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Induction of autophagy by spermidine promotes longevity
Tobias Eisenberg1, Heide Knauer1, Alexandra Schauer1, Sabrina Büttner1, Christoph Ruckenstuhl1, Didac Carmona-Gutierrez1, Julia Ring1, Sabrina Schroeder1, Christoph Magnes2, Lucia Antonacci1, Heike Fussi1, Luiza Deszcz3,4, Regina Hartl3,4, Elisabeth Schraml5, Alfredo Criollo6,7,8, Evgenia Megalou9, Daniela Weiskopf10, Peter Laun11, Gino Heeren11, Michael Breitenbach11, Beatrix Grubeck-Loebenstein10, Eva Herker12, Birthe Fahrenkrog13, Kai-Uwe Fr?hlich1, Frank Sinner2, Nektarios Tavernarakis9, Nadege Minois3,4,14, Guido Kroemer6,7,8 & Frank Madeo1
Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause programmed cell death. Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells. In addition, spermidine administration potently inhibited oxidative stress in ageing mice. In ageing yeast, spermidine treatment triggered epigenetic deacetylation of histone H3 through inhibition of histone acetyltransferases (HAT), suppressing oxidative stress and necrosis. Conversely, depletion of endogenous polyamines led to hyperacetylation, generation of reactive oxygen species, early necrotic death and decreased lifespan. The altered acetylation status of the chromatin led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells. Finally, we found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity.
1 Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
2 Institute of Medical Technologies and Health Management, Joanneum Research, Graz, Austria.
3 Research Institute of Molecular Pathology (IMP), Vienna, Austria.
4 Institute of Molecular Biotechnology (IMBA), Austrian Academy of Sciences, Vienna, Austria.
5 Institute of Applied Microbiology, University of Natural Resources and Applied Life Sciences, Vienna, Austria.
6 INSERM, U848; 94805 Villejuif, France.
7 Institut Gustave Roussy, 94805 Villejuif, France.
8 University Paris Sud, Paris-11, 94805 Villejuif, France.
9 Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, 70013, Heraklion, Crete, Greece.
10 Institute for Biomedical Ageing Research, Austrian Academy of Sciences, 6020 Innsbruck, Austria.
11 Department of Cell Biology, Division of Genetics, University of Salzburg, 5020 Salzburg, Austria.
12 Gladstone Institute of Virology and Immunology, San Francisco, CA 94158, USA.
13 M.E. Mueller Institute for Structural Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
14 Current address: School of Biology, University of St Andrews, St Andrews, Scotland, Fife KY16 9AJ, UK.
