Life span extension by targeting a link between metabolism and histone acetylation in Drosophila.
Life span extension by targeting a link between metabolism and histone acetylation in Drosophila.
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DOI：
10.15252/embr.201541132
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发表时间：
2016-03
期刊：
影响因子：
7.7
通讯作者：
Ladurner AG
中科院分区：
文献类型：
--
作者：
Peleg S;Feller C;Forne I;Schiller E;Sévin DC;Schauer T;Regnard C;Straub T;Prestel M;Klima C;Schmitt Nogueira M;Becker L;Klopstock T;Sauer U;Becker PB;Imhof A;Ladurner AG
老年与线粒体功能的进行性下降和核染色质的变化有关。然而，很少有人知道代谢活动和表观遗传修饰如何随着生物体进入中年而变化。在这里，我们评估了细胞代谢和蛋白质乙酰化的变化，在早期衰老的果蝇。与通常的假设相反，我们发现果蝇在中年时会增加耗氧量，对组蛋白去乙酰化酶抑制剂的敏感性降低。此外，中年果蝇显示代谢组的变化，乙酰辅酶A水平升高，蛋白质-特别是组蛋白-乙酰化的改变，以及相关的转录组变化。基于这些观察结果，我们降低了乙酰辅酶A合成酶ATP柠檬酸裂解酶（ATPCL）的活性或组蛋白H4 K12特异性乙酰转移酶Chameau的水平。我们发现，这些有针对性的干预措施既减轻了观察到的衰老相关变化，又促进了长寿。我们的研究结果揭示了一种途径，该途径将衰老过程中中间代谢的变化与染色质介导的转录调节和调节生物体寿命的相关酶活性的变化相结合。
Old age is associated with a progressive decline of mitochondrial function and changes in nuclear chromatin. However, little is known about how metabolic activity and epigenetic modifications change as organisms reach their midlife. Here, we assessed how cellular metabolism and protein acetylation change during early aging in Drosophila melanogaster. Contrary to common assumptions, we find that flies increase oxygen consumption and become less sensitive to histone deacetylase inhibitors as they reach midlife. Further, midlife flies show changes in the metabolome, elevated acetyl‐CoA levels, alterations in protein—notably histone—acetylation, as well as associated transcriptome changes. Based on these observations, we decreased the activity of the acetyl‐CoA‐synthesizing enzyme ATP citrate lyase (ATPCL) or the levels of the histone H4 K12‐specific acetyltransferase Chameau. We find that these targeted interventions both alleviate the observed aging‐associated changes and promote longevity. Our findings reveal a pathway that couples changes of intermediate metabolism during aging with the chromatin‐mediated regulation of transcription and changes in the activity of associated enzymes that modulate organismal life span.