageing-associated disorders, such as neurodegenerative diseases. Sirt1's activation patterns and roles in energy metabolism appear to have tissue specific differences. A deeper understanding of the mechanistic underpinnings of Sirt1's metabolic functions is necessary to effectively design Sirt1-based therapeutic interventions for metabolic disorders. (C) 2009 Elsevier Inc All rights reserved.