NAD Aging

Manipulation of a Nuclear NAD+ Salvage Pathway Delays Aging without Altering Steady-state NAD+ Levels 

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 Npt1 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.

SIRT3, a Mitochondrial Sirtuin Deacetylase, Regulates Mitochondrial Function and Thermogenesis in Brown Adipocytes

Caloric restriction ribosylation google scholar search

SIRT3, a Mitochondrial Sirtuin Deacetylase, Regulates Mitochondrial Function and Thermogenesis in …Find It @ MUgroup of 4 »
T Shi, F Wang, E Stieren, Q Tong – Journal of Biological Chemistry, 2005 –
ribosylation (13) and protein deacetylase activities (14–16). Blocking NAD synthesis
in yeast abolishes the life span extension of caloric restriction (17).
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Small molecule regulation of Sir2 protein deacetylasesFind It @ MUgroup of 5 »
O Grubisha, BC Smith, JM Denu – 2005 – Blackwell Synergy
the ADP-ribose moiety of NAD + and undergo mono-ADP-ribosylation [18]. Originally,
caloric restriction (CR) in yeast was thought to increase the NAD + levels
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 Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases

Intra-mitochondrial Poly(ADP-ribosylation) Contributes to NAD+ Depletion and Cell Death Induced by Oxidative Stress


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