Restricting calorie intake in many organisms — from mammals to yeast — delays the ageing process and extends lifespan, but explaining why calorie restriction (CR) has this effect has eluded biologists for many years. Recent advances have implicated oxidative stress among the mediators of this phenomenon, but its molecular basis remains unknown.
Budding yeast are particularly suitable for studies into this mystery because their lifespan is measured by a finite number of cell divisions — once completed, the cell dies — and because they are acutely sensitive to environmental nutrients. Yeast also accumulate ribosomal DNA (rDNA) circles with age — these are created by homologous recombination at the repetitive rDNA locus and are excised to form extrachromosomal circles that are toxic to the cell. By assaying these read-outs of ageing in mutant yeast, Lin and colleagues have now discovered a key mechanism that links CR to longevity — genomic silencing.
To confirm the link between CR and longevity, the authors grew yeast on a low-glucose medium. This extended yeast lifespan, as did inactivating the genes that enable yeast to sense and respond to glucose. Next, the authors tested whether these glucose-insensitive mutants could rescue the shortened lifespan of the sir2 mutant. The sir2 gene encodes a NAD (nicotinamide adenine dinucleotide)-dependent histone deacetylase that modifies chromatin and silences gene expression at several genomic loci, including at repetitive rDNA. Loss of sir2 causes a rapid accumulation of toxic rDNA circles, a phenotype that can be rescued by suppressing hyper-recombination at the rDNA locus. When hyper-recombination is suppressed, sir2 mutant cells return to a normal lifespan but do not further extend it when they are made to be glucose insensitive. These results gave the first indication that CR-mediated longevity requires Sir2.
So what's the connection between longevity, CR and Sir2? A possible molecular basis of CR-induced yeast longevity is the reduction of rDNA recombination and of rDNA circle formation — in long-living, glucose-insensitive yeast, for example, both recombination rates and rDNA circle formation are significantly reduced. The authors believe that this effect is mediated by increased genomic silencing by Sir2. Furthermore, if yeast NAD synthesis is disrupted then CR can no longer induce longevity. This, perhaps, is not surprising, as Sir2 activity is dependent on NAD, which is a key intermediate in energy metabolism. CR might therefore be having a two-fold effect on ageing — by reducing oxidative stress, and by activating Sir2 through NAD to coordinate genomic silencing, stability and gene expression with the energy status of the cell. Sir2 has a mammalian homologue, so whether the long-life benefits of CR can be achieved without counting calories throughout life remains to be seen.
ORIGINAL RESEARCH PAPER
Li, S.-J. et al. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126– 2128 (2000) [ Contents page]
Campisi, J. Aging, chromatin and food restriction — connecting the dots. Science 289, 2062 ( 2000) [ Contents page]
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Alfred, J. Counting the calories to immortality. Nat Rev Genet 1, 88 (2000). https://doi.org/10.1038/35038524
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