Dietary and Endocrine Regulation of Endogenous Hydrogen Sulfide Production: Implications for Longevity.

SIGNIFICANCE: Hydrogen sulfide (H2S) 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 H2S and modulation of endogenous H2S metabolism. Recent Advances: Recently, it was reported that hepatic H2S 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 H2S 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 H2S production largely via repression of H2S 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 H2S 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 H2S levels. FUTURE DIRECTIONS: The relative contribution of increased H2S 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 H2S levels using exogenous H2S donors or by modifying the endogenous H2S 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.