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

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

Nature chemical biology (2013-10-01)
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
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Nicotinamide, ≥99.5% (HPLC)
Sigma-Aldrich
Nicotinamide, ≥98.5% (HPLC)
Supelco
Niacinamide, Pharmaceutical Secondary Standard; Certified Reference Material
Nicotinamide, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Nicotinamide, BioReagent, suitable for cell culture, suitable for insect cell culture
Sigma-Aldrich
Nicotinamide, ≥98% (HPLC), powder
Sigma-Aldrich
Niacinamide, meets USP testing specifications
Supelco
Nicotinamide (Vitamin B3) solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
Supelco
Nicotinamide (Niacinamide), analytical standard