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

Kathrin Schmeisser; Johannes Mansfeld; Doreen Kuhlow; Sandra Weimer; Steffen Priebe; Ines Heiland; Marc Birringer; Marco Groth; Alexandra Segref; Yariv Kanfi; Nathan L. Price; Sebastian Schmeisser; Stefan Schuster; Andreas F.H. Pfeiffer; Reinhard Guthke; Matthias Platzer; Thorsten Hoppe; Haim Y. Cohen; Kim Zarse; David A. Sinclair; Michael Ristow

doi:10.1038/nchembio.1352

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

Kathrin Schmeisser, Johannes Mansfeld, Doreen Kuhlow, Sandra Weimer, Steffen Priebe, Ines Heiland, Marc Birringer, Marco Groth, Alexandra Segref, Yariv Kanfi, Nathan L. Price, Sebastian Schmeisser, Stefan Schuster, Andreas F.H. Pfeiffer, Reinhard Guthke, Matthias Platzer, Thorsten Hoppe, Haim Y. Cohen, Kim Zarse, David A. SinclairMichael Ristow

The Mina and Everard Goodman Faculty of Life Sciences

Research output: Contribution to journal › Article › peer-review

187 Scopus citations

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.

Original language	English
Pages (from-to)	693-700
Number of pages	8
Journal	Nature Chemical Biology
Volume	9
Issue number	11
DOIs	https://doi.org/10.1038/nchembio.1352
State	Published - Nov 2013

Bibliographical note

Funding Information:
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.

Funding

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.

Funders	Funder number
Glenn Medical Foundation
Jena Centre for Systems Biology of Ageing
National Institutes of Health	P40 OD010440
National Institute on Aging	R37AG028730
University of Minnesota
United Mitochondrial Disease Foundation
Bundesministerium für Bildung und Forschung	0315581

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Schmeisser, K., Mansfeld, J., Kuhlow, D., Weimer, S., Priebe, S., Heiland, I., Birringer, M., Groth, M., Segref, A., Kanfi, Y., Price, N. L., Schmeisser, S., Schuster, S., Pfeiffer, A. F. H., Guthke, R., Platzer, M., Hoppe, T., Cohen, H. Y., Zarse, K., ... Ristow, M. (2013). Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide. Nature Chemical Biology, 9(11), 693-700. https://doi.org/10.1038/nchembio.1352

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title = "Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide",

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.",

author = "Kathrin Schmeisser and Johannes Mansfeld and Doreen Kuhlow and Sandra Weimer and Steffen Priebe and Ines Heiland and Marc Birringer and Marco Groth and Alexandra Segref and Yariv Kanfi and Price, {Nathan L.} and Sebastian Schmeisser and Stefan Schuster and Pfeiffer, {Andreas F.H.} and Reinhard Guthke and Matthias Platzer and Thorsten Hoppe and Cohen, {Haim Y.} and Kim Zarse and Sinclair, {David A.} and Michael Ristow",

note = "Funding Information: 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. M{\"u}ller, 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 f{\"u}r 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.",

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month = nov,

doi = "10.1038/nchembio.1352",

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Schmeisser, K, Mansfeld, J, Kuhlow, D, Weimer, S, Priebe, S, Heiland, I, Birringer, M, Groth, M, Segref, A, Kanfi, Y, Price, NL, Schmeisser, S, Schuster, S, Pfeiffer, AFH, Guthke, R, Platzer, M, Hoppe, T, Cohen, HY, Zarse, K, Sinclair, DA & Ristow, M 2013, 'Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide', Nature Chemical Biology, vol. 9, no. 11, pp. 693-700. https://doi.org/10.1038/nchembio.1352

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AU - Schmeisser, Kathrin

AU - Mansfeld, Johannes

AU - Kuhlow, Doreen

AU - Weimer, Sandra

AU - Priebe, Steffen

AU - Heiland, Ines

AU - Birringer, Marc

AU - Groth, Marco

AU - Segref, Alexandra

AU - Kanfi, Yariv

AU - Price, Nathan L.

AU - Schmeisser, Sebastian

AU - Schuster, Stefan

AU - Pfeiffer, Andreas F.H.

AU - Guthke, Reinhard

AU - Platzer, Matthias

AU - Hoppe, Thorsten

AU - Cohen, Haim Y.

AU - Zarse, Kim

AU - Sinclair, David A.

AU - Ristow, Michael

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

Abstract

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Funding

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