TY - JOUR
T1 - Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels
AU - Anderson, Rozalyn M.
AU - Bitterman, Kevin J.
AU - Wood, Jason G.
AU - Medvedik, Oliver
AU - Cohen, Haim
AU - Lin, Stephen S.
AU - Manchester, Jill K.
AU - Gordon, Jeffrey I.
AU - Sinclair, David A.
PY - 2002/5/24
Y1 - 2002/5/24
N2 - Yeast deprived of nutrients exhibit a marked life span extension that requires the activity of the NAD+-dependent histone deacetylase, Sir2p. Here we show that increased dosage of NPT1, encoding a nicotinate phosphoribosyltransferase critical for the NAD+ salvage pathway, increases Sir2-dependent silencing, stabilizes the rDNA locus, and extends yeast replicative life span by up to 60%. Both NPT1 and SIR2 provide resistance against heat shock, demonstrating that these genes act in a more general manner to promote cell survival. We show that Nptl and a previously uncharacterized salvage pathway enzyme, Nma2, are both concentrated in the nucleus, indicating that a significant amount of NAD+ is regenerated in this organelle. Additional copies of the salvage pathway genes, PNC1, NMA1, and NMA2, increase telomeric and rDNA silencing, implying that multiple steps affect the rate of the pathway. Although Sir2-dependent processes are enhanced by additional NPT1 steady-state NAD+ levels and NAD+/NADH ratios remain unaltered. This finding suggests that yeast life span extension may be facilitated by an increase in the availability of NAD+ to Sir2, although not through a simple increase in steady-state levels. We propose a model in which increased flux through the NAD+ salvage pathway is responsible for the Sir2-dependent extension of life span.
AB - Yeast deprived of nutrients exhibit a marked life span extension that requires the activity of the NAD+-dependent histone deacetylase, Sir2p. Here we show that increased dosage of NPT1, encoding a nicotinate phosphoribosyltransferase critical for the NAD+ salvage pathway, increases Sir2-dependent silencing, stabilizes the rDNA locus, and extends yeast replicative life span by up to 60%. Both NPT1 and SIR2 provide resistance against heat shock, demonstrating that these genes act in a more general manner to promote cell survival. We show that Nptl and a previously uncharacterized salvage pathway enzyme, Nma2, are both concentrated in the nucleus, indicating that a significant amount of NAD+ is regenerated in this organelle. Additional copies of the salvage pathway genes, PNC1, NMA1, and NMA2, increase telomeric and rDNA silencing, implying that multiple steps affect the rate of the pathway. Although Sir2-dependent processes are enhanced by additional NPT1 steady-state NAD+ levels and NAD+/NADH ratios remain unaltered. This finding suggests that yeast life span extension may be facilitated by an increase in the availability of NAD+ to Sir2, although not through a simple increase in steady-state levels. We propose a model in which increased flux through the NAD+ salvage pathway is responsible for the Sir2-dependent extension of life span.
UR - http://www.scopus.com/inward/record.url?scp=0037166274&partnerID=8YFLogxK
U2 - 10.1074/jbc.M111773200
DO - 10.1074/jbc.M111773200
M3 - Article
C2 - 11884393
AN - SCOPUS:0037166274
SN - 0021-9258
VL - 277
SP - 18881
EP - 18890
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 21
ER -