MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae
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 alternat...
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| description | 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. |
| doi_str_mv | 10.1371/journal.pbio.0050261 |
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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.</description><identifier>ISSN: 1545-7885</identifier><identifier>ISSN: 1544-9173</identifier><identifier>EISSN: 1545-7885</identifier><identifier>DOI: 10.1371/journal.pbio.0050261</identifier><identifier>PMID: 17914901</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aging ; Caloric Restriction ; Cell Biology ; Cellular signal transduction ; DNA binding proteins ; DNA, Ribosomal - genetics ; DNA-Binding Proteins - physiology ; Genes ; Genetic aspects ; Genetics ; Genetics and Genomics ; Health aspects ; Kinases ; Life Expectancy ; Microbiology ; Molecular Biology ; Protein Serine-Threonine Kinases ; Rapamycin ; Saccharomyces ; Saccharomyces cerevisiae - physiology ; Saccharomyces cerevisiae Proteins - physiology ; Signal Transduction ; Transcription Factors - physiology ; Yeast</subject><ispartof>PLoS biology, 2007-10, Vol.5 (10), p.e261</ispartof><rights>COPYRIGHT 2007 Public Library of Science</rights><rights>2007 Medvedik et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Medvedik O, Lamming DW, Kim KD, Sinclair DA (2007) MSN2 and MSN4 Link Calorie Restriction and TOR to Sirtuin-Mediated Lifespan Extension in Saccharomyces cerevisiae. 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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.</description><subject>Aging</subject><subject>Caloric Restriction</subject><subject>Cell Biology</subject><subject>Cellular signal transduction</subject><subject>DNA binding proteins</subject><subject>DNA, Ribosomal - genetics</subject><subject>DNA-Binding Proteins - physiology</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetics</subject><subject>Genetics and Genomics</subject><subject>Health aspects</subject><subject>Kinases</subject><subject>Life Expectancy</subject><subject>Microbiology</subject><subject>Molecular Biology</subject><subject>Protein Serine-Threonine Kinases</subject><subject>Rapamycin</subject><subject>Saccharomyces</subject><subject>Saccharomyces cerevisiae - physiology</subject><subject>Saccharomyces cerevisiae Proteins - physiology</subject><subject>Signal Transduction</subject><subject>Transcription Factors - 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>17914901</pmid><doi>10.1371/journal.pbio.0050261</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aging Caloric Restriction Cell Biology Cellular signal transduction DNA binding proteins DNA, Ribosomal - genetics DNA-Binding Proteins - physiology Genes Genetic aspects Genetics Genetics and Genomics Health aspects Kinases Life Expectancy Microbiology Molecular Biology Protein Serine-Threonine Kinases Rapamycin Saccharomyces Saccharomyces cerevisiae - physiology Saccharomyces cerevisiae Proteins - physiology Signal Transduction Transcription Factors - physiology Yeast |
| title | MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae |
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