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Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide

Nature Chemical Biology 9, 693–700 (2013) | Download Citation

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Abstract

Sirtuins, a family of histone deacetylases, have a fiercely debated role in regulating lifespan. In contrast with recent observations, here we find that overexpression of sir-2.1, the ortholog of mammalian SirT1, does extend Caenorhabditis elegans lifespan. Sirtuins mandatorily convert NAD+ into nicotinamide (NAM). We here find that NAM and its metabolite, 1-methylnicotinamide (MNA), extend C. elegans lifespan, even in the absence of sir-2.1. We identify a previously unknown C. elegans nicotinamide-N-methyltransferase, encoded by a gene now named anmt-1, to generate MNA from NAM. Disruption and overexpression of anmt-1 have opposing effects on lifespan independent of sirtuins, with loss of anmt-1 fully inhibiting sir-2.1–mediated lifespan extension. MNA serves as a substrate for a newly identified aldehyde oxidase, GAD-3, to generate hydrogen peroxide, which acts as a mitohormetic reactive oxygen species signal to promote C. elegans longevity. Taken together, sirtuin-mediated lifespan extension depends on methylation of NAM, providing an unexpected mechanistic role for sirtuins beyond histone deacetylation.

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Acknowledgements

Most of the C. elegans strains used in this work were provided by the Caenorhabditis Genetics Center (University of Minnesota), which is funded by the US National Institutes of Health (NIH) Office of Research Infrastructure Programs (P40 OD010440). The strains LG389 and LG390 were a kind gift of L. Guarente and M. Viswanathan (both from Massachusetts Institute of Technology). The excellent technical assistance of I. Heinze, B. Laube, A. Müller, S. Richter and W. Scheiding as well as the excellent secretarial assistance of M. Schalowski are gratefully acknowledged. The RNA sequencing data contained in this manuscript were funded by the research program of the Jena Centre for Systems Biology of Ageing (JenAge) funded by the German Ministry for Education and Research (Bundesministerium für Bildung und Forschung; support code BMBF 0315581). D.A.S. is supported by grants from the NIH and National Institute on Aging, the United Mitochondrial Disease Foundation and the Glenn Medical Foundation.

Author information

    • Ines Heiland

    Present address: Department of Arctic and Marine Biology, The Arctic University of Norway, Tromsø, Norway.

    • Kathrin Schmeisser
    •  & Johannes Mansfeld

    These authors contributed equally to this work. .

Affiliations

  1. Department of Human Nutrition, Institute of Nutrition, University of Jena, Jena, Germany.

    • Kathrin Schmeisser
    • , Johannes Mansfeld
    • , Doreen Kuhlow
    • , Sebastian Schmeisser
    • , Kim Zarse
    •  & Michael Ristow

  2. Energy Metabolism Laboratory, Swiss Federal Institute of Technology (ETH) Zürich, Zürich, Switzerland.

    • Johannes Mansfeld
    • , Sandra Weimer
    • , Kim Zarse
    •  & Michael Ristow

  3. DFG Research Training Group 1715–Molecular Signatures of Adaptive Stress Responses, Jena, Germany.

    • Johannes Mansfeld

  4. Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.

    • Doreen Kuhlow
    • , Sandra Weimer
    • , Andreas F H Pfeiffer
    •  & Michael Ristow

  5. Systems Biology and Bioinformatics Group, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany.

    • Steffen Priebe
    •  & Reinhard Guthke

  6. Department of Bioinformatics, University of Jena, Jena, Germany.

    • Ines Heiland
    •  & Stefan Schuster

  7. Department of Nutritional, Food and Consumer Studies, University of Applied Sciences, Fulda, Germany.

    • Marc Birringer

  8. Genome Analysis, Leibniz Institute for Age Research, Fritz-Lipmann-Institute, Jena, Germany.

    • Marco Groth
    •  & Matthias Platzer

  9. Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

    • Alexandra Segref
    •  & Thorsten Hoppe

  10. The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.

    • Yariv Kanfi
    •  & Haim Y Cohen

  11. Glenn Laboratories for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Nathan L Price
    •  & David A Sinclair

  12. Leibniz Graduate School of Aging, Leibniz Institute for Age Research, Fritz-Lipmann-Institute, Jena, Germany.

    • Sebastian Schmeisser

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Contributions

K.S. and J.M. designed, performed, and evaluated all of the experiments with the following exceptions: M.G. and M.P. performed next-generation sequencing analysis of mRNA, whereas sample provision, RNA extraction and quality control were done by K.S. Bioinformatical evaluation was done by S.P., R.G., I.H. and S. Schuster. Promoter analysis and gene classification was done by K.S. and J.M. A.S. and T.H. helped with strain constructions. S.W., D.K., A.P., M.B., S. Schmeisser, K.Z., N.L.P., Y.K., D.A.S. and H.Y.C. were involved in the study design and sample contribution and contributed several assays. The entire work was designed and supervised by M.R. The manuscript was written by K.S., J.M. and M.R. All of the authors discussed and commented on the manuscript.

Competing interests

D.S. is a consultant and inventor on patents licensed to GlaxoSmithKline, PA, a company developing sirtuin-based medicines.

Corresponding author

Correspondence to Michael Ristow.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Results, Supplementary Figures 1–6 and Supplementary Tables 1 and 2.

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    Supplementary Data Set 1

    MNA-regulated genes

  2. 2.

    Supplementary Data Set 2

    NA-regulated genes

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DOI

https://doi.org/10.1038/nchembio.1352

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