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Induction of autophagy by spermidine promotes longevity

Abstract

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.

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Figure 1: Application of spermidine extends the lifespan of yeast, flies and human immune cells, and inhibits oxidative stress in ageing mice.
Figure 2: Polyamine depletion shortens yeast chronological lifespan evoking markers of oxidative stress and necrosis.
Figure 3: Spermidine application suppresses necrotic cell death.
Figure 4: Lifespan extension by spermidine application is accompanied by epigenetic hypoacetylation of histone H3.
Figure 5: Spermidine-induced longevity is mediated by inhibition of HAT activity and correlates with upregulation of autophagy-related genes.
Figure 6: Autophagy is induced by spermidine and critical for maximal life span extension in yeast.
Figure 7: Autophagy is essential for spermidine-induced life span extension in flies and worms.

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Acknowledgements

We thank Ulrike Potocnik, Silvia Dichtinger, Arno Absenger and Elfgard Heintz for assistance. We are grateful to the Austrian Science Fund FWF (Austria) for grant S-9304-B05 (to F.M., S.B. and D.C.-G.), grant S-9303-B05 (to K.-U.F. and H.K.), grant LIPOTOX (to F.M. and S.B.), and grant S-9301-B05 (to B.G.-L.) and to the European Commission for project TransDeath (to K.-U.F. and C.R.), project APOSYS (to F.M., T.E. and G.K.) and project Lifespan (FP6 036894 to B.G.-L.). We are grateful to the Austrian Science Fund FWF (Vienna, Austria) for grants S9302-B05 (to M.B.) and to the European Commission (Brussels, Europe) for project MIMAGE (contract no. 512020; to M.B.).

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T.E., G.K. and F.M. designed and organized this study and wrote the manuscript. T.E. performed the largest part of the yeast and mouse experiments and contributed significantly to the fly and PBMC cell culture data. H.K., A.S., S.B., C.R., D.C-G., J.R., S.S., H.F., L.A. and B.A. contributed to the yeast experiments. C.M. and F.S. performed polyamine measurements by MassSpec. L.D., R.H. and N.M. performed the fly experiments. E.S. contributed to mouse data. A.C. performed HELA cell culture experiments. E.M. and N.T. contributed the worm data. D.W. and B.G-L. performed PBMC experiments. P.L., G.H. and M.B. determined yeast replicative life spans. N.M., E.H., K.-U.F., S.B., C.R. and D.C-G. contributed with decisive discussions and helped to design experiments.

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Correspondence to Guido Kroemer or Frank Madeo.

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Eisenberg, T., Knauer, H., Schauer, A. et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol 11, 1305–1314 (2009). https://doi.org/10.1038/ncb1975

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