Down-regulating sphingolipid synthesis increases yeast lifespan.
Knowledge of the mechanisms for regulating lifespan is advancing rapidly, but lifespan is a complex phenotype and new features are likely to be identified. Here we reveal a novel approach for regulating lifespan. Using a genetic or a pharmacological strategy to lower the rate of sphingolipid synthesis, we show that Saccharomyces cerevisiae cells live longer. The longer lifespan is due in part to a reduction in Sch9 protein kinase activity and a consequent reduction in chromosomal mutations and rearrangements and increased stress resistance. Longer lifespan also arises in ways that are independent of Sch9 or caloric restriction, and we speculate on ways that sphingolipids might mediate these aspects of increased lifespan. Sch9 and its mammalian homolog S6 kinase work downstream of the target of rapamycin, TOR1, protein kinase, and play evolutionarily conserved roles in regulating lifespan. Our data establish Sch9 as a focal point for regulating lifespan by integrating nutrient signals from TOR1 with growth and stress signals from sphingolipids. Sphingolipids are found in all eukaryotes and our results suggest that pharmacological down-regulation of one or more sphingolipids may provide a means to reduce age-related diseases and increase lifespan in other eukaryotes.
Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, USA.
Xinhe
X
Huang
Jun
J
Liu
Robert C
RC
Dickson
D004318:Doxycycline / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D008136:Longevity / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051102:Serine C-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013107:Sphingolipids / Q000235:genetics* / Q000378:metabolism; D013312:Stress, Physiological
D004318:Doxycycline; D005229:Fatty Acids, Monounsaturated; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins; D051102:Serine C-Palmitoyltransferase; D013107:Sphingolipids; C495086:LCB1 protein, S cerevisiae; C495087:LCB2 protein, S cerevisiae; C083324:TOR1 protein, S cerevisiae; C530964:SCH9 protein, S cerevisiae; C001996:thermozymocidin