西亚试剂：The me-tabolite α-ketoglutarate extends lifespan by inhibit

Randall M. Chin, Xudong Fu, Melody Y. Pai, Laurent Vergnes, Heejun Hwang, Gang Deng,Simon Diep, Brett Lomenick, Vijaykumar S. Meli, Gabriela C. Monsalve, Eileen Hu, Stephen A. Whelan, Jennifer X. Wang, Gwanghyun Jung, Gregory M. Solis, Farbod Fazlollahi,Chitrada Kaweeteerawat, Austin Quach, Mahta Nili, Abby S. Krall, Hilary A. Godwin, Helena R. Chang, Kym F. Faull, Feng Guo, Meisheng Jiang et al.

me-tabolism and ageing are intimately 1inked. 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 me-tabolism also have longevity benefits. Recently, several me-tabolites 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)7. 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 andα-KG does not extend the lifespan of dietary-restricted animals, indicating that α-KG is a key me-tabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular 1inks between a common me-tabolite, 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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