Eisenberg Tobias, Knauer Heide, Schauer Alexandra, Büttner Sabrina, Ruckenstuhl Christoph, Carmona-Gutierrez Didac, Ring Julia, Schroeder Sabrina, Magnes Christoph, Antonacci Lucia, Fussi Heike, Deszcz Luiza, Hartl Regina, Schraml Elisabeth, Criollo Alfredo, Megalou Evgenia, Weiskopf Daniela, Laun Peter, Heeren Gino, Breitenbach Michael, Grubeck-Loebenstein Beatrix, Herker Eva, Fahrenkrog Birthe, Fröhlich Kai-Uwe, Sinner Frank, Tavernarakis Nektarios, Minois Nadege, Kroemer Guido, Madeo Frank
Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Nat Cell Biol. 2009 Nov;11(11):1305-14. doi: 10.1038/ncb1975. Epub 2009 Oct 4.
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.
衰老源于复杂的基因和表观遗传编程过程，这些过程部分由导致程序性细胞死亡的有害或应激事件引发。在此，我们报告，亚精胺（一种在人类衰老过程中细胞内浓度下降的天然多胺）的施用显著延长了酵母、果蝇、蠕虫和人类免疫细胞的寿命。此外，施用亚精胺能有效抑制衰老小鼠的氧化应激。在衰老酵母中，亚精胺处理通过抑制组蛋白乙酰转移酶（HAT）触发组蛋白H3的表观遗传去乙酰化，抑制氧化应激和坏死。相反，内源性多胺的消耗导致超乙酰化、活性氧的产生、早期坏死性死亡和寿命缩短。染色质乙酰化状态的改变导致各种自噬相关转录本的显著上调，从而在酵母、果蝇、蠕虫和人类细胞中触发自噬。最后，我们发现增强自噬对于多胺诱导的坏死抑制和寿命延长至关重要。
