Sci. STKE, 13 May 2003
LONGEVITY Beyond Caloric Restriction
Restricting calories extends the life-span of various organisms. In the yeast Saccharomyces cerevisiae, this depends upon increased activity of Sir2, a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase. Sir2-related proteins may also promote longevity in higher organisms. Anderson et al. investigated regulation of Sir2 activity by the vitamin B3 precursor nicotinamide, a product of Sir2 activity that acts as a noncompetitive Sir2 inhibitor. They discovered that nicotinamide depletion following increased expression of PNC1 (pyrazinamidase/nicotinamidase) accounted for Sir2 activation in response to caloric restriction and other stresses and thereby increased yeast life-span. The authors investigated the effect of combinations of PNC1 or SIR2 deletion or PNC1 overexpression on yeast life-span under various conditions and concluded that PNC1 was necessary and sufficient for life extension in response to calorie restriction and heat stress. These experiments indicated that PNC1 acts through SIR2. Western analysis of Pnc-1 fused to green fluorescent protein (Pnc1-GFP), combined with measurements of Pnc1 activity, showed increased Pnc1 concentration and activity following caloric restriction and other stresses known to extend yeast life-span. These treatments increased Pnc1-GFP in cytoplasmic foci identified as peroxisomes through marker colocalization and by use of a peroxisome-deficient mutant. Because Pnc1 deaminates nicotinamide as part of the NAD+ salvage pathway, the authors investigated the possibilities that PNC1 exerted its effects on Sir2 through increased NAD+ or decreased nicotinamide. Based on manipulations of nicotinamide metabolism and NAD+ synthesis, the authors concluded that PNC1 regulated Sir2 by modulating levels of nicotinamide and speculated that nicotinamide might regulate critical processes in higher organisms.
R. M. Anderson, K. J. Bitterman, J. G. Wood, O. Medvedik, D. A. Sinclair, Nicotinamide and PNC1 govern lifespan extension by caloric restriction in Saccharomyces cerevisiae. Nature 423, 181-185 (2003). [Online Journal]
Citation: Beyond Caloric Restriction. Sci. STKE 2003, tw188 (2003).
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