Living longer without simultaneously extending years spent in good health ("health span") is an increasing societal burden, demanding new therapeutic strategies. Hydrogen sulfide (H₂S) can correct disease-related mitochondrial metabolic deficiencies, and supraphysiological H₂S concentrations can pro health span. However, the efficacy and mechanisms of mitochondrion-targeted sulfide delivery molecules (mtH₂S) administered across the adult life course are unknown. Using a Caenorhabditis elegans aging model, we compared untargeted H₂S (NaGYY4137, 100 µM and 100 nM) and mtH₂S (AP39, 100 nM) donor effects on life span, neuromuscular health span, and mitochondrial integrity. H₂S donors were administered from birth or in young/middle-aged animals (day 0, 2, or 4 postadulthood). RNAi pharmacogenetic interventions and transcriptomics/network analysis explored molecular events governing mtH₂S donor-mediated health span. Developmentally administered mtH₂S (100 nM) improved life/health span vs. equivalent untargeted H₂S doses. mtH₂S preserved aging mitochondrial structure, content (citrate synthase activity) and neuromuscular strength. Knockdown of H₂S metabolism enzymes and FoxO/daf-16 prevented the positive health span effects of mtH₂S, whereas DCAF11/wdr-23 - Nrf2/skn-1 oxidative stress protection pathways were dispensable. Health span, but not life span, increased with all adult-onset mtH₂S treatments. Adult mtH₂S treatment also rejuvenated aging transcriptomes by minimizing expression declines of mitochondria and cytoskeletal components, and peroxisome metabolism hub components, under mechanistic control by the elt-6/elt-3 transcription factor circuit. H₂S health span extension likely acts at the mitochondrial level, the mechanisms of which dissociate from life span across adult vs. developmental treatment timings. The small mtH₂S doses required for health span extension, combined with efficacy in adult animals, suggest mtH₂S is a potential healthy aging therapeutic.

	Year	Citations

About