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.
Highlights
Methionine restriction extends the lifespan of various model organisms
We first knocked down sams to test whether it increases the lifespan in Drosophila, as reported in C. elegans
GnmtMi has a different genetic background since it showed lethality when backcrossed to w1118, we found that dietary restriction (DR)-induced longevity was not observed in gnmtMi mutant (Fig. 3i–l), suggesting the possibility that glycine N-methyltransferase (Gnmt)-dependent SAM catabolism mediates DR longevity
Summary
Limiting S-adenosylmethionine (SAM) synthesis, the first metabolic reaction of dietary methionine, extends longevity in Caenorhabditis elegans but accelerates pathology in mammals. 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. The most successful regimen to delay ageing and extend longevity is dietary restriction (DR), which was shown to increase lifespan from yeast to mammals[1]. Since various MTases catalyse the transfer of methyl groups to nucleic acids, proteins and metabolites, changes in SAM levels can result in altered epigenetic regulation, lipid metabolism or protein function[6]. Overexpressing Gnmt could rescue the age-dependent SAM increases and extend Drosophila lifespan. Our data demonstrate that enhanced SAM catabolism by Gnmt is a key factor for lifespan control
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