The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR.
The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR.
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代谢物α-酮戊二酸酸盐通过抑制ATP合酶和TOR来延长寿命。
DOI：
10.1038/nature13264
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发表时间：
2014-06-19
期刊：
影响因子：
64.8
通讯作者：
Huang J
中科院分区：
文献类型：
--
作者：
Chin RM;Fu X;Pai MY;Vergnes L;Hwang H;Deng G;Diep S;Lomenick B;Meli VS;Monsalve GC;Hu E;Whelan SA;Wang JX;Jung G;Solis GM;Fazlollahi F;Kaweeteerawat C;Quach A;Nili M;Krall AS;Godwin HA;Chang HR;Faull KF;Guo F;Jiang M;Trauger SA;Saghatelian A;Braas D;Christofk HR;Clarke CF;Teitell MA;Petrascheck M;Reue K;Jung ME;Frand AR;Huang J
新陈代谢和衰老密切相关。与自由采食相比，饮食限制（DR）或热量限制（CR）持续延长寿命，并延迟进化多样性生物体中与年龄相关的疾病。类似的营养限制和营养或能量代谢的遗传或药理学干扰条件也有长寿的好处。最近，已经确定了几种代谢物，调节衰老，在很大程度上不确定的分子机制。在这里，我们表明，三羧酸（TCA）循环中间体α-酮戊二酸（α-KG）延长了成年C。优雅的。ATP合成酶β亚基是一种新的α-KG结合蛋白，使用称为DARTS（药物亲和反应靶点稳定性）的小分子靶点识别策略进行鉴定。ATP合酶，也称为线粒体电子传递链（ETC）的复合物V，是主要的细胞能量产生机制，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ETC的部分抑制已被证明可延长C。elegans寿命。我们发现，α-KG抑制ATP合酶，并且与ATP合酶敲低类似，α-KG的抑制导致两种C.线虫和哺乳动物细胞。我们提供的证据表明，α-KG的寿命增加需要ATP合酶亚基β，并依赖于雷帕霉素（TOR）下游的目标。内源性α-KG水平在饥饿时增加，α-KG不会延长DR动物的寿命，表明α-KG是通过DR介导寿命的关键代谢物。我们的分析揭示了一种常见代谢物，一种通用的细胞能量生成器和DR之间在生物体寿命调节中的新分子联系，从而为预防和治疗衰老和年龄相关疾病提出了新的策略。
Metabolism and ageing are intimately linked. Compared to ad libitum feeding, dietary restriction (DR) or calorie restriction (CR) 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 with largely undefined molecular mechanisms. Here we show that the tricarboxylic acid (TCA) cycle intermediate α-ketoglutarate (α-KG) extends the lifespan of adult C. elegans. ATP synthase subunit beta is identified as a novel binding protein of α-KG using a small-molecule target identification strategy called DARTS (drug affinity responsive target stability). The ATP synthase, also known as Complex V of the mitochondrial electron transport chain (ETC), 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 ETC 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 beta and is dependent on the target of rapamycin (TOR) downstream. Endogenous α-KG levels are increased upon starvation and α-KG does not extend the lifespan of DR animals, indicating that α-KG is a key metabolite that mediates longevity by DR. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator, and DR 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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DOI：
10.1126/science.1173635
发表时间：
2009-07-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Colman RJ;Anderson RM;Johnson SC;Kastman EK;Kosmatka KJ;Beasley TM;Allison DB;Cruzen C;Simmons HA;Kemnitz JW;Weindruch R
通讯作者：
Weindruch R
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
3.8
作者：
Abada, Emad Abd-elmoniem;Sung, Hyun;Ahnn, Joohong
通讯作者：
Ahnn, Joohong
影响因子：
56.9
作者：
Dillin, A;Hsu, AL;Kenyon, C
通讯作者：
Kenyon, C
DOI：
10.1073/pnas.95.22.13091
发表时间：
1998-10-27
影响因子：
11.1
作者：
Lakowski, B;Hekimi, S
通讯作者：
Hekimi, S