【原】代谢物α-酮戊二酸通过抑制ATP合成酶和TOR来延长寿命

The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR.

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|核心内容：

新陈代谢和衰老密切相关。

与随意喂养相比，饮食限制在进化多样性的生物体中持续延长寿命并延缓与年龄相关的疾病。

类似的营养限制条件和营养或能量代谢的遗传或药理学干扰也有长寿的好处。

最近，几种代谢物已被鉴定为调节衰老；然而，其背后的分子机制在很大程度上还不清楚。

在这里，我们发现α-酮戊二酸(α-KG)，一种三羧酸循环中间体，可以延长秀丽线虫成虫的寿命。

三磷酸腺苷合成酶亚单位β被称为药物亲和反应性靶标稳定性(DARTS)的小分子靶标识别策略被鉴定为α-KG的一种新的结合蛋白。

ATP合成酶，也被称为线粒体电子传输链的复合体V，是细胞的主要能量产生机制，在整个进化过程中高度保守。

虽然线粒体功能的完全丧失是有害的，但部分抑制电子传输链可以延长线虫的寿命。

我们发现α-KG抑制三磷酸腺苷合成酶，与三磷酸腺苷合酶基因敲除相似，α-KG抑制导致线虫和哺乳动物细胞中三磷酸腺苷含量减少，氧耗减少，自噬增加。

我们提供的证据表明，α-KG的寿命延长需要ATP合成酶亚单位β，并且依赖于雷帕霉素(TOR)下游的靶点。

饥饿时内源性α-KG水平升高，α-KG不能延长限食动物的寿命，表明α-KG是通过限食调节长寿的关键代谢物。

我们的分析揭示了一种常见的代谢物、一种通用的细胞能量发生器和调节生物寿命的饮食限制之间的新的分子联系，从而为预防和治疗衰老和与年龄相关的疾病提出了新的策略。

原文摘要：

Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits. Recently, several metabolites have been identified that modulate ageing; however, the molecular mechanisms underlying this are largely undefined. Here we show that α-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit β is identified as a novel binding protein of α-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan. We show that α-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by α-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by α-KG requires ATP synthase subunit β and is dependent on target of rapamycin (TOR) downstream. Endogenous α-KG levels are increased on starvation and α-KG does not extend the lifespan of dietary-restricted animals, indicating that α-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.

#不能吃得太多，但是也不要饿着。每顿7分饱就很好！

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参考文献：10.1038/nature13264

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