Dietary restriction of the essential amino acid, methionine, has been shown to induce unique metabolic protection. The peripheral benefits of methionine restriction (MR) are well established and include improvements in metabolic, energy, inflammatory, and lifespan parameters in preclinical models. These benefits all occur despite MR increasing energy intake, making MR an attractive dietary intervention for the prevention or reversal of many metabolic and chronic conditions. New and emerging evidence suggests that MR also benefits the brain and promotes cognitive health. Despite widespread interest in MR over the past few decades, many findings are limited in scope, and gaps remain in our understanding of its comprehensive effects on the brain and cognition. This review details the current literature investigating the impact of MR on cognition in various mouse models, highlights some of the key mechanisms responsible for its cognitive benefits, and identifies gaps that should be addressed in MR research moving forward. Overall findings indicate that in animal models, MR is associated with protection against obesity-, age-, and Alzheimer's disease-induced impairments in learning and memory that depend on different brain regions, including the prefrontal cortex, amygdala, and hippocampus. These benefits are likely mediated by increases in fibroblast growth factor 21, alterations in methionine metabolism pathways, reductions in neuroinflammation and central oxidative stress, and potentially alterations in the gut microbiome, mitochondrial function, and synaptic plasticity.
Keywords: Alzheimer’s disease; age; behavior; brain; cognition; female; high-fat diet; methionine restriction; obesity; sex.