Is systemic activation of Sirt1 beneficial for ageing-associated metabolic disorders?
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 (PPARgamma), and its transcriptional coactivator, PPARgammacoactivator-1alpha (PGC-1alpha). 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.
Tang
Bor Luen
BL
Department of Biochemistry, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 8 Medical Drive, Singapore. bchtbl@nus.edu.sg
Chua
Christelle En Lin
CE
D000375:Aging / Q000378:metabolism*; D000818:Animals; D004734:Energy Metabolism; D006801:Humans; D008659:Metabolic Diseases / Q000201:enzymology*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
C447939:SIRT1 protein, human; D056564:Sirtuin 1