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 organisms1,2. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits3,4. Recently, several metabolites have been identified that modulate ageing5,6; 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 evolution8,9. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan10,11,12,13. 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 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.

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Acknowledgements

We thank S. Lee, M. Hansen, B. Lemire, A. van der Bliek, S. Clarke, T. K. Blackwell, R. Johnson, J. E. Walker, A. G. W. Leslie, K. N. Houk, B. Martin, J. Lusis, J. Gober, Y. Wang and H. Sun for advice and discussions. J. Avruch for the let-363 RNAi vector; J. Powell-Coffman for strains and advice; and K. Yan for technical assistance. Worm strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health (NIH) Office of Research Infrastructure Programs (P40 OD010440). We thank the NIH for traineeship support of R.M.C. (T32 GM007104), M.Y.P. (T32 GM007185), B.L. (T32 GM008496) and M.N. (T32 CA009120). X.F. is a recipient of the China Scholarship Council Scholarship. G.C.M. was supported by Ford Foundation and National Science Foundation Graduate Research Fellowships.

Author information

Author notes

    • Melody Y. Pai
    • , Laurent Vergnes
    •  & Heejun Hwang

    These authors contributed equally to this work.

Affiliations

  1. Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA

    • Randall M. Chin
    • , Melody Y. Pai
    • , Catherine F. Clarke
    • , Michael A. Teitell
    • , Karen Reue
    • , Michael E. Jung
    •  & Jing Huang
  2. Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA

    • Xudong Fu
    • , Heejun Hwang
    • , Simon Diep
    • , Brett Lomenick
    • , Eileen Hu
    • , Gwanghyun Jung
    • , Austin Quach
    • , Abby S. Krall
    • , Meisheng Jiang
    • , Daniel Braas
    • , Heather R. Christofk
    •  & Jing Huang
  3. Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, USA

    • Laurent Vergnes
    •  & Karen Reue
  4. Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095, USA

    • Gang Deng
    • , Catherine F. Clarke
    •  & Michael E. Jung
  5. Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA

    • Vijaykumar S. Meli
    • , Gabriela C. Monsalve
    • , Feng Guo
    •  & Alison R. Frand
  6. Department of Surgery, University of California Los Angeles, Los Angeles, California 90095, USA

    • Stephen A. Whelan
    •  & Helena R. Chang
  7. Small Molecule Mass Spectrometry Facility, FAS Division of Science, Harvard University, Cambridge, Massachusetts 02138, USA

    • Jennifer X. Wang
    •  & Sunia A. Trauger
  8. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA

    • Gregory M. Solis
    •  & Michael Petrascheck
  9. 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 Fazlollahi
    •  & Kym F. Faull
  10. Department of Environmental Health Sciences, University of California Los Angeles, Los Angeles, California 90095, USA

    • Chitrada Kaweeteerawat
    •  & Hilary A. Godwin
  11. Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, USA

    • Mahta Nili
    •  & Michael A. Teitell
  12. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    • Alan Saghatelian
  13. UCLA Metabolomics Center, University of California Los Angeles, Los Angeles, California 90095, USA

    • Daniel Braas
    •  & Heather R. Christofk

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Contributions

Lifespan assays were performed by R.M.C., M.P. and E.H.; DARTS-mass spectrometry by S.D. and B.L.; DARTS-western blots by M.Y.P., H.H. and R.M.C.; mammalian cell experiments by X.F. and H.H.; mitochondrial respiration study design and analyses by L.V. and K.R.; enzyme kinetics and analyses by R.M.C. and J.H.; confocal microscopy by V.S.M., G.C.M. and A.R.F.; ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UHPLC-ESI/MS/MS) by J.X.W. and S.A.T.; compound syntheses by G.D. and M.E.J.; other analyses by H.H., X.F., M.Y.P., D.B., R.M.C., E.H., G.J., G.M.S., C.K. and A.Q. S.A.W., F.F., M.N., A.S.K., H.A.G., H.R. Chang, K.F.F., F.G., M.J., S.A.T., A.S., D.B., H.R. Christofk, C.F.C., M.A.T., M.E.J., L.V., K.R., A.R.F. and M.P. provided guidance, specialized reagents and expertise. J.H. conceived the study. R.M.C. and J.H. wrote the paper. R.M.C., X.F. and J.H. analysed data. All authors discussed the results, commented on the studies and contributed to aspects of preparing the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jing Huang.

Extended data

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    Supplementary Information

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Videos

  1. 1.

    Example of a vehicle-treated day 16 adult animal

    The animal had lost all motility in the body and could only move its head slowly.

  2. 2.

    Example of a α-KG-treated day 16 adult animal

    The animal remained youthful and exhibited full body movements.

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DOI

https://doi.org/10.1038/nature13264

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