Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide.
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.
1] Department of Human Nutrition, Institute of Nutrition, University of Jena, Jena, Germany. [2].
Kathrin
K
Schmeisser
Johannes
J
Mansfeld
Doreen
D
Kuhlow
Sandra
S
Weimer
Steffen
S
Priebe
Ines
I
Heiland
Marc
M
Birringer
Marco
M
Groth
Alexandra
A
Segref
Yariv
Y
Kanfi
Nathan L
NL
Price
Sebastian
S
Schmeisser
Stefan
S
Schuster
Andreas F H
AF
Pfeiffer
Reinhard
R
Guthke
Matthias
M
Platzer
Thorsten
T
Hoppe
Haim Y
HY
Cohen
Kim
K
Zarse
David A
DA
Sinclair
Michael
M
Ristow
D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D008136:Longevity; D008745:Methylation; D009536:Niacinamide / Q000737:chemistry / Q000378:metabolism*; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D009536:Niacinamide; D037761:Sirtuins