Methionine restriction beyond life‐span extension

Abstract

Dietary methionine restriction (MR) extends life span across species via various intracellular regulatory mechanisms. In rodents, MR induces resistance against adiposity, improves hepatic glucose metabolism, preserves cardiac function, and reduces body size, all of which can affect the onset of age-related diseases. Recent studies have shown that MR-affected biomarkers, such as fibroblast growth factor 21, adiponectin, leptin, cystathionine β synthase, and insulin-like growth factor 1, can potentially alter physiology. The beneficial effects of MR could be explained in part by its ability to reduce mitochondrial oxidative stress. Studies have revealed that MR can reduce reactive oxygen species that damage cells and promote cancer progression. It has been demonstrated that either MR or the targeting of specific genes in the methionine cycle could induce cell apoptosis while decreasing proliferation in several cancer models. The complete mechanism underlying the actions of MR on the cell cycle during cancer has not been fully elucidated. Epigenetic mechanisms, such as methylation and noncoding RNAs, are also possible downstream effectors of MR; future studies should help to elucidate some of these mechanisms. Despite evidence that changes in dietary methionine can affect epigenetics, it remains unknown whether epigenetics is a mechanism in MR. This review summarizes research on MR and its involvement in metabolism, cancer, and epigenetics.

Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species

“…Transgenic mice overexpressing FGF21 are markedly smaller, have decreased circulating IGF‐1 concentrations, and have a significantly extended lifespan (Zhang et al, ). The multiple physiological outcomes of MetR were recently reviewed and will not be further discussed here (Ables, Hens, & Nichenametla, ; Cavuoto & Fenech, ; Lee, Kaya, & Gladyshev, ; McIsaac, Lewis, Gibney, & Buffenstein, ; Sanchez‐Roman & Barja, ; Zhou et al, ). Methionine metabolism is also altered in the tissues of long‐lived Ames mice (Uthus & Brown‐Borg, ) and naked mole‐rats (Ma et al, ); however, whether these changes are causative or correlative is not known.…”

Homocysteine and homocysteine-related compounds: an overview of the roles in the pathology of the cardiovascular and nervous systems

“…SAH is then hydrolyzed to adenosine and homocysteine in reversible reaction regulated enzyme SAH hydrolase. This point has a key role in the further direction of homocysteine metabolism -remethylation or transsulfuration (Ables et al 2016;Steed and Tyagi 2011).…”

“…The crucial enzyme in this metabolic pathway of homocysteine is cystathionine β-synthase (CBS), enzyme that requires vitamin B 6 as cofactor, and catalyzes reaction of serine and homocysteine to form cystathionine. In next step cystathionine is hydrolyzed by γ-cystathionase (CTH) (also requires vitamin B 6 ) to cysteine and a-ketobutyrate (Ables et al 2016;Steed and Tyagi 2011).…”

Exercise and the Skeletal Muscle Epigenome

“…The major substrate for DNA methylation is S-adenosylmethionine (SAM), which is produced in the methionine-recycling pathway (Sauter et al 2013). Changes in the cellular levels of SAM result in altered levels of DNA methylation, with concomitant effects on gene transcription (Ables et al 2016). Ultimately, the methyl groups required for DNA methylation are derived from a range of dietary sources, and altering the availability of dietary methyl donors such as folate and selenium has been shown to affect DNA methylation and gene expression, including improving diseases such as neural tube defects associated with DNA hypomethylation (Chango and Pogribny 2015).…”

“…Ultimately, the methyl groups required for DNA methylation are derived from a range of dietary sources, and altering the availability of dietary methyl donors such as folate and selenium has been shown to affect DNA methylation and gene expression, including improving diseases such as neural tube defects associated with DNA hypomethylation (Chango and Pogribny 2015). Although there are numerous studies that have investigated the impact of increasing or decreasing dietary methionine, which has impacts including extending life span in a number of species following dietary methionine restriction (Ables et al 2016), there is no information regarding whether any of the phenotypic differences seen may be mediated by altered levels of DNA methylation. Similarly, the effects of exercise on the methionine-recycling pathway are currently unknown.…”