Caffeine extends yeast lifespan by targeting TORC1.
Dietary nutrient limitation (dietary restriction) is known to increase lifespan in a variety of organisms. Although the molecular events that couple dietary restriction to increased lifespan are not clear, studies of the model eukaryote Saccharomyces cerevisiae have implicated several nutrient-sensitive kinases, including the target of rapamycin complex 1 (TORC1), Sch9, protein kinase A (PKA) and Rim15. We have recently demonstrated that TORC1 activates Sch9 by direct phosphorylation. We now show that Sch9 inhibits Rim15 also by direct phosphorylation. Treatment of yeast cells with the specific TORC1 inhibitor rapamycin or caffeine releases Rim15 from TORC1-Sch9-mediated inhibition and consequently increases lifespan. This kinase cascade appears to have been evolutionarily conserved, suggesting that caffeine may extend lifespan in other eukaryotes, including man.
Department of Microbiology and Molecular Medicine, University of Geneva Medical School CH-1211 Geneva, Switzerland.
Valeria
V
Wanke
Elisabetta
E
Cameroni
Aino
A
Uotila
Manuele
M
Piccolis
Jörg
J
Urban
Robbie
R
Loewith
Claudio
C
De Virgilio
D002110:Caffeine / Q000494:pharmacology*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*
D029701:Saccharomyces cerevisiae Proteins; D002110:Caffeine; D011494:Protein Kinases; C410736:Rim15 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C530964:SCH9 protein, S cerevisiae; C500749:target of rapamycin protein, S cerevisiae; D020123:Sirolimus