Tor1/Sch9-regulated carbon source substitution is as effective as calorie restriction in life span extension.
The effect of calorie restriction (CR) on life span extension, demonstrated in organisms ranging from yeast to mice, may involve the down-regulation of pathways, including Tor, Akt, and Ras. Here, we present data suggesting that yeast Tor1 and Sch9 (a homolog of the mammalian kinases Akt and S6K) is a central component of a network that controls a common set of genes implicated in a metabolic switch from the TCA cycle and respiration to glycolysis and glycerol biosynthesis. During chronological survival, mutants lacking SCH9 depleted extracellular ethanol and reduced stored lipids, but synthesized and released glycerol. Deletion of the glycerol biosynthesis genes GPD1, GPD2, or RHR2, among the most up-regulated in long-lived sch9Delta, tor1Delta, and ras2Delta mutants, was sufficient to reverse chronological life span extension in sch9Delta mutants, suggesting that glycerol production, in addition to the regulation of stress resistance systems, optimizes life span extension. Glycerol, unlike glucose or ethanol, did not adversely affect the life span extension induced by calorie restriction or starvation, suggesting that carbon source substitution may represent an alternative to calorie restriction as a strategy to delay aging.
Wei
Min
M
Andrus Gerontology Center, University of Southern California, Los Angeles, CA, USA.
Fabrizio
Paola
P
Madia
Federica
F
Hu
Jia
J
Ge
Huanying
H
Li
Lei M
LM
Longo
Valter D
VD
D000818:Animals; D031204:Caloric Restriction; D002244:Carbon / Q000378:metabolism; D019069:Cell Respiration; D002952:Citric Acid Cycle; D003470:Culture Media; D000431:Ethanol / Q000378:metabolism; D020869:Gene Expression Profiling; D005800:Genes, Fungal; D005990:Glycerol / Q000378:metabolism; D006019:Glycolysis; D008136:Longevity; D008954:Models, Biological; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D002244:Carbon; D003470:Culture Media; D000431:Ethanol; D005990:Glycerol; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins; D018631:ras Proteins; C083324:TOR1 protein, S cerevisiae; C530964:SCH9 protein, S cerevisiae; C489015:RAS2 protein, S cerevisiae