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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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.
D.S. is a consultant and inventor on patents licensed to GlaxoSmithKline, PA, a company developing sirtuin-based medicines.
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Schmeisser, K., Mansfeld, J., Kuhlow, D. et al. Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide. Nat Chem Biol 9, 693–700 (2013). https://doi.org/10.1038/nchembio.1352
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