Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide
Open accessAbstract
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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A supraphysiologic dose of NAM (1-5 mM compared with 200 μM used in lifespan extension experiments) has been associated with reduced lifespan in yeast and C. elegans.
“a supraphysiologic dose of NAM (1–5 mM as compared with 200 μM used in experiments with lifespan extension190) has also been associated with reduced lifespan in yeast and C. elegans190–192.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [191]
NAD+ supplementation results in production of N-methylnicotinamide via sirtuins.
“As NAD+ supplementation also results in potentially beneficial production of N-methylnicotinamide via sirtuins ((Schmeisser et al. 2013)), evidence such as the link to MnSOD affirms roles for acylation both as a direct effector modulated by NAD+ and in transducing NAD+ into an N-methylnicotinamide signal.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Schmeisser et al. 2013
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- Authors
- 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., Sinclair, D. A., & Ristow, M.
- Affiliations
- Friedrich Schiller University Jena (DE)
- ETH Zurich (CH)
- German Institute of Human Nutrition (DE)
- Fulda University of Applied Sciences (DE)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- University of Cologne (DE)
- Bar-Ilan University (IL)
- Harvard University (US)
- Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
- Corresponding author
- Ristow, Michael
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2013-09-29
- Volume
- 9
- Issue
- 11
- Pages
- 693-700
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC4076143
- OpenAlex
- W1974979950
- Cited by
- 236
- References
- 56
- Citations by year
- 2026: 2 · 2025: 12 · 2024: 14 · 2023: 14 · 2022: 25 · 2021: 20 · 2020: 27 · 2019: 18 · 2018: 17 · 2017: 15 · 2016: 20 · 2015: 27 · 2014: 22 · 2013: 3
- FWCI
- 8.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (P40OD010440)
- National Institute on Aging (R37AG028730)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- sirtuins, SIRT1, sir-2.1, lifespan extension, Caenorhabditis elegans, nicotinamide, N1-methylnicotinamide, nicotinamide N-methyltransferase, aldehyde oxidase, hydrogen peroxide, mitohormesis, reactive oxygen species signaling, NAD+ metabolism, longevity
- MeSH terms
- Animals, Longevity, Methylation, Niacinamide, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Sirtuins
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