title: Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan.
abstract: Methionine restriction extends the lifespan of various model organisms. Limiting S-adenosyl-methionine (SAM) synthesis, the first metabolic reaction of dietary methionine, extends longevity in Caenorhabditis elegans but accelerates pathology in mammals. Here, we show that, as an alternative to inhibiting SAM synthesis, enhancement of SAM catabolism by glycine N-methyltransferase (Gnmt) extends the lifespan in Drosophila. Gnmt strongly buffers systemic SAM levels by producing sarcosine in either high-methionine or low-sams conditions. During ageing, systemic SAM levels in flies are increased. Gnmt is transcriptionally induced in a dFoxO-dependent manner; however, this is insufficient to suppress SAM elevation completely in old flies. Overexpression of gnmt suppresses this age-dependent SAM increase and extends longevity. Pro-longevity regimens, such as dietary restriction or reduced insulin signalling, attenuate the age-dependent SAM increase, and rely at least partially on Gnmt function to exert their lifespan-extending effect in Drosophila. Our study suggests that regulation of SAM levels by Gnmt is a key component of lifespan extension.
authors.affiliation: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Obata
authors.affiliation: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.|CREST, Japan Agency for Medical Research and Development, 20F Yomiuri Shimbun Building 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miura
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D031204:Caloric Restriction; D002853:Chromatography, Liquid; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D050938:Glycine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008136:Longevity; D008716:Methionine Adenosyltransferase / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012436:S-Adenosylmethionine / Q000378:metabolism*; D012521:Sarcosine / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D029721:Drosophila Proteins; D007328:Insulin; D012436:S-Adenosylmethionine; D050938:Glycine N-Methyltransferase; D008716:Methionine Adenosyltransferase; D012521:Sarcosine