Authors: Anderson RM; Bitterman KJ; Wood JG; Medvedik O; Sinclair DA
Abstract: Calorie restriction extends lifespan in a broad range of organisms, from yeasts to mammals. Numerous hypotheses have been proposed to explain this phenomenon, including decreased oxidative damage and altered energy metabolism. In Saccharomyces cerevisiae, lifespan extension by calorie restriction requires the NAD+-dependent histone deacetylase, Sir2 (ref. 1). We have recently shown that Sir2 and its closest human homologue SIRT1, a p53 deacetylase, are strongly inhibited by the vitamin B3 precursor nicotinamide. Here we show that increased expression of PNC1 (pyrazinamidase/nicotinamidase 1), which encodes an enzyme that deaminates nicotinamide, is both necessary and sufficient for lifespan extension by calorie restriction and low-intensity stress. We also identify PNC1 as a longevity gene that is responsive to all stimuli that extend lifespan. We provide evidence that nicotinamide depletion is sufficient to activate Sir2 and that this is the mechanism by which PNC1 regulates longevity. We conclude that yeast lifespan extension by calorie restriction is the consequence of an active cellular response to a low-intensity stress and speculate that nicotinamide might regulate critical cellular processes in higher organisms.Keywords: *Caloric Restriction; Cell Nucleus/metabolism; Cytoplasm/metabolism; Energy Metabolism; Gene Expression Regulation, Fungal; Gene Silencing; Heat-Shock Response; Histone Deacetylases/metabolism; Longevity/genetics/physiology; NAD/metabolism; Niacin/metabolism; Niacinamide/*metabolism; Nicotinamidase/genetics/*metabolism; Saccharomyces cerevisiae/cytology/enzymology/genetics/*metabolism; Saccharomyces cerevisiae Proteins/genetics/*metabolism; Silent Information Regulator Proteins, Saccharomyces cerevisiae/metabolism; Sirtuin 2; Sirtuins/metabolism
Date: May 9, 2003
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Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Sinclair DA (2003) Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423: 181-5.