Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegans

Living longer without simultaneously extending years spent in good health (“health span”) is an increasing societal burden, demanding new therapeutic strategies. Hydrogen sulfide (H(2)S) can correct disease-related mitochondrial metabolic deficiencies, and supraphysiological H(2)S concentrations can pro health span. However, the efficacy and mechanisms of mitochondrion-targeted sulfide delivery molecules (mtH(2)S) administered across the adult life course are unknown. Using a Caenorhabditis elegans aging model, we compared untargeted H(2)S (NaGYY4137, 100 µM and 100 nM) and mtH(2)S (AP39, 100 nM) donor effects on life span, neuromuscular health span, and mitochondrial integrity. H(2)S 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 mtH(2)S donor-mediated health span. Developmentally administered mtH(2)S (100 nM) improved life/health span vs. equivalent untargeted H(2)S doses. mtH(2)S preserved aging mitochondrial structure, content (citrate synthase activity) and neuromuscular strength. Knockdown of H(2)S metabolism enzymes and FoxO/daf-16 prevented the positive health span effects of mtH(2)S, whereas DCAF11/wdr-23 – Nrf2/skn-1 oxidative stress protection pathways were dispensable. Health span, but not life span, increased with all adult-onset mtH(2)S treatments. Adult mtH(2)S 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. H(2)S 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 mtH(2)S doses required for health span extension, combined with efficacy in adult animals, suggest mtH(2)S is a potential healthy aging therapeutic.