@article {269816,
	title = {The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR},
	journal = {NatureNatureNature},
	volume = {510},
	year = {2014},
	note = {Chin, Randall MFu, XudongPai, Melody YVergnes, LaurentHwang, HeejunDeng, GangDiep, SimonLomenick, BrettMeli, Vijaykumar SMonsalve, Gabriela CHu, EileenWhelan, Stephen AWang, Jennifer XJung, GwanghyunSolis, Gregory MFazlollahi, FarbodKaweeteerawat, ChitradaQuach, AustinNili, MahtaKrall, Abby SGodwin, Hilary AChang, Helena RFaull, Kym FGuo, FengJiang, MeishengTrauger, Sunia ASaghatelian, AlanBraas, DanielChristofk, Heather RClarke, Catherine FTeitell, Michael APetrascheck, MichaelReue, KarenJung, Michael EFrand, Alison RHuang, JingP40 OD010440/OD/NIH HHS/T32 CA009120/CA/NCI NIH HHS/T32 GM007104/GM/NIGMS NIH HHS/T32 GM007185/GM/NIGMS NIH HHS/T32 GM008496/GM/NIGMS NIH HHS/EnglandNature. 2014 Jun 19;510(7505):397-401. doi: 10.1038/nature13264. Epub 2014 May 14.},
	month = {Jun 19},
	pages = {397-401},
	type = {Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t},
	edition = {2014/05/16},
	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 alpha-ketoglutarate (alpha-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit beta is identified as a novel binding protein of alpha-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 alpha-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by alpha-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 alpha-KG requires ATP synthase subunit beta and is dependent on target of rapamycin (TOR) downstream. Endogenous alpha-KG levels are increased on starvation and alpha-KG does not extend the lifespan of dietary-restricted animals, indicating that alpha-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.},
	keywords = {Animals, Caenorhabditis elegans/*drug effects, Cell Line, Enzyme Activation/drug effects, Enzyme Inhibitors/pharmacology, Gene Knockdown Techniques, HEK293 Cells, Humans, Jurkat Cells, Ketoglutaric Acids/*pharmacology, Longevity/drug effects/genetics/*physiology, Mice, Mitochondrial Proton-Translocating ATPases/genetics/*metabolism, Protein Binding, TOR Serine-Threonine Kinases/*metabolism},
	isbn = {1476-4687 (Electronic)0028-0836 (Linking)},
	author = {Chin, R. M. and Fu, X and Pai, M. Y. and Vergnes, L. and Hwang, H. and Deng, G. and Diep, S. and Lomenick, B. and Meli, V. S. and Monsalve, G. C. and Hu, E. and Whelan, S. A. and Wang, J. X. and Jung, G. and Solis, G. M. and Fazlollahi, F. and Kaweeteerawat, C. and Quach, A. and Nili, M. and Krall, A. S. and Godwin, H. A. and Chang, H. R. and Faull, K. F. and Guo, F. and Jiang, M. and Trauger, S. A. and Saghatelian, A. and Braas, D. and Christofk, H. R. and Clarke, C. F. and Teitell, M. A. and Petrascheck, M. and Reue, K. and Jung, M. E. and Frand, A. R. and Huang, J.}
}
