Journal
NATURE CHEMICAL BIOLOGY
Volume 9, Issue 11, Pages 693-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/NCHEMBIO.1352
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Funding
- US National Institutes of Health (NIH) Office of Research Infrastructure Programs [P40 OD010440]
- research program of the Jena Centre for Systems Biology of Ageing (JenAge)
- German Ministry for Education and Research (Bundesministerium fur Bildung und Forschung) [BMBF 0315581]
- NIH
- National Institute on Aging
- United Mitochondrial Disease Foundation
- Glenn Medical Foundation
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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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