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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

Gnmt is a predominant regulator of systemic SAM levels.(a) Schematic view of methionine metabolism in Drosophila melanogaster. Gly, glycine; Sar, sarcosine; Met, methionine; SAM, S-adenosyl-methionine; SAH, S-adenosyl-homocysteine; Hcy, homocysteine; Sams, S-adenosyl-methionine synthase; Gnmt, glycine N-methyltransferase. (b) Lifespan analysis of ubiquitous sams-RNAi male flies under 10% SY diet. In total, 200 μM RU486 (RU) is used to knock down sams after adult eclosion in TubGS>sams-RNAi. Statistics, log-rank test, P<0.0001 (N=70 for −RU, N=79 for +RU). (c) Western blot analysis of Sams and Gnmt in day-5 male flies with either sams-RNAi or gnmt-RNAi driven by the fat-body drivers: r4-Gal4 and FB-Gal4, or no driver. + Indicates UAS-only or Gal4-only controls. (d–l) UPLC–MS/MS analysis of SAM, methionine (Met) and sarcosine (Sar) levels in day-5 male flies with either sams-RNAi or gnmt-RNAi driven by the fat-body drivers (FB-Gal4, r4-Gal4) or no driver. + Indicates UAS-only or Gal4-only controls. Error bars represent mean±s.d. (N=4). Statistics, one-way analysis of variance with Bonferroni's multiple comparison test. *P<0.05, **P<0.01, ***P<0.001 from the biological replicates. NS, not significant.
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f1: Gnmt is a predominant regulator of systemic SAM levels.(a) Schematic view of methionine metabolism in Drosophila melanogaster. Gly, glycine; Sar, sarcosine; Met, methionine; SAM, S-adenosyl-methionine; SAH, S-adenosyl-homocysteine; Hcy, homocysteine; Sams, S-adenosyl-methionine synthase; Gnmt, glycine N-methyltransferase. (b) Lifespan analysis of ubiquitous sams-RNAi male flies under 10% SY diet. In total, 200 μM RU486 (RU) is used to knock down sams after adult eclosion in TubGS>sams-RNAi. Statistics, log-rank test, P<0.0001 (N=70 for −RU, N=79 for +RU). (c) Western blot analysis of Sams and Gnmt in day-5 male flies with either sams-RNAi or gnmt-RNAi driven by the fat-body drivers: r4-Gal4 and FB-Gal4, or no driver. + Indicates UAS-only or Gal4-only controls. (d–l) UPLC–MS/MS analysis of SAM, methionine (Met) and sarcosine (Sar) levels in day-5 male flies with either sams-RNAi or gnmt-RNAi driven by the fat-body drivers (FB-Gal4, r4-Gal4) or no driver. + Indicates UAS-only or Gal4-only controls. Error bars represent mean±s.d. (N=4). Statistics, one-way analysis of variance with Bonferroni's multiple comparison test. *P<0.05, **P<0.01, ***P<0.001 from the biological replicates. NS, not significant.

Mentions: Drosophila melanogaster has a single SAM synthase (sams) (Fig. 1a). We first knocked down sams to test whether it increases the lifespan in Drosophila, as reported in C. elegans. UAS-sams-RNA interference (RNAi) crossed with an ubiquitous driver, da-Gal4, showed developmental lethality, indicating that sams is an essential gene for proper development. Next, we checked the lifespan of male flies with adult-specific knockdown of sams by TubGS-Gal4, which is the RU486-inducible binary expression system in the whole body. We were able to bypass the developmental lethality of sams-RNAi, and thus, we analysed the adult lifespan in the presence or absence of RU486. In contrast to sams-RNAi in C. elegans, we observed a significantly shortened lifespan in Drosophila (Fig. 1b).


Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan.

Obata F, Miura M - Nat Commun (2015)

Gnmt is a predominant regulator of systemic SAM levels.(a) Schematic view of methionine metabolism in Drosophila melanogaster. Gly, glycine; Sar, sarcosine; Met, methionine; SAM, S-adenosyl-methionine; SAH, S-adenosyl-homocysteine; Hcy, homocysteine; Sams, S-adenosyl-methionine synthase; Gnmt, glycine N-methyltransferase. (b) Lifespan analysis of ubiquitous sams-RNAi male flies under 10% SY diet. In total, 200 μM RU486 (RU) is used to knock down sams after adult eclosion in TubGS>sams-RNAi. Statistics, log-rank test, P<0.0001 (N=70 for −RU, N=79 for +RU). (c) Western blot analysis of Sams and Gnmt in day-5 male flies with either sams-RNAi or gnmt-RNAi driven by the fat-body drivers: r4-Gal4 and FB-Gal4, or no driver. + Indicates UAS-only or Gal4-only controls. (d–l) UPLC–MS/MS analysis of SAM, methionine (Met) and sarcosine (Sar) levels in day-5 male flies with either sams-RNAi or gnmt-RNAi driven by the fat-body drivers (FB-Gal4, r4-Gal4) or no driver. + Indicates UAS-only or Gal4-only controls. Error bars represent mean±s.d. (N=4). Statistics, one-way analysis of variance with Bonferroni's multiple comparison test. *P<0.05, **P<0.01, ***P<0.001 from the biological replicates. NS, not significant.
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Related In: Results  -  Collection

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f1: Gnmt is a predominant regulator of systemic SAM levels.(a) Schematic view of methionine metabolism in Drosophila melanogaster. Gly, glycine; Sar, sarcosine; Met, methionine; SAM, S-adenosyl-methionine; SAH, S-adenosyl-homocysteine; Hcy, homocysteine; Sams, S-adenosyl-methionine synthase; Gnmt, glycine N-methyltransferase. (b) Lifespan analysis of ubiquitous sams-RNAi male flies under 10% SY diet. In total, 200 μM RU486 (RU) is used to knock down sams after adult eclosion in TubGS>sams-RNAi. Statistics, log-rank test, P<0.0001 (N=70 for −RU, N=79 for +RU). (c) Western blot analysis of Sams and Gnmt in day-5 male flies with either sams-RNAi or gnmt-RNAi driven by the fat-body drivers: r4-Gal4 and FB-Gal4, or no driver. + Indicates UAS-only or Gal4-only controls. (d–l) UPLC–MS/MS analysis of SAM, methionine (Met) and sarcosine (Sar) levels in day-5 male flies with either sams-RNAi or gnmt-RNAi driven by the fat-body drivers (FB-Gal4, r4-Gal4) or no driver. + Indicates UAS-only or Gal4-only controls. Error bars represent mean±s.d. (N=4). Statistics, one-way analysis of variance with Bonferroni's multiple comparison test. *P<0.05, **P<0.01, ***P<0.001 from the biological replicates. NS, not significant.
Mentions: Drosophila melanogaster has a single SAM synthase (sams) (Fig. 1a). We first knocked down sams to test whether it increases the lifespan in Drosophila, as reported in C. elegans. UAS-sams-RNA interference (RNAi) crossed with an ubiquitous driver, da-Gal4, showed developmental lethality, indicating that sams is an essential gene for proper development. Next, we checked the lifespan of male flies with adult-specific knockdown of sams by TubGS-Gal4, which is the RU486-inducible binary expression system in the whole body. We were able to bypass the developmental lethality of sams-RNAi, and thus, we analysed the adult lifespan in the presence or absence of RU486. In contrast to sams-RNAi in C. elegans, we observed a significantly shortened lifespan in Drosophila (Fig. 1b).

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