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The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR.
Chin, Randall M; Fu, Xudong; Pai, Melody Y; Vergnes, Laurent; Hwang, Heejun; Deng, Gang; Diep, Simon; Lomenick, Brett; Meli, Vijaykumar S; Monsalve, Gabriela C; Hu, Eileen; Whelan, Stephen A; Wang, Jennifer X; Jung, Gwanghyun; Solis, Gregory M; Fazlollahi, Farbod; Kaweeteerawat, Chitrada; Quach, Austin; Nili, Mahta; Krall, Abby S; Godwin, Hilary A; Chang, Helena R; Faull, Kym F; Guo, Feng; Jiang, Meisheng; Trauger, Sunia A; Saghatelian, Alan; Braas, Daniel; Christofk, Heather R; Clarke, Catherine F; Teitell, Michael A; Petrascheck, Michael; Reue, Karen; Jung, Michael E; Frand, Alison R; Huang, Jing.
Affiliation
  • Chin RM; Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Fu X; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Pai MY; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2].
  • Vergnes L; 1] Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, USA [2].
  • Hwang H; 1] Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA [2].
  • Deng G; Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Diep S; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Lomenick B; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Meli VS; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Monsalve GC; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Hu E; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Whelan SA; Department of Surgery, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Wang JX; Small Molecule Mass Spectrometry Facility, FAS Division of Science, Harvard University, Cambridge, Massachusetts 02138, USA.
  • Jung G; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Solis GM; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
  • Fazlollahi F; Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Kaweeteerawat C; Department of Environmental Health Sciences, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Quach A; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Nili M; Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Krall AS; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Godwin HA; Department of Environmental Health Sciences, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Chang HR; Department of Surgery, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Faull KF; Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Guo F; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Jiang M; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Trauger SA; Small Molecule Mass Spectrometry Facility, FAS Division of Science, Harvard University, Cambridge, Massachusetts 02138, USA.
  • Saghatelian A; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
  • Braas D; 1] Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA [2] UCLA Metabolomics Center, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Christofk HR; 1] Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA [2] UCLA Metabolomics Center, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Clarke CF; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Teitell MA; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Petrascheck M; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
  • Reue K; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Jung ME; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Frand AR; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
  • Huang J; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Nature ; 510(7505): 397-401, 2014 Jun 19.
Article in En | MEDLINE | ID: mdl-24828042
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 ß 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 ß 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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Full text: 1 Database: MEDLINE Main subject: Caenorhabditis elegans / Mitochondrial Proton-Translocating ATPases / TOR Serine-Threonine Kinases / Ketoglutaric Acids / Longevity Limits: Animals / Humans Language: En Journal: Nature Year: 2014 Type: Article Affiliation country: United States
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Full text: 1 Database: MEDLINE Main subject: Caenorhabditis elegans / Mitochondrial Proton-Translocating ATPases / TOR Serine-Threonine Kinases / Ketoglutaric Acids / Longevity Limits: Animals / Humans Language: En Journal: Nature Year: 2014 Type: Article Affiliation country: United States