Altered dietary methionine differentially impacts glutathione and methionine metabolism in long-living growth hormone-deficient Ames dwarf and wild-type mice

Abstract

BackgroundExtending mammalian health span and life span has been achieved under a variety of dietary restriction protocols. Reducing the intake of a specific amino acid has also been shown to extend health and longevity. We recently reported that methionine (MET) restriction is not effective in life span extension in growth hormone (GH) signaling mutants. To better understand the apparent necessity of GH in the ‘sensing’ of altered dietary MET, the current study was designed to evaluate MET and glutathione (GSH) metabolism (as well as other pathways) in long-living GH-deficient Ames dwarf and wild-type mice following 8 weeks of restricted (0.16%), low (0.43%), or enriched (1.3%) dietary MET consumption. Metabolite expression was examined in liver tissue, while gene and protein expression were evaluated in liver, kidney, and muscle tissues.ResultsBody weight was maintained in dwarf mice on the MET diets, while wild-type mice on higher levels of MET gained weight. Liver MET levels were similar in Ames mice, while several MET pathway enzymes were elevated regardless of dietary MET intake. Transsulfuration enzymes were also elevated in Ames mice but differences in cysteine levels were not different between genotypes. Dwarf mice maintained higher levels of GSH on MET restriction compared to wild-type mice, while genotype and diet effects were also detected in thioredoxin and glutaredoxin. MET restriction increased transmethylation in both genotypes as indicated by increased S-adenosylmethionine (SAM), betaine, and dimethylglycine. Diet did not impact levels of glycolytic components, but dwarf mice exhibited higher levels of key members of this pathway. Coenzyme A and measures of fatty acid oxidation were elevated in dwarf mice and unaffected by diet.ConclusionsThis component analysis between Ames and wild-type mice suggests that the life span differences observed may result from the atypical MET metabolism and downstream effects on multiple systems. The overall lack of responsiveness to the different diets is well reflected across many metabolic pathways in dwarf mice indicating the importance of GH signaling in the ability to discriminate dietary amino acid levels.Electronic supplementary materialThe online version of this article (doi:10.1186/2046-2395-3-10) contains supplementary material, which is available to authorized users.

Replicatively senescent human fibroblasts reveal a distinct intracellular metabolic profile with alterations in NAD+ and nicotinamide metabolism

“…Ames Dwarf mice mount an increased oxidative defence in the liver and show increased levels of SAM and its SAH and largely maintain cysteine and reduced glutathione levels, especially when fed low levels of methionine in the diet44 while SAM and SAH were specifically depleted in PEsen cells; Ames Dwarf mice also showed reduced levels of hypotaurine, multiple gamma glutamyl amino acids, opthalmate and noropthalmate compared to control mice44 and these metabolites were generally elevated in PEsen cells (this study and ref. 23) consistent with Ames Dwarf mouse liver cells using these antioxidant pathways to prevent senescence initiation.…”

“…Further work will be required to established the PEsen metabolome of muscle and liver cells in vitro . There are also differences between liver and muscle in methionine metabolism4344.…”

The somatotropic axis and longevity in mice

“…Restricting a single amino acid such as methionine also increases longevity in normal rats and mice (74,83,119) yet does not impact lifespan in GH signaling mutants (Ames dwarf, GHRKO) (20). Thus intact signaling of the somatotropic pathway appears to be necessary for amino acid sensing in terms of metabolism and lifespan regulation (19). We also know that GH treatment abolishes the DR lifespan benefits in dwarf mice (30% DR started at 5 mo of age; GH administration started 2 wk after DR at 4 mg·g body wt Ϫ1 ·day Ϫ1 ) (42).…”

Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health

“…Over the last decade, evidence has mounted that certain individual amino acids (AAs), the building blocks of protein, have distinct effects on metabolism (Brown-Borg et al, 2014; Edwards et al, 2015; Grandison et al, 2009; Miller et al, 2005). In particular, several studies have observed increased serum levels of the three branched-chain amino acids (BCAAs) – leucine, isoleucine, and valine – in insulin-resistant humans, and indeed BCAA levels are predictive of development of type 2 diabetes (Lynch and Adams, 2014).…”