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 nicotinamide2. 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.
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We thank members of the Sinclair laboratory, R. Veech, C. Wolberger, W. Forrester, S. Luikenhuis and D. Finkelstein, for reagents and discussions. This work was supported by the NIA and the Harvard–Armenise Foundation. D.S. is an Ellison Medical Research Foundation Special Fellow. R.A. is supported by a John Taplan Postdoctoral Fellowship, J.W. by a National Science Foundation Scholarship, and K.B. and O.M. by the American Federation of Aging Research.
The authors declare that they have no competing financial interests.
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