Evidence map›Paper›PMID 24828042›Full record

ArticleNature2014

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

Randall M Chin, Xudong Fu, Melody Y Pai, Laurent Vergnes, Heejun Hwang, Gang Deng, Simon Diep, Brett Lomenick, Vijaykumar S Meli, Gabriela C Monsalve and 26 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 365 papers.

0numbers the graph read from it
0cells of the map it votes in
365citing papers in PubMed
20.9field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

365 citing papers in PubMed, 601 citations in OpenAlex.

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  17. GOT2-mediated suppression of CoQCommunications biology · 2026
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305 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

36 authors at 3 institutions in 1 country.

Randall M ChinMolecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA.
Xudong FuDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Melody Y Pai1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2].
Laurent Vergnes1] Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, USA [2].
Heejun Hwang1] Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA [2].
Gang DengDepartment of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
Simon DiepDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Brett LomenickDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Vijaykumar S MeliDepartment of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
Gabriela C MonsalveDepartment of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
Eileen HuDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Stephen A WhelanDepartment of Surgery, University of California Los Angeles, Los Angeles, California 90095, USA.
Jennifer X WangSmall Molecule Mass Spectrometry Facility, FAS Division of Science, Harvard University, Cambridge, Massachusetts 02138, USA.
Gwanghyun JungDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Gregory M SolisDepartment of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
Farbod FazlollahiPasarow 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.
Chitrada KaweeteerawatDepartment of Environmental Health Sciences, University of California Los Angeles, Los Angeles, California 90095, USA.
Austin QuachDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Mahta NiliDepartment of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
Abby S KrallDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Hilary A GodwinDepartment of Environmental Health Sciences, University of California Los Angeles, Los Angeles, California 90095, USA.
Helena R ChangDepartment of Surgery, University of California Los Angeles, Los Angeles, California 90095, USA.
Kym F FaullPasarow 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.
Feng GuoDepartment of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
Meisheng JiangDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Sunia A TraugerSmall Molecule Mass Spectrometry Facility, FAS Division of Science, Harvard University, Cambridge, Massachusetts 02138, USA.
Alan SaghatelianDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Daniel Braas1] 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.
Heather R Christofk1] 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.
Catherine F Clarke1] 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.
Michael A Teitell1] 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.
Michael PetrascheckDepartment of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
Karen Reue1] 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.
Michael E Jung1] 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.
Alison R FrandDepartment of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
Jing Huang1] 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.
University of California, Los Angeles · USHarvard University · USScripps Research Institute · US

Funding

Systems genomics of metabolic syndrome traitsP01HL028481 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CANTOR, RITA M. · 1985 to 2019
$50.2M
The Lipin Protein Family and Triglyceride Metabolism P01HL090553 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI YOUNG, STEPHEN G. · 2008 to 2018
$23.3M
UCLA NIGMS T32 Program AssessmentT32GM007185 · NIGMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI TORRES, JORGE · 1985 to 2020
$21.7M
UCLA Tumor Immunology Training ProgramT32CA009120 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Steven M. Dubinett, MICHAEL A TEITELL · 1985 to 2026
$10.3M
Enhancing and expanding the CGC Strain CollectionP40OD010440 · OD · UNIVERSITY OF MINNESOTA · PI Aric L Daul, Ann E. Rougvie · 2012 to 2026
$7.5M
CHEMISTRY BIOLOGY INTERFACE TRAINING PROGRAMT32GM008496 · NIGMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI MAYNARD, HEATHER D · 1993 to 2019
$6.3M
PREDOCTORAL TRAINING PROGRAM IN GENETIC MECHANISMS AT UCT32GM007104 · NIGMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI GOBER, JAMES W · 1985 to 2011
$3.6M
Modulation of Sensory Perception to Treat Age Related DiseaseDP2OD008398 · OD · SCRIPPS RESEARCH INSTITUTE, THE · PI PETRASCHECK, MICHAEL · 2011 to 2011
$2.8M
NCI NIH HHS T32 CA009120NHLBI NIH HHS P01 HL028481NHLBI NIH HHS P01 HL090553NIGMS NIH HHS T32 GM007104NIGMS NIH HHS T32 GM007185NIGMS NIH HHS T32 GM008496NIH HHS DP2 OD008398NIH HHS P40 OD010440
6 · The paper itself

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 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). 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 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.

Indexed as

AnimalsCaenorhabditis elegansCell LineEnzyme ActivationEnzyme InhibitorsGene Knockdown TechniquesHEK293 CellsHumansJurkat CellsKetoglutaric AcidsLongevityMiceMitochondrial Proton-Translocating ATPasesProtein BindingTOR Serine-Threonine KinasesEnzyme InhibitorsKetoglutaric AcidsMitochondrial Proton-Translocating ATPasesTOR Serine-Threonine Kinases

Identifiers

PMID24828042
PMCPMC4263271
OpenAlexW2048776985

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.