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Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegans.
- Source :
- Proceedings of the National Academy of Sciences of the United States of America; 8/8/2023, Vol. 120 Issue 32, p1-12, 35p
- Publication Year :
- 2023
-
Abstract
- Living longer without simultaneously extending years spent in good health ("health span") is an increasing societal burden, demanding new therapeutic strategies. Hydrogen sulfide (H<subscript>2</subscript>S) can correct disease-related mitochondrial metabolic deficiencies, and supraphysiological H<subscript>2</subscript>S concentrations can pro health span. However, the efficacy and mechanisms of mitochondrion-targeted sulfide delivery molecules (mtH<subscript>2</subscript>S) administered across the adult life course are unknown. Using a Caenorhabditis elegans aging model, we compared untargeted H<subscript>2</subscript>S (NaGYY4137, 100 µM and 100 nM) and mtH<subscript>2</subscript>S (AP39, 100 nM) donor effects on life span, neuromuscular health span, and mitochondrial integrity. H<subscript>2</subscript>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<subscript>2</subscript>S donor-mediated health span. Developmentally administered mtH<subscript>2</subscript>S (100 nM) improved life/health span vs. equivalent untargeted H<subscript>2</subscript>S doses. mtH<subscript>2</subscript>S preserved aging mitochondrial structure, content (citrate synthase activity) and neuromuscular strength. Knockdown of H<subscript>2</subscript>S metabolism enzymes and FoxO/daf-16 prevented the positive health span effects of mtH<subscript>2</subscript>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<subscript>2</subscript>S treatments. Adult mtH<subscript>2</subscript>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<subscript>2</subscript>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<subscript>2</subscript>S doses required for health span extension, combined with efficacy in adult animals, suggest mtH<subscript>2</subscript>S is a potential healthy aging therapeutic. [ABSTRACT FROM AUTHOR]
- Subjects :
- LIFE spans
CAENORHABDITIS elegans
MITOCHONDRIA
CITRATE synthase
PARTURITION
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 120
- Issue :
- 32
- Database :
- Complementary Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 169990272
- Full Text :
- https://doi.org/10.1073/pnas.2216141120