Fig. 4.

Schematic representation of methionine metabolism. Underlined are metabolites and enzymes that were associated with lifespan extension. Red font color represents downregulation or depletion from food, while green font color represents overexpression or supplementation. In the methionine cycle, methionine is converted to S-adenosyl-l-methionine (SAM), which acts as a methyl donor for methyltransferases, forming S-adenosyl-l-homocysteine (SAH), and finally, homocysteine. Downregulation of methionine adenosyltransferase (SAMS) and S-adenosyl-l-homocysteine hydrolase (ACHY), and overexpression of Glycine N- methyltransferase (GNMT) were associated with lifespan extension. In the methionine salvage pathway, methionine can be regenerated from SAM, forming polyamines during the cycle. Supplementation of the polyamines spermine and spermidine was associated with lifespan extension in several species. In the transsulfuration pathway, homocysteine is converted into cysteine, which can then be metabolized into taurine, pyruvate, and glutathione. Upregulation of cystathionine-β-synthase (CBS) and glutamate-cysteine ligase (GCL), as well as supplementation with the cysteine donor N-acetylcysteine (NAC) were associated with lifespan increase.