Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9.
Calorie restriction (CR), the only non-genetic intervention known to slow aging and extend life span in organisms ranging from yeast to mice, has been linked to the down-regulation of Tor, Akt, and Ras signaling. In this study, we demonstrate that the serine/threonine kinase Rim15 is required for yeast chronological life span extension caused by deficiencies in Ras2, Tor1, and Sch9, and by calorie restriction. Deletion of stress resistance transcription factors Gis1 and Msn2/4, which are positively regulated by Rim15, also caused a major although not complete reversion of the effect of calorie restriction on life span. The deletion of both RAS2 and the Akt and S6 kinase homolog SCH9 in combination with calorie restriction caused a remarkable 10-fold life span extension, which, surprisingly, was only partially reversed by the lack of Rim15. These results indicate that the Ras/cAMP/PKA/Rim15/Msn2/4 and the Tor/Sch9/Rim15/Gis1 pathways are major mediators of the calorie restriction-dependent stress resistance and life span extension, although additional mediators are involved. Notably, the anti-aging effect caused by the inactivation of both pathways is much more potent than that caused by CR.
Wei
Min
M
Andrus Gerontology Center, University of Southern California, Los Angeles, California, United States of America.
Fabrizio
Paola
P
Hu
Jia
J
Ge
Huanying
H
Cheng
Chao
C
Li
Lei
L
Longo
Valter D
VD
D031204:Caloric Restriction; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D020218:Response Elements; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013696:Temperature; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011494:Protein Kinases; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D018631:ras Proteins; C410736:Rim15 protein, S cerevisiae; C071569:SCH9 protein kinase; C083324:TOR1 protein, S cerevisiae