Methionine restriction (MR)

Methionine restriction (MR), also known as methionine deprivation, refers to a dietary intervention that limits intake of the essential sulfur-containing amino acid methionine, triggering adaptive metabolic responses rather than targeting a specific molecule like a receptor or enzyme. Biologically, MR activates amino acid deficiency sensing pathways such as GCN2 kinase and PERK/NRF2, leading to eIF2α phosphorylation, ATF4 induction, and downstream effects including increased fibroblast growth factor 21 (FGF21) expression, elevated energy expenditure, enhanced insulin sensitivity, and altered lipid metabolism in liver and adipose tissue. These changes promote fat loss, prevent hepatic steatosis, and improve glucose tolerance even on high-fat diets, with mechanisms independent of hepatic mTORC1 suppression in some contexts. In disease, MR extends lifespan, counters age-related metabolic decline, ameliorates obesity and type 2 diabetes in rodent models, and shows translational potential in humans, though benefits like FGF21-UCP1 axis activation are often sex-specific (stronger in males). Methionine metabolism itself supports methylation (via SAM), polyamine synthesis, transsulfuration to glutathione for redox balance, and immune cell epigenetic reprogramming, but restriction disrupts these to favor homeostasis. No direct drugs target MR as a molecule; instead, it is pursued via diet, with challenges like adherence limiting clinical use.

Other names

Methionine deprivationMDdietary methionine restrictionlow-methionine diet