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Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan.

Obata F, Miura M - Nat Commun (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

The effect of overexpression of Sams and Gnmt on metabolite levels.(a–i) UPLC–MS/MS analysis of SAM, Met and Sar levels in day-5 male flies with sams, samsR275H, gnmt and gnmtS145A overexpression by ubiquitous (da-Gal4) or fat-body (r4-Gal4) drivers or no driver. + Indicates UAS-only or Gal4-only controls. Statistics, two-tailed unpaired t-test. Error bars represent mean±s.d. (N=5 for da-Gal4, N=3 for r4-Gal4, N=4 for no-driver control). *P<0.05, **P<0.01, ***P<0.001 from the biological replicates. NS, not significant.
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f2: The effect of overexpression of Sams and Gnmt on metabolite levels.(a–i) UPLC–MS/MS analysis of SAM, Met and Sar levels in day-5 male flies with sams, samsR275H, gnmt and gnmtS145A overexpression by ubiquitous (da-Gal4) or fat-body (r4-Gal4) drivers or no driver. + Indicates UAS-only or Gal4-only controls. Statistics, two-tailed unpaired t-test. Error bars represent mean±s.d. (N=5 for da-Gal4, N=3 for r4-Gal4, N=4 for no-driver control). *P<0.05, **P<0.01, ***P<0.001 from the biological replicates. NS, not significant.

Mentions: We further analysed how these metabolites are affected by overexpressing either sams or gnmt ubiquitously or in a fat-body-specific manner (Fig. 2a–i; supplementary Fig. 2a). sams overexpression decreased Met and increased SAM. Introducing the R275H mutation, which was observed in several human hypermethioninemia patients who had a dominant MAT1AR264H mutation14, led to increased Met without affecting SAM levels. This result resembled the sams-RNAi phenotype. MAT1A in mammals forms dimers (called MAT III) or tetramers (called MAT I). R264 is essential for dimerization, and the R264/R264H dimer is enzymatically inactive14. Thus, we considered that SamsR275H may behave as a dominant-negative form in Drosophila as well. On the other hand, gnmt overexpression decreased SAM levels, although subtly, as well as methionine levels. The reason methionine was also reduced in gnmt-overexpressing male flies was unknown; however, we thought that the reduction in SAM accelerated SAM synthesis from methionine as a feedback mechanism for maintaining SAM levels. We also established a mutant version of a gnmt overexpression line by introducing a serine 145 to alanine substitution. Since S145A is located at the SAM-binding site of Gnmt15, we speculated that this mutation might result in reduced enzymatic Gnmt function. Indeed, the effect of gnmtS145A overexpression on SAM and methionine was attenuated, although it was not complete (Fig. 2a–i; supplementary Fig. 2b–d).


Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan.

Obata F, Miura M - Nat Commun (2015)

The effect of overexpression of Sams and Gnmt on metabolite levels.(a–i) UPLC–MS/MS analysis of SAM, Met and Sar levels in day-5 male flies with sams, samsR275H, gnmt and gnmtS145A overexpression by ubiquitous (da-Gal4) or fat-body (r4-Gal4) drivers or no driver. + Indicates UAS-only or Gal4-only controls. Statistics, two-tailed unpaired t-test. Error bars represent mean±s.d. (N=5 for da-Gal4, N=3 for r4-Gal4, N=4 for no-driver control). *P<0.05, **P<0.01, ***P<0.001 from the biological replicates. NS, not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4595730&req=5

f2: The effect of overexpression of Sams and Gnmt on metabolite levels.(a–i) UPLC–MS/MS analysis of SAM, Met and Sar levels in day-5 male flies with sams, samsR275H, gnmt and gnmtS145A overexpression by ubiquitous (da-Gal4) or fat-body (r4-Gal4) drivers or no driver. + Indicates UAS-only or Gal4-only controls. Statistics, two-tailed unpaired t-test. Error bars represent mean±s.d. (N=5 for da-Gal4, N=3 for r4-Gal4, N=4 for no-driver control). *P<0.05, **P<0.01, ***P<0.001 from the biological replicates. NS, not significant.
Mentions: We further analysed how these metabolites are affected by overexpressing either sams or gnmt ubiquitously or in a fat-body-specific manner (Fig. 2a–i; supplementary Fig. 2a). sams overexpression decreased Met and increased SAM. Introducing the R275H mutation, which was observed in several human hypermethioninemia patients who had a dominant MAT1AR264H mutation14, led to increased Met without affecting SAM levels. This result resembled the sams-RNAi phenotype. MAT1A in mammals forms dimers (called MAT III) or tetramers (called MAT I). R264 is essential for dimerization, and the R264/R264H dimer is enzymatically inactive14. Thus, we considered that SamsR275H may behave as a dominant-negative form in Drosophila as well. On the other hand, gnmt overexpression decreased SAM levels, although subtly, as well as methionine levels. The reason methionine was also reduced in gnmt-overexpressing male flies was unknown; however, we thought that the reduction in SAM accelerated SAM synthesis from methionine as a feedback mechanism for maintaining SAM levels. We also established a mutant version of a gnmt overexpression line by introducing a serine 145 to alanine substitution. Since S145A is located at the SAM-binding site of Gnmt15, we speculated that this mutation might result in reduced enzymatic Gnmt function. Indeed, the effect of gnmtS145A overexpression on SAM and methionine was attenuated, although it was not complete (Fig. 2a–i; supplementary Fig. 2b–d).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

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.

No MeSH data available.


Related in: MedlinePlus