The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR.
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.
Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA.
Randall M
RM
Chin
Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Xudong
X
Fu
1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2].
Melody Y
MY
Pai
1] Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, USA [2].
Laurent
L
Vergnes
1] Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA [2].
Heejun
H
Hwang
Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
Gang
G
Deng
Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Simon
S
Diep
Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Brett
B
Lomenick
Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
Vijaykumar S
VS
Meli
Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
Gabriela C
GC
Monsalve
Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Eileen
E
Hu
Department of Surgery, University of California Los Angeles, Los Angeles, California 90095, USA.
Stephen A
SA
Whelan
Small Molecule Mass Spectrometry Facility, FAS Division of Science, Harvard University, Cambridge, Massachusetts 02138, USA.
Jennifer X
JX
Wang
Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Gwanghyun
G
Jung
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
Gregory M
GM
Solis
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.
Farbod
F
Fazlollahi
Department of Environmental Health Sciences, University of California Los Angeles, Los Angeles, California 90095, USA.
Chitrada
C
Kaweeteerawat
Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Austin
A
Quach
Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
Mahta
M
Nili
Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Abby S
AS
Krall
Department of Environmental Health Sciences, University of California Los Angeles, Los Angeles, California 90095, USA.
Hilary A
HA
Godwin
Department of Surgery, University of California Los Angeles, Los Angeles, California 90095, USA.
Helena R
HR
Chang
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.
Kym F
KF
Faull
Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
Feng
F
Guo
Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.
Meisheng
M
Jiang
Small Molecule Mass Spectrometry Facility, FAS Division of Science, Harvard University, Cambridge, Massachusetts 02138, USA.
Sunia A
SA
Trauger
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Alan
A
Saghatelian
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.
Daniel
D
Braas
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.
Heather R
HR
Christofk
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.
Catherine F
CF
Clarke
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.
Michael A
MA
Teitell
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
Michael
M
Petrascheck
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.
Karen
K
Reue
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.
Michael E
ME
Jung
Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA.
Alison R
AR
Frand
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.
Jing
J
Huang
D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D007656:Ketoglutaric Acids / Q000494:pharmacology*; D008136:Longevity / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051379:Mice; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007656:Ketoglutaric Acids; D058570:TOR Serine-Threonine Kinases; D025261:Mitochondrial Proton-Translocating ATPases