Lifespan extension by methionine restriction requires autophagy-dependent vacuolar acidification.
Reduced supply of the amino acid methionine increases longevity across species through an as yet elusive mechanism. Here, we report that methionine restriction (MetR) extends yeast chronological lifespan in an autophagy-dependent manner. Single deletion of several genes essential for autophagy (ATG5, ATG7 or ATG8) fully abolished the longevity-enhancing capacity of MetR. While pharmacological or genetic inhibition of TOR1 increased lifespan in methionine-prototroph yeast, TOR1 suppression failed to extend the longevity of methionine-restricted yeast cells. Notably, vacuole-acidity was specifically enhanced by MetR, a phenotype that essentially required autophagy. Overexpression of vacuolar ATPase components (Vma1p or Vph2p) suffices to increase chronological lifespan of methionine-prototrophic yeast. In contrast, lifespan extension upon MetR was prevented by inhibition of vacuolar acidity upon disruption of the vacuolar ATPase. In conclusion, autophagy promotes lifespan extension upon MetR and requires the subsequent stimulation of vacuolar acidification, while it is epistatic to the equally autophagy-dependent anti-aging pathway triggered by TOR1 inhibition or deletion.
Institute for Molecular Biosciences, University of Graz, Graz, Austria.
Christoph
C
Ruckenstuhl
Institute for Molecular Biosciences, University of Graz, Graz, Austria.
Christine
C
Netzberger
Institute for Molecular Biosciences, University of Graz, Graz, Austria.
Iryna
I
Entfellner
Institute for Molecular Biosciences, University of Graz, Graz, Austria.
Didac
D
Carmona-Gutierrez
Institute for Molecular Biosciences, University of Graz, Graz, Austria.
Thomas
T
Kickenweiz
Institute for Molecular Biosciences, University of Graz, Graz, Austria.
Slaven
S
Stekovic
Institute for Molecular Biosciences, University of Graz, Graz, Austria.
Christina
C
Gleixner
Institute for Molecular Biosciences, University of Graz, Graz, Austria.
Christian
C
Schmid
Institute for Molecular Biosciences, University of Graz, Graz, Austria.
Lisa
L
Klug
Institute for Molecular Biosciences, University of Graz, Graz, Austria.
Alice G
AG
Sorgo
Institute for Molecular Biosciences, University of Graz, Graz, Austria.
Tobias
T
Eisenberg
Institute for Molecular Biosciences, University of Graz, Graz, Austria.
Sabrina
S
Büttner
INSERM, U848, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Université Paris Sud, Paris 11, Villejuif, France.
Guillermo
G
Mariño
Institute for Biomedical Aging Research (IBA), Austrian Academy of Sciences, Innsbruck, Austria.
Rafal
R
Koziel
Institute for Biomedical Aging Research (IBA), Austrian Academy of Sciences, Innsbruck, Austria.
Pidder
P
Jansen-Dürr
Institute for Molecular Biosciences, University of Graz, Graz, Austria.
Kai-Uwe
KU
Fröhlich
INSERM, U848, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Metabolomics Platform, Institut Gustave Roussy, Villejuif, France; Centre de Recherche des Cordeliers, Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Université Paris Descartes, Paris 5, Paris, France.
Guido
G
Kroemer
Institute for Molecular Biosciences, University of Graz, Graz, Austria.
Frank
F
Madeo
D000143:Acids / Q000378:metabolism*; D001343:Autophagy; D017353:Gene Deletion; D005800:Genes, Fungal; D006863:Hydrogen-Ion Concentration; D008136:Longevity; D008715:Methionine / Q000008:administration & dosage*; D012441:Saccharomyces cerevisiae / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D014617:Vacuoles / Q000378:metabolism*
D000143:Acids; D008715:Methionine