Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+.
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.
Belenky
Peter
P
Departments of Genetics and Biochemistry and the Norris Cotton Cancer Center, Dartmouth Medical School, Rubin 733-HB7937, Lebanon, NH 03756, USA.
Racette
Frances G
FG
Bogan
Katrina L
KL
McClure
Julie M
JM
Smith
Jeffrey S
JS
Brenner
Charles
C
D020868:Gene Silencing / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D009699:N-Glycosyl Hydrolases / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D009525:Niacin / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009535:Nicotinamidase / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011683:Purine-Nucleoside Phosphorylase / Q000378:metabolism*; D011726:Pyridinium Compounds; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015398:Signal Transduction; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000378:metabolism*; D056565:Sirtuin 2; D037761:Sirtuins / Q000378:metabolism*
D011726:Pyridinium Compounds; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C018613:nicotinamide-beta-riboside; D009243:NAD; D009536:Niacinamide; D009525:Niacin; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; C487432:NRK1 protein, S cerevisiae; D017853:Phosphotransferases (Alcohol Group Acceptor); D009699:N-Glycosyl Hydrolases; C454867:URH1 protein, S cerevisiae; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; D037761:Sirtuins; D009535:Nicotinamidase; D006655:Histone Deacetylases