Hydrogen sulfide in longevity and pathologies: Inconsistency is malodorous

Hydrogen sulfide (H₂S) is one of the biologically active gases (gasotransmitters), which plays an important role in various physiological processes and aging. Its production in the course of methionine and cysteine catabolism and its degradation are finely balanced, and impairment of H₂S homeostasis is associated with various pathologies. Despite the strong geroprotective action of exogenous H₂S in C. elegans, there are controversial effects of hydrogen sulfide and its donors on longevity in other models, as well as on stress resistance, age-related pathologies and aging processes, including regulation of senescence-associated secretory phenotype (SASP) and senescent cell anti-apoptotic pathways (SCAPs). Here we discuss that the translation potential of H₂S as a geroprotective compound is influenced by a multiplicity of its molecular targets, pleiotropic biological effects, and the overlapping ranges of toxic and beneficial doses. We also consider the challenges of the targeted delivery of H₂S at the required dose. Along with this, the complexity of determining the natural levels of H₂S in animal and human organs and their ambiguous correlations with longevity are reviewed.