Limits...
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.


Age-dependent SAM increase is attenuated by lifespan-extending regimens.(a,b) UPLC–MS/MS analysis of SAM and Met levels in yw and gnmtMi young (1 weeks old) or old (5 weeks old) male flies maintained under dietary restriction or a nutrient-rich condition. Error bars represent mean±s.d. (N=3–4). Statistics: one-way analysis of variance (ANOVA) with Bonferroni's multiple comparison test. (c–e) UPLC–MS/MS analysis of SAM levels in lacZ-, InRDNor TORTED-overexpressing male flies at young (1 week old) or old (5 weeks old) stages. Error bars represent mean±s.d. (N=3–4). Statistics: one-way ANOVA with Bonferroni's multiple comparison test. (f) Schematic view of the relationship between SAM metabolism and longevity control. Compared with young flies, SAM levels are increased despite Gnmt induction in old flies. Strengthening the dFoxO–Gnmt axis rescues age-dependent SAM increases and extends lifespan. *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
getmorefigures.php?uid=PMC4595730&req=5

f5: Age-dependent SAM increase is attenuated by lifespan-extending regimens.(a,b) UPLC–MS/MS analysis of SAM and Met levels in yw and gnmtMi young (1 weeks old) or old (5 weeks old) male flies maintained under dietary restriction or a nutrient-rich condition. Error bars represent mean±s.d. (N=3–4). Statistics: one-way analysis of variance (ANOVA) with Bonferroni's multiple comparison test. (c–e) UPLC–MS/MS analysis of SAM levels in lacZ-, InRDNor TORTED-overexpressing male flies at young (1 week old) or old (5 weeks old) stages. Error bars represent mean±s.d. (N=3–4). Statistics: one-way ANOVA with Bonferroni's multiple comparison test. (f) Schematic view of the relationship between SAM metabolism and longevity control. Compared with young flies, SAM levels are increased despite Gnmt induction in old flies. Strengthening the dFoxO–Gnmt axis rescues age-dependent SAM increases and extends lifespan. *P<0.05, **P<0.01, ***P<0.001 from the biological replicates. NS, not significant.

Mentions: Since Gnmt is required for DR-dependent lifespan extension, we analysed how DR altered systemic SAM levels. We analysed young (1 weeks (w)) and aged (5 w) male flies from two wild-type strains as well as a gnmt mutant strain maintained on a DR- (5% SY) or nutrient-rich (20% SY) diet. Since the 20% SY diet contains much Met, young flies maintained on 20% SY diet showed a slight increase in Met levels; however, changes in SAM levels were not statistically significant (Fig. 5a,b; Supplementary Fig. 5a,b), suggesting that Gnmt buffered SAM increase. Indeed, the lack of regulation by Gnmt resulted in increased SAM in male flies on the 20% SY diet compared with that of files on the 5% SY diet (Fig. 5a). As previously mentioned, Met levels tended to decrease with ageing in all three genotypes, but this phenotype was not affected by the diet (Fig. 5b; Supplementary Fig. 5b). In contrast, an age-dependent increase in SAM levels was suppressed by DR (Fig. 5a; Supplementary Fig. 5a). The gnmt mutants showed high SAM levels in young flies, but this was not further elevated by ageing (Fig. 5a), suggesting that a threshold for SAM increases exists in aged flies.


Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan.

Obata F, Miura M - Nat Commun (2015)

Age-dependent SAM increase is attenuated by lifespan-extending regimens.(a,b) UPLC–MS/MS analysis of SAM and Met levels in yw and gnmtMi young (1 weeks old) or old (5 weeks old) male flies maintained under dietary restriction or a nutrient-rich condition. Error bars represent mean±s.d. (N=3–4). Statistics: one-way analysis of variance (ANOVA) with Bonferroni's multiple comparison test. (c–e) UPLC–MS/MS analysis of SAM levels in lacZ-, InRDNor TORTED-overexpressing male flies at young (1 week old) or old (5 weeks old) stages. Error bars represent mean±s.d. (N=3–4). Statistics: one-way ANOVA with Bonferroni's multiple comparison test. (f) Schematic view of the relationship between SAM metabolism and longevity control. Compared with young flies, SAM levels are increased despite Gnmt induction in old flies. Strengthening the dFoxO–Gnmt axis rescues age-dependent SAM increases and extends lifespan. *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

f5: Age-dependent SAM increase is attenuated by lifespan-extending regimens.(a,b) UPLC–MS/MS analysis of SAM and Met levels in yw and gnmtMi young (1 weeks old) or old (5 weeks old) male flies maintained under dietary restriction or a nutrient-rich condition. Error bars represent mean±s.d. (N=3–4). Statistics: one-way analysis of variance (ANOVA) with Bonferroni's multiple comparison test. (c–e) UPLC–MS/MS analysis of SAM levels in lacZ-, InRDNor TORTED-overexpressing male flies at young (1 week old) or old (5 weeks old) stages. Error bars represent mean±s.d. (N=3–4). Statistics: one-way ANOVA with Bonferroni's multiple comparison test. (f) Schematic view of the relationship between SAM metabolism and longevity control. Compared with young flies, SAM levels are increased despite Gnmt induction in old flies. Strengthening the dFoxO–Gnmt axis rescues age-dependent SAM increases and extends lifespan. *P<0.05, **P<0.01, ***P<0.001 from the biological replicates. NS, not significant.
Mentions: Since Gnmt is required for DR-dependent lifespan extension, we analysed how DR altered systemic SAM levels. We analysed young (1 weeks (w)) and aged (5 w) male flies from two wild-type strains as well as a gnmt mutant strain maintained on a DR- (5% SY) or nutrient-rich (20% SY) diet. Since the 20% SY diet contains much Met, young flies maintained on 20% SY diet showed a slight increase in Met levels; however, changes in SAM levels were not statistically significant (Fig. 5a,b; Supplementary Fig. 5a,b), suggesting that Gnmt buffered SAM increase. Indeed, the lack of regulation by Gnmt resulted in increased SAM in male flies on the 20% SY diet compared with that of files on the 5% SY diet (Fig. 5a). As previously mentioned, Met levels tended to decrease with ageing in all three genotypes, but this phenotype was not affected by the diet (Fig. 5b; Supplementary Fig. 5b). In contrast, an age-dependent increase in SAM levels was suppressed by DR (Fig. 5a; Supplementary Fig. 5a). The gnmt mutants showed high SAM levels in young flies, but this was not further elevated by ageing (Fig. 5a), suggesting that a threshold for SAM increases exists in aged flies.

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.