Effect of Methionine Restriction on Aging: Its Relationship to Oxidative Stress

Abstract

Enhanced oxidative stress is closely related to aging and impaired metabolic health and is influenced by diet-derived nutrients and energy. Recent studies have shown that methionine restriction (MetR) is related to longevity and metabolic health in organisms from yeast to rodents. The effect of MetR on lifespan extension and metabolic health is mediated partially through a reduction in oxidative stress. Methionine metabolism is involved in the supply of methyl donors such as S-adenosyl-methionine (SAM), glutathione synthesis and polyamine metabolism. SAM, a methionine metabolite, activates mechanistic target of rapamycin complex 1 and suppresses autophagy; therefore, MetR can induce autophagy. In the process of glutathione synthesis in methionine metabolism, hydrogen sulfide (H₂S) is produced through cystathionine-β-synthase and cystathionine-γ-lyase; however, MetR can induce increased H₂S production through this pathway. Similarly, MetR can increase the production of polyamines such as spermidine, which are involved in autophagy. In addition, MetR decreases oxidative stress by inhibiting reactive oxygen species production in mitochondria. Thus, MetR can attenuate oxidative stress through multiple mechanisms, consequently associating with lifespan extension and metabolic health. In this review, we summarize the current understanding of the effects of MetR on lifespan extension and metabolic health, focusing on the reduction in oxidative stress.

Keywords: autophagy; lifespan extension; metabolic health; methionine restriction; oxidative stress.

Figure 1

Methionine metabolism. Methionine cycle pathway: Methionine is catabolized by methionine adenosyltransferase 2A (MAT2A), producing the methyl donor S-adenosyl-methionine (SAM). Methyltransferases (MTs), including glycine N-methyltransferase (Gnmt), use SAM as a methyl source, thereby producing S-adenosyl-homocysteine (SAH). SAH is then converted by SAH hydrolase (SAHH, also known as adenosylhomocysteinase, AHCY) to homocysteine. Homocysteine can then either contribute to the transsulfuration pathway for glutathione synthesis or be converted back to methionine by methionine synthase (MS) or betaine homocysteine methyltransferase (BHMT), thus completing the methionine cycle. Salvage pathway and polyamine biosynthesis: Methionine contributes to polyamine biosynthesis by serving as a source of SAM. SAM is decarboxylated by SAM decarboxylase 1 (AMD1) to decarboxylated SAM (dcSAM), which acts as an aminopropyl group donor. Arginine is converted by arginase (ARG) to ornithine and is decarboxylated by ornithine decarboxylase (ODC) to produce putrescine. Putrescine is converted to spermidine and spermine through spermidine synthase (SRM) and spermine synthase (SMS), which both use dcSAM as an aminopropyl donor. On the other hand, dcSAM is converted to MTA after the donation of an aminopropyl group for polyamine synthesis, and MTA is converted by multiple enzymatic steps to methionine. Transsulfuration pathway: Homocysteine produced through the methionine cycle is metabolized in the transsulfuration pathway to generate cysteine. CBS synthesizes cystathionine by the condensation of homocysteine and serine. Thereafter, cystathionine is hydrolyzed by cystathionine-γ-lyase (CGL) to generate cysteine, and cysteine is further utilized in glutathione (GSH) and taurine synthesis. In addition, homocysteine is catalyzed by CGL, producing homoserine and H₂S, and both CGL and CBS catalyze the H₂S production from cysteine and the production of pyruvate and serine, respectively.

Figure 2

Mechanism of the activation of mTORC1 and the regulation of autophagy by methionine metabolism. (A) Regulation of mTORC1 and autophagy by methionine: Intracellular SAM concentration is sensed by SAMTOR, leading to mTORC1 activation and autophagy suppression through the inactivation of GASTOR1, a negative regulator of mTORC1. On the other hand, intracellular SAM promotes the methylation of protein phosphatase 2A (PP2A) via Ppm1 (in yeast) or leucine carboxy methyltransferase 1 (LCMT1) (in mammals), resulting in its activation. Methylated PP2A activates mTORC1 and suppresses autophagy, through the inactivation of SECIT in yeast and GASTOR in mammals via the dephosphorylation of Npr2 in yeast and possibly NPRL2 in mammals. (B) TAS1R1–TAS1R3 can serve as a sensor for extracellular methionine, leading to mTORC1 activation through phospholipase C (PLC) activation, an increase in intracellular calcium, and mitogen-activated protein kinase (MAPK) activation. (C) Spermidine induced by methionine restriction can promote autophagy by decreasing the acetylation of autophagy-related genes (ATGs) by suppressing Ep300. In addition, spermidine can promote autophagy through the upregulation of starvation response gene expression induced by the suppression of Akt and the transcriptional activation of FOXO. ↑: upregulation, ↓: downregulation.

Figure 3

Effect of methionine restriction on longevity and age-related pathologies. Methionine restriction may be one of the dietary interventions involved in longevity and the amelioration of age-related pathologies, including metabolic disease and cancer growth, partially through the enhancement of antioxidative defenses and attenuation of oxidative stress. Several diet patterns, such as the vegan diet, the DASH diet, ketogenic diet (fat based) and Japanese diet (carbohydrate based), may be candidates for a dietary pattern that restricts methionine intake. ↑: upregulation, ↓: downregulation.