Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+

Cell. 2007 May 4;129(3):473-84. doi: 10.1016/j.cell.2007.03.024.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • Gene Silencing / drug effects
  • Histone Deacetylases / metabolism*
  • Metabolic Networks and Pathways
  • N-Glycosyl Hydrolases / metabolism*
  • NAD / metabolism*
  • Niacin / metabolism
  • Niacinamide / analogs & derivatives*
  • Niacinamide / metabolism
  • Niacinamide / pharmacology
  • Nicotinamidase / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Purine-Nucleoside Phosphorylase / metabolism*
  • Saccharomyces cerevisiae / cytology
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Signal Transduction
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae / metabolism*
  • Sirtuin 2
  • Sirtuins / metabolism*

Substances

  • Saccharomyces cerevisiae Proteins
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae
  • nicotinamide-beta-riboside
  • NAD
  • Niacinamide
  • Niacin
  • Purine-Nucleoside Phosphorylase
  • 5'-methylthioadenosine phosphorylase
  • NRK1 protein, S cerevisiae
  • Phosphotransferases (Alcohol Group Acceptor)
  • N-Glycosyl Hydrolases
  • URH1 protein, S cerevisiae
  • SIR2 protein, S cerevisiae
  • Sirtuin 2
  • Sirtuins
  • Nicotinamidase
  • Histone Deacetylases