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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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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006742/
https://www.ncbi.nlm.nih.gov/pubmed/24785424
http://dx.doi.org/10.1371/journal.pgen.1004347
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author 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
author_facet 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
author_sort Ruckenstuhl, Christoph
collection PubMed
description 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.
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spelling pubmed-40067422014-05-09 Lifespan Extension by Methionine Restriction Requires Autophagy-Dependent Vacuolar Acidification 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 PLoS Genet Research Article 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. Public Library of Science 2014-05-01 /pmc/articles/PMC4006742/ /pubmed/24785424 http://dx.doi.org/10.1371/journal.pgen.1004347 Text en © 2014 Ruckenstuhl et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
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
Lifespan Extension by Methionine Restriction Requires Autophagy-Dependent Vacuolar Acidification
title Lifespan Extension by Methionine Restriction Requires Autophagy-Dependent Vacuolar Acidification
title_full Lifespan Extension by Methionine Restriction Requires Autophagy-Dependent Vacuolar Acidification
title_fullStr Lifespan Extension by Methionine Restriction Requires Autophagy-Dependent Vacuolar Acidification
title_full_unstemmed Lifespan Extension by Methionine Restriction Requires Autophagy-Dependent Vacuolar Acidification
title_short Lifespan Extension by Methionine Restriction Requires Autophagy-Dependent Vacuolar Acidification
title_sort lifespan extension by methionine restriction requires autophagy-dependent vacuolar acidification
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006742/
https://www.ncbi.nlm.nih.gov/pubmed/24785424
http://dx.doi.org/10.1371/journal.pgen.1004347
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