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...

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Published in:PLoS genetics 2014-05, Vol.10 (5), p.e1004347
Main Authors: Ruckenstuhl, Christoph, Netzberger, Christine, Entfellner, Iryna, Carmona-Gutierrez, Didac, Kickenweiz, Thomas, Stekovic, Slaven, Gleixner, Christina, Schmid, Christian, Klug, Lisa, Sorgo, Alice G, Eisenberg, Tobias, Büttner, Sabrina, Mariño, Guillermo, Koziel, Rafal, Jansen-Dürr, Pidder, Fröhlich, Kai-Uwe, Kroemer, Guido, Madeo, Frank
Format: Article
Language:English
Subjects:
Acidification
Acids - metabolism
Aging
Autophagy
Autophagy (Cytology)
Biology and Life Sciences
Biosynthesis
Cancer
Experiments
Gene Deletion
Genes, Fungal
Grants
Health aspects
Hydrogen-Ion Concentration
Longevity
Medical research
Methionine
Methionine - administration & dosage
Microscopy
Protein research
Research and Analysis Methods
Saccharomyces cerevisiae - immunology
Saccharomyces cerevisiae - metabolism
Saccharomyces cerevisiae - physiology
Vacuoles - metabolism
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1004347