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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 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.

Pubmed ID: 17914901


  • Medvedik O
  • Lamming DW
  • Kim KD
  • Sinclair DA


PLoS biology

Publication Data

October 2, 2007

Associated Grants

  • Agency: NIA NIH HHS, Id: R01 AG019719
  • Agency: NIA NIH HHS, Id: R01 AG019719-06A1
  • Agency: NIA NIH HHS, Id: R01 AG019719-07
  • Agency: NIA NIH HHS, Id: R01 AG028730
  • Agency: NIA NIH HHS, Id: R01 AG028730-01A1
  • Agency: NIA NIH HHS, Id: R01 AG028730-02
  • Agency: NIA NIH HHS, Id: R01 AG028730-03
  • Agency: NIA NIH HHS, Id: R01AG19972
  • Agency: NIGMS NIH HHS, Id: R01GM068072

Mesh Terms

  • Caloric Restriction
  • DNA, Ribosomal
  • DNA-Binding Proteins
  • Life Expectancy
  • Protein-Serine-Threonine Kinases
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Signal Transduction
  • Transcription Factors