Calorie restriction and methionine restriction in control of endogenous hydrogen sulfide production by the transsulfuration pathway

Abstract

H2S is a gas easily identified by its distinctive odor. Although environmental exposure to H2S has been viewed alternately as therapeutic or toxic through the centuries, H2S has recently regained recognition for its numerous beneficial biological effects. Most experiments documenting such benefits, including improved glucose tolerance, increased stress resistance, and even lifespan extension, are based on exposure of experimental organisms to exogenous sources of H2S. However, appreciation is growing for the importance of H2S produced endogenously by the evolutionary conserved transsulfuration pathway (TSP) in health and longevity. Recent data implicate H2S produced by the TSP in pleiotropic benefits of dietary restriction (DR), or reduced nutrient/energy intake without malnutrition. DR, best known as the most reliable way to extend lifespan in a wide range of experimental organisms, includes various regimens aimed at either reducing overall calorie intake (calorie restriction, intermittent/every-other-day fasting) or reducing particular nutrients such as protein or the essential amino acid, methionine (methionine restriction), with overlapping functional benefits on stress resistance, metabolic fitness and lifespan. Here we will review the small but growing body of literature linking the TSP to the functional benefits of DR in part through the production of endogenous H2S, with an emphasis on regulation of the TSP and H2S production by diet and mechanisms of beneficial H2S action.

Keywords: Aging; Dietary restriction; Hydrogen sulfide; Metabolism; Methionine; Stress; Transsulfuration.

Fig. 1

Pathways of H₂S production. Model of the transmethylation and transsulfuration pathway (TSP) in metazoans (left) and in yeast (right). Solid arrows trace canonical sulfur transfer from Met to Cys (in metazoans), or from inorganic sulfate and/or Met to Cys (in yeast), through various metabolites and downstream cellular processes via the enzymes Cystathionine Beta-Synthase (CBS;STR4) and Cystathionine Gamma-Lyase (CGL;STR1). Dotted arrows trace alternative pathways/usage of transmethylation products or TSP enzymes for production of H₂S. MAT: methionine adenosyl transferase, SAM: S-adenosylmethionine, SAH: S-adenosylhomocysteine, SAHH: S-adenosylhomocysteine hydrolase, and MS: methionine synthase.

Fig. 2

Overlapping benefits of DR and H₂S. Shared benefits of reduced intake of SAA common to various DR regimens including CR, PR and SAA restriction, and H₂S from endogenous or exogenous sources.