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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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.).
The authors declare no competing financial interests.
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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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