SIGNIFICANCE: Hydrogen sulfide (HS) at the right concentration is associated with numerous health benefits in experimental organisms, ranging from protection from ischemia/reperfusion injury to life span extension. Given the considerable translation potential, two major strategies have emerged: supplementation of exogenous HS and modulation of endogenous HS metabolism. Recent Advances: Recently, it was reported that hepatic HS production capacity is increased in two of the best-characterized mammalian models of life span extension, dietary restriction, and hypopituitary dwarfism, leading to new insights into dietary and hormonal regulation of endogenous HS production together with broader changes in sulfur amino acid (SAA) metabolism with implications for DNA methylation and redox status.

CRITICAL ISSUES: Here, we discuss the role of dietary SAAs and growth hormone (GH)/thyroid hormone (TH) signaling in regulation of endogenous HS production largely via repression of HS generating enzymes cystathionine γ-lyase (CGL) and cystathionine β-synthase (CBS) on the level of gene transcription, as well as reciprocal regulation of GH and TH signaling by HS itself. We also discuss plasticity of CGL and CBS gene expression in response to environmental stimuli and the potential of the microbiome to impact overall HS levels.

FUTURE DIRECTIONS: The relative contribution of increased HS to health span or lifespan benefits in models of extended longevity remains to be determined, as does the mechanism by which such benefits occur. Nonetheless, our ability to control HS levels using exogenous HS donors or by modifying the endogenous HS production/consumption equilibrium has the potential to improve health and increase "shelf-life" across evolutionary boundaries, including our own. Antioxid. Redox Signal. 28, 1483-1502.