Dietary methionine supplementation improves cognitive dysfunction associated with transsulfuration pathway upregulation in mouse models of subacute aging

Abstract

Methionine (Met), an important substrate for protein synthesis and methyl donors, has also been shown to improve redox homeostasis in the body. However, its ability to ameliorate aging-induced cognitive dysfunction and the underlying mechanisms involved are still unknown. This study aimed to explore the effects of dietary Met supplementation on D-galactose-induced cognitive dysfunction and the associated mechanisms in mouse models of subacute aging. The mice were administrated 0.15 g/kg/day D-galactose subcutaneously and fed a normal (0.86% Met) or a Met-supplemented diet (1.72% Met) for 11 weeks. Various behavioral experiments were conducted, and we measured the plasma metabolite levels, hippocampal and plasma redox and inflammatory states, and hippocampal transsulfuration pathway-related parameters. We observed that dietary Met supplementation prevented aging-induced anxiety and cognitive deficiencies in subacute aging mice. Moreover, dietary Met supplementation normalized the plasma levels of multiple systemic metabolites involved in cognitive function as well as the redox and inflammatory states (e.g., betaine, taurine, and choline). Furthermore, dietary Met supplementation abolished oxidative stress and inflammation, selectively modulated the expression of multiple cognition-related genes, and increased flux via the transsulfuration pathway in the hippocampi of subacute aging mice, with significant increase in H2S and glutathione production. Our findings suggest that dietary Met supplementation prevented cognitive deficiencies in subacute aging mice, probably as a result of increased flux via the transsulfuration pathway.