Reviewing Methionine Restriction as a Basis for Calorie Restriction Benefits
The practice of calorie restriction has been shown to extend life in most mammalian species tested, including primates, and to at least greatly improve measures of health in humans. There is some consensus for the primary mechanism of calorie restriction to involve sensing of methionine levels in the diet, as feeding animals a normal level of calories using foods that contain very little methionine produces fairly similar outcomes to those observed in calorie restricted animals. Methionine is one of the essential amino acids, those not manufactured by our biochemistry and which must be obtained via the diet. It is required for synthesis of proteins, and so less of it requires cells to recycle more aggressively, among other changes.
Methionine restriction (MR) extends lifespan across different species. The main responses of rodent models to MR are well-documented in adipose tissue and liver, which have reduced mass and improved insulin sensitivity, respectively. Recently, molecular mechanisms that improve healthspan have been identified in both organs during MR. In fat, MR induced a futile lipid cycle concomitant with beige adipose tissue accumulation, producing elevated energy expenditure. In liver, MR upregulated fibroblast growth factor 21 and improved glucose metabolism in aged mice and in response to a high-fat diet. Furthermore, MR also reduces mitochondrial oxidative stress in various organs such as liver, heart, kidneys, and brain. Other effects of MR have also been reported in such areas as cardiac function in response to hyperhomocysteinemia, identification of molecular mechanisms in bone development, and enhanced epithelial tight junction. In addition, rodent models of cancer responded positively to MR, as has been reported in colon, prostate, and breast cancer studies.
The beneficial effects of MR have also been documented in a number of invertebrate model organisms, including yeast, nematodes, and fruit flies. MR not only promotes extended longevity in these organisms, but in the case of yeast has also been shown to improve stress tolerance. In addition, expression analyses of yeast and Drosophila undergoing MR have identified multiple candidate mediators of the beneficial effects of MR in these models. In this review, we emphasize other in vivo effects of MR such as in cardiovascular function, bone development, epithelial tight junction, and cancer. We also discuss the effects of MR in invertebrates.