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PMID: 17914901 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae.

PLoS biology ·Vol. 5 ·No. 10 ·2007-10-02 ·Pages e261

Medvedik O, Lamming DW, Kim KD, Sinclair DA

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.

MeSH Terms
Caloric Restriction DNA, Ribosomal/genetics DNA-Binding Proteins/physiology Life Expectancy Protein Serine-Threonine Kinases Saccharomyces cerevisiae/physiology Saccharomyces cerevisiae Proteins/physiology Signal Transduction Transcription Factors/physiology
Chemicals
DNA, Ribosomal DNA-Binding Proteins MSN2 protein, S cerevisiae MSN4 protein, S cerevisiae Saccharomyces cerevisiae Proteins Transcription Factors Protein Serine-Threonine Kinases target of rapamycin protein, S cerevisiae
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Medvedik Oliver
Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America.
Lamming Dudley W
Kim Keyman D
Sinclair David A
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Article Info
Journal
PLoS biology
Abbr.
PLoS Biol
ISSN
1545-7885
DOI
10.1371/journal.pbio.0050261
Published
2007-10-02
Pages
e261
Language
English
Region
United States
NLM ID
101183755
PMCID
PMC1994990
Subset
IM
Grants
NIA NIH HHS · R01AG19972 · United States
NIGMS NIH HHS · R01 GM068072 · United States
NIA NIH HHS · R01 AG028730 · United States
NIA NIH HHS · R01 AG019972 · United States
NIA NIH HHS · R01 AG019719-07 · United States
NIA NIH HHS · R01 AG028730-02 · United States
NIA NIH HHS · R01 AG028730-01A1 · United States
NIGMS NIH HHS · R01GM068072 · United States
NIA NIH HHS · R01 AG019719 · United States
NIA NIH HHS · R01 AG019719-06A1 · United States
NIA NIH HHS · R01 AG028730-03 · United States
External Links
PubMed source DOI: 10.1371/journal.pbio.0050261 PMC Full Text View journal details
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