MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae.
MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae.
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DOI：
10.1371/journal.pbio.0050261
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发表时间：
2007-10-02
期刊：
影响因子：
9.8
通讯作者：
Sinclair DA
中科院分区：
文献类型：
--
作者：
Medvedik O;Lamming DW;Kim KD;Sinclair DA
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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. There are only a few techniques that reliably promote longevity in multiple, distantly related species. Perhaps the best known, caloric restriction (CR), was first shown to promote lifespan in rodents in the 1930s and has since been shown to work in most species it has been tested on. We and others have previously proposed that CR extends lifespan in budding yeast by boosting the activity of sirtuin deacetylases, which work to extend lifespan by suppressing genomic instability. A competing theory is that CR works by suppressing the TOR (target of rapamycin) signaling pathway, which has recently been discovered to extend the lifespan of yeast and worms, but the downstream players are not yet known. We show that TOR inhibition and sirtuins are part of the same CR pathway that extends yeast lifespan by stabilizing the genome. CR and TOR inhibition promote longevity by relocalizing two transcription factors, Msn2p and Msn4p, from the cytoplasm to the nucleus, where they increase expression of the nicotinamidase gene PNC1, a regulator of sirtuin activity. We propose that TOR signaling and sirtuins may also be part of the same CR pathway in mammals. Both caloric restriction and suppression of the TOR signaling pathway are known to extend lifespan in yeast. Here, both manipulations are shown to act via the same mechanism.
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