Nature2014-06-23 5:11 PM

一个小分子怎样延长线虫的寿命 The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR

论文摘要 

限制热量能延长很多不同生物的寿命和延迟与年龄相关的退化。少数小分子代谢物被发现调控衰老过程,但我们对其中所涉及的机制却知之甚少。Jing Huang及同事在这篇论文中报告,三羧酸循环中间体α-ketoglutarate (α-KG)能将成年线虫的寿命延长大约50%。α-KG的分子目标是ATPase的β亚单元。α-KG依赖于TOR (target of rapamycin) 通道,并且不会延长限制饮食动物的寿命,这说明在α-KG的效应与饥饿/限制饮食之间存在一个联系。

Abstract 

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.

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