Schmeisser, Kathrin, Mansfeld, Johannes, Kuhlow, Doreen, Weimer, Sandra, Priebe, Steffen, Heiland, Ines ORCID: 0000-0002-9124-5112, Birringer, Marc ORCID: 0000-0003-0343-4704, Groth, Marco, Segref, Alexandra ORCID: 0000-0001-8095-4469, Kanfi, Yariv, Price, Nathan L., Schmeisser, Sebastian, Schuster, Stefan, Pfeiffer, Andreas F. H., Guthke, Reinhard, Platzer, Matthias, Hoppe, Thorsten ORCID: 0000-0002-4734-9352, Cohen, Haim Y., Zarse, Kim ORCID: 0000-0003-2542-6123, Sinclair, David A. and Ristow, Michael ORCID: 0000-0003-2109-2453 (2013). Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide. Nat. Chem. Biol., 9 (11). S. 693 - 704. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1552-4469

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schmeisser, KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mansfeld, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuhlow, DoreenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weimer, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Priebe, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heiland, InesUNSPECIFIEDorcid.org/0000-0002-9124-5112UNSPECIFIED
Birringer, MarcUNSPECIFIEDorcid.org/0000-0003-0343-4704UNSPECIFIED
Groth, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Segref, AlexandraUNSPECIFIEDorcid.org/0000-0001-8095-4469UNSPECIFIED
Kanfi, YarivUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Price, Nathan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmeisser, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schuster, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfeiffer, Andreas F. H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guthke, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Platzer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoppe, ThorstenUNSPECIFIEDorcid.org/0000-0002-4734-9352UNSPECIFIED
Cohen, Haim Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zarse, KimUNSPECIFIEDorcid.org/0000-0003-2542-6123UNSPECIFIED
Sinclair, David A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ristow, MichaelUNSPECIFIEDorcid.org/0000-0003-2109-2453UNSPECIFIED
URN: urn:nbn:de:hbz:38-473605
DOI: 10.1038/NCHEMBIO.1352
Journal or Publication Title: Nat. Chem. Biol.
Volume: 9
Number: 11
Page Range: S. 693 - 704
Date: 2013
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1552-4469
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DIFFERENTIAL EXPRESSION ANALYSIS; ALDEHYDE OXIDASE; COMPLEX-I; SACCHAROMYCES-CEREVISIAE; CALORIE RESTRICTION; LONGEVITY; ELEGANS; STRESS; SIR2; GENEMultiple languages
Biochemistry & Molecular BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/47360

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