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

Ageing in the worm Caenorhabditis elegans is shown to be delayed by supplementation with α-ketoglutarate, an effect that is probably mediated by ATP synthase—which is identified as a direct target of α-ketoglutarate—and target of rapamycin (TOR). How a small molecule extends C. elegans lifespan Calorie restriction can extend lifespan and delay age-related deterioration in a range of organisms. A few small-molecule metabolites have been shown to regulate the ageing process, but little is known about the mechanisms involved. Here Jing Huang and colleagues report that the tricarboxylic acid cycle intermediate α-ketoglutarate (α-KG) extends the lifespan of adult Caenorhabditis elegans roundworms by approximately 50%. The molecular target of α-KG is the β subunit of ATPase. α-KG is dependent on the TOR (target of rapamycin) pathway and it does not extend the lifespan of dietary-restricted animals, suggesting a link between the effects of α-KG and starvation/dietary restriction. 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 1 , 2 . Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits 3 , 4 . Recently, several metabolites have been identified that modulate ageing 5 , 6 ; 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 8 , 9 . Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan 10 , 11 , 12 , 13 . 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