Abstract
Although NAD(+) biosynthesis is required for Sir2 functions and replicative lifespan in yeast, alterations in NAD(+) precursors have been reported to accelerate aging but not to extend lifespan. In eukaryotes, nicotinamide riboside is a newly discovered NAD(+) precursor that is converted to nicotinamide mononucleotide by specific nicotinamide riboside kinases, Nrk1 and Nrk2. In this study, we discovered that exogenous nicotinamide riboside promotes Sir2-dependent repression of recombination, improves gene silencing, and extends lifespan without calorie restriction. The mechanism of action of nicotinamide riboside is totally dependent on increased net NAD(+) synthesis through two pathways, the Nrk1 pathway and the Urh1/Pnp1/Meu1 pathway, which is Nrk1 independent. Additionally, the two nicotinamide riboside salvage pathways contribute to NAD(+) metabolism in the absence of nicotinamide-riboside supplementation. Thus, like calorie restriction in the mouse, nicotinamide riboside elevates NAD(+) and increases Sir2 function.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Gene Silencing / drug effects
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Histone Deacetylases / metabolism*
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Metabolic Networks and Pathways
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N-Glycosyl Hydrolases / metabolism*
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NAD / metabolism*
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Niacin / metabolism
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Niacinamide / analogs & derivatives*
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Niacinamide / metabolism
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Niacinamide / pharmacology
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Nicotinamidase / metabolism
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Phosphotransferases (Alcohol Group Acceptor) / metabolism*
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Purine-Nucleoside Phosphorylase / metabolism*
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Pyridinium Compounds
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Saccharomyces cerevisiae / cytology
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism*
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Saccharomyces cerevisiae Proteins / metabolism*
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Signal Transduction
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Silent Information Regulator Proteins, Saccharomyces cerevisiae / metabolism*
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Sirtuin 2
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Sirtuins / metabolism*
Substances
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Pyridinium Compounds
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Saccharomyces cerevisiae Proteins
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Silent Information Regulator Proteins, Saccharomyces cerevisiae
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nicotinamide-beta-riboside
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NAD
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Niacinamide
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Niacin
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Purine-Nucleoside Phosphorylase
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5'-methylthioadenosine phosphorylase
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NRK1 protein, S cerevisiae
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Phosphotransferases (Alcohol Group Acceptor)
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N-Glycosyl Hydrolases
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URH1 protein, S cerevisiae
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SIR2 protein, S cerevisiae
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Sirtuin 2
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Sirtuins
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Nicotinamidase
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Histone Deacetylases