Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae

Summary

Genetic demonstration in budding yeast that calorie restriction extends replicative lifespan through an NAD+/Sir2-dependent pathway. Lin and colleagues showed that reducing glucose from 2% to 0.5% extended mean lifespan by roughly 30%, and that this extension was completely abolished in sir2 deletion mutants and in strains with impaired NAD+ biosynthesis (npt1 mutants). Glucose restriction increased Sir2 silencing activity at rDNA and telomeric loci, consistent with elevated cellular NAD+ availability. The paper established the conceptual framework that underlies modern NAD+-boosting therapeutics: metabolic state sets NAD+ levels, NAD+ levels gate sirtuin activity, and sirtuin activity modulates lifespan and stress resistance. It also implicated the NAD+ salvage pathway (via Npt1/Pnc1) as rate-limiting for this effect. Though yeast replicative lifespan is not mammalian aging, the molecular logic — NAD+ as the metabolic sensor linking nutrient intake to longevity-regulating enzymes — translated to flies, worms, and mammals in subsequent decades.

Frequently asked questions

What did Lin et al. (2000) find about NAD+?

Calorie-restriction-induced lifespan extension requires intact NAD+ biosynthesis and Sir2, linking nutrient sensing to sirtuin-mediated longevity. Source: Lin SJ, Defossez PA, Guarente L "Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae." Science, 2000.

What kind of study is Lin 2000?

It is a mechanism study on NAD+ published in Science in 2000. Genetic demonstration in budding yeast that calorie restriction extends replicative lifespan through an NAD+/Sir2-dependent pathway. Lin and colleagues showed that reducing glucose from 2% to 0.5% extended mean lifespan by roughly 30%, and that this extension was completely abolished in sir2 deletion mutants and in strains with impaired NAD+ biosynthesis (npt1 mutants). Glucose restriction increased Sir2 silencing activity at rDNA and telomeric loci, consistent with elevated cellular NAD+ availability. The paper established the conceptual framework that underlies modern NAD+-boosting therapeutics: metabolic state sets NAD+ levels, NAD+ levels gate sirtuin activity, and sirtuin activity modulates lifespan and stress resistance. It also implicated the NAD+ salvage pathway (via Npt1/Pnc1) as rate-limiting for this effect. Though yeast replicative lifespan is not mammalian aging, the molecular logic — NAD+ as the metabolic sensor linking nutrient intake to longevity-regulating enzymes — translated to flies, worms, and mammals in subsequent decades.

Where can I read the full Lin 2000 paper?

The primary source is available on PubMed (PMID 11000115) and via DOI 10.1126/science.289.5487.2126.

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