Abstract
Calorie restriction (CR) robustly extends the lifespan of numerous species. In the yeast Saccharomyces cerevisiae, CR has been proposed to extend lifespan by boosting the activity of sirtuin deacetylases, thereby suppressing the formation of toxic repetitive ribosomal DNA (rDNA) circles. An alternative theory is that CR works by suppressing the TOR (target of rapamycin) signaling pathway, which extends lifespan via mechanisms that are unknown but thought to be independent of sirtuins. Here we show that TOR inhibition extends lifespan by the same mechanism as CR: by increasing Sir2p activity and stabilizing the rDNA locus. Further, we show that rDNA stabilization and lifespan extension by both CR and TOR signaling is due to the relocalization of the transcription factors Msn2p and Msn4p from the cytoplasm to the nucleus, where they increase expression of the nicotinamidase gene PNC1. These findings suggest that TOR and sirtuins may be part of the same longevity pathway in higher organisms, and that they may promote genomic stability during aging.
Highlights
In the budding yeast Saccharomyces cerevisiae, replicative lifespan is measured by the number of divisions that a mother cell undergoes before senescing [1,2,3]
In contrast to previous work using a genetic mimic of calorie restriction (CR) [14], we found that lifespan extension by CR was completely MSN2/4-dependent (Figure 1A)
We have shown that TOR signaling, which was previously thought to regulate lifespan independently of sirtuins and extrachromosomal ribosomal DNA circle (ERC), governs the activity of the sirtuins and suppresses ribosomal DNA (rDNA) recombination (Figure 8)
Summary
In the budding yeast Saccharomyces cerevisiae, replicative lifespan is measured by the number of divisions that a mother cell undergoes before senescing [1,2,3]. RDNA recombination is not known to play a role in the aging of metazoans, the function of Sir2p enzymes in lifespan determination appears to be conserved. In Caenorhabditis elegans and Drosophila melanogaster, additional copies of the SIR2 gene or pharmacological modulation of the Sir2p deacetylase extend lifespan [8,9,10,11]. Whether or not Sir2p enzymes play a role in CR-mediated lifespan extension is hotly debated. In support of their playing a role, additional copies of either SIR2 or HST2 suppress rDNA recombination and extend yeast replicative lifespan, whereas strains lacking SIR2 and HST2 fail to live longer when subjected to CR [14,15]. Other researchers favor a model in which Sir2p plays no role in CR-mediated lifespan extension, and instead the TOR (target of rapamycin) pathway is proposed to play the central role [17,18]
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