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.
Highlights
Extending mammalian health span and life span has been achieved under a variety of dietary restriction protocols
We evaluated the gene and protein expression of MET metabolic components as well as associated metabolites to understand the role of growth hormone (GH) status
In dwarf mice, the altered expression of key MET pathway enzymes results in a lack of dietary MET effects on homocysteine, serine, cysteine, cystathionine, GSH, hypotaurine, MET, THF, folate, and homoserine among others. This component analysis between dwarf and wild-type mice suggests that the life span differences observed in these mice may result from the atypical MET metabolism and downstream effects on multiple systems in dwarf mice
Summary
Extending mammalian health span and life span has been achieved under a variety of dietary restriction protocols. The dwarfism results from a point mutation in the Prop-1 gene that directs the differentiation of anterior pituitary While these mice lack plasma growth hormone (GH), prolactin, and thyrotropin, the GH deficiency is primarily responsible for the lifeextending effects [6]. Studies conducted by Bartke and coworkers demonstrated that a 30% DR increased life span by an additional 12% in these mice over Ames dwarf mice fed ad libitum [7]. These observations suggested that DR and GH deficiency exert different but overlapping effects that extend health and longevity
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