title: Autophagy extends lifespan via vacuolar acidification.
abstract: Methionine restriction (MetR) is one of the rare regimes that prolongs lifespan across species barriers. Using a yeast model, we recently demonstrated that this lifespan extension is promoted by autophagy, which in turn requires vacuolar acidification. Our study is the first to place autophagy as one of the major players required for MetR-mediated longevity. In addition, our work identifies vacuolar acidification as a key downstream element of autophagy induction under MetR, and possibly after rapamycin treatment. Unlike other amino acids, methionine plays pleiotropic roles in many metabolism-relevant pathways. For instance, methionine (i) is the N-terminal amino acid of every newly translated protein; (ii) acts as the central donor of methyl groups through S-adenosyl methionine (SAM) during methylation reactions of proteins, DNA or RNA; and (iii) provides the sulfhydryl groups for FeS-cluster formation and redox detoxification via transsulfuration to cysteine. Intriguingly, MetR causes lifespan extension, both in yeast and in rodents. We could show that inSaccharomyces cerevisiae, chronological lifespan (CLS) is increased in two specific methionine-auxotrophic strains (namely Δmet2and Δmet15).
authors.affiliation: Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Ruckenstuhl
authors.affiliation: Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Netzberger
authors.affiliation: Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Iryna
authors.initials: I
authors.lastname: Entfellner
authors.affiliation: Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Didac
authors.initials: D
authors.lastname: Carmona-Gutierrez
authors.affiliation: Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kickenweiz
authors.affiliation: Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Slaven
authors.initials: S
authors.lastname: Stekovic
authors.affiliation: Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Gleixner
authors.affiliation: Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Schmid
authors.affiliation: Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Lisa
authors.initials: L
authors.lastname: Klug
authors.affiliation: Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Ivan
authors.initials: I
authors.lastname: Hajnal
authors.affiliation: Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Alice G
authors.initials: AG
authors.lastname: Sorgo
authors.affiliation: Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Tobias
authors.initials: T
authors.lastname: Eisenberg
authors.affiliation: Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Büttner
authors.affiliation: INSERM, U848, F-94805 Villejuif, France. ; Institut Gustave Roussy, F-94805 Villejuif, France.; Université Paris Sud, Paris 11, F-94805 Villejuif, France.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Marin O
authors.affiliation: Institute for Biomedical Aging Research (IBA), Austrian Academy of Sciences, 6020 Innsbruck, Austria.
authors.forename: Rafael
authors.initials: R
authors.lastname: Koziel
authors.affiliation: HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H., 8010 Graz, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Magnes
authors.affiliation: HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H., 8010 Graz, Austria.; Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.
authors.forename: Frank
authors.initials: F
authors.lastname: Sinner
authors.affiliation: HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H., 8010 Graz, Austria.; Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Pieber
authors.affiliation: Institute for Biomedical Aging Research (IBA), Austrian Academy of Sciences, 6020 Innsbruck, Austria.
authors.forename: Pidder
authors.initials: P
authors.lastname: Jansen-Dürr
authors.affiliation: Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Fröhlich
authors.affiliation: INSERM, U848, F-94805 Villejuif, France. ; Institut Gustave Roussy, F-94805 Villejuif, France.; Metabolomics Platform, Institut Gustave Roussy, F-94805 Villejuif, France.; Centre de Recherche des Cordeliers, F-75005 Paris, France.; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, F-75908 Paris, France.; Université Paris Descartes, Paris 5, F-75270 Paris, France.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo
keywords: acidification; autophagy; chronological lifespan; dietary restriction; longevity; lysosome; methionine restriction; vacuole