From: Doug Skrecky (oberon@vcn.bc.ca)
Date: Fri May 16 2003 - 21:08:52 MDT
Nature 2003 May 8;423(6936):181-5
Nicotinamide and PNC1 govern lifespan extension by calorie restriction in
Saccharomyces cerevisiae.
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 B(3)
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.
This archive was generated by hypermail 2.1.5 : Fri May 16 2003 - 21:20:58 MDT