Is there a role of HS in mediating health span benefits of caloric restriction?

Caloric restriction (CR) is a dietary regimen that aims to reduce the intake of total calories while maintaining adequate supply of key nutrients so as to avoid malnutrition. CR is one of only a small number of interventions that show promising outcomes on health span and lifespan across different species. There is growing interest in the development of compounds that might replicate CR-related benefits without actually restricting food intake. Hydrogen sulfide (HS) is produced inside the bodies of many animals, including humans, by evolutionarily conserved HS synthesizing enzymes. Endogenous HS is increasingly recognized as an important gaseous signalling molecule involved in diverse cellular and molecular processes. However, the specific role of HS in diverse biological processes remains to be elucidated and not all its biological effects are beneficial. Nonetheless, recent evidence suggests that the biological functions of HS intersect with the network of evolutionarily conserved nutrient sensing and stress response pathways that govern organismal responses to CR. Induction of HS synthesizing enzymes appears to be a conserved and essential feature of the CR response in evolutionarily distant organisms, including nematodes and mice. Here we review the evidence for a role of HS in CR and lifespan modulation. HS releasing drugs, capable of controlled delivery of exogenous HS, are currently in clinical development. These findings suggest such HS releasing drugs as a promising novel avenue for the development of CR mimetic compounds.