title: Tor-Sch9 deficiency activates catabolism of the ketone body-like acetic acid to promote trehalose accumulation and longevity.
abstract: In mammals, extended periods of fasting leads to the accumulation of blood ketone bodies including acetoacetate. Here we show that similar to the conversion of leucine to acetoacetate in fasting mammals, starvation conditions induced ketone body-like acetic acid generation from leucine in S. cerevisiae. Whereas wild-type and ras2Δ cells accumulated acetic acid, long-lived tor1Δ and sch9Δ mutants rapidly depleted it through a mitochondrial acetate CoA transferase-dependent mechanism, which was essential for lifespan extension. The sch9Δ-dependent utilization of acetic acid also required coenzyme Q biosynthetic genes and promoted the accumulation of intracellular trehalose. These results indicate that Tor-Sch9 deficiency extends longevity by switching cells to an alternative metabolic mode, in which acetic acid can be utilized for the storage of stress resistance carbon sources. These effects are reminiscent of those described for ketone bodies in fasting mammals and raise the possibility that the lifespan extension caused by Tor-S6K inhibition may also involve analogous metabolic changes in higher eukaryotes.
authors.affiliation: Longevity Institute, Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA; Department of Biological Sciences, School of Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Hu
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Hamed
authors.initials: H
authors.lastname: Mirzaei
authors.forename: Federica
authors.initials: F
authors.lastname: Madia
authors.forename: Mario
authors.initials: M
authors.lastname: Mirisola
authors.forename: Camille
authors.initials: C
authors.lastname: Amparo
authors.forename: Shawna
authors.initials: S
authors.lastname: Chagoury
authors.forename: Brian
authors.initials: B
authors.lastname: Kennedy
authors.forename: Valter D
authors.initials: VD
authors.lastname: Longo
mesh_terms: D019342:Acetic Acid / Q000378:metabolism*; D006801:Humans; D008136:Longevity / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency* / Q000378:metabolism; D011494:Protein Kinases / Q000172:deficiency* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D014199:Trehalose / Q000378:metabolism*
chemical_list: D019342:Acetic Acid; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D029701:Saccharomyces cerevisiae Proteins; D014199:Trehalose; C071569:SCH9 protein kinase; C083324:TOR1 protein, S cerevisiae
keywords: Sch9; acetic acid; aging; chronological lifespan; leucine