Induction of autophagy by spermidine promotes longevity
Induction of autophagy by spermidine promotes longevity
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DOI：
10.1038/ncb1975
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发表时间：
2009-11-01
影响因子：
21.3
通讯作者：
Madeo, Frank
中科院分区：
文献类型：
--
作者：
Eisenberg, Tobias;Knauer, Heide;Madeo, Frank
衰老是由复杂的遗传和表观遗传程序化过程引起的，这些过程部分是由导致程序化细胞死亡的有害或应激事件引起的。在这里，我们报告说，亚精胺，一种天然的多胺，其细胞内浓度下降，在人类衰老过程中，显着延长酵母，苍蝇和蠕虫，和人类免疫细胞的寿命。此外，亚精胺给药有效地抑制了衰老小鼠的氧化应激。在老化酵母中，亚精胺处理通过抑制组蛋白乙酰转移酶（HAT），抑制氧化应激和坏死，引发组蛋白H3的表观遗传脱乙酰化。相反，内源性多胺的耗竭导致乙酰化过度，产生活性氧，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物的显著上调，引发酵母、苍蝇、蠕虫和人类细胞中的自噬。最后，我们发现增强的自噬对于多胺诱导的坏死抑制和延长寿命至关重要。
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.