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dc.contributor.authorVintila, A.R.
dc.contributor.authorSlade, L.
dc.contributor.authorCooke, M.
dc.contributor.authorWillis, Craig R.G.
dc.contributor.authorTorregrossa, R.
dc.contributor.authorRahman, M.
dc.contributor.authorAnupom, T.
dc.contributor.authorVanapalli, S.A.
dc.contributor.authorGaffney, Christopher F.
dc.contributor.authorGharahdaghi, N.
dc.contributor.authorSzabo, C.
dc.contributor.authorSzewczyk, N.J.
dc.contributor.authorWhiteman, M.
dc.contributor.authorEtheridge, T.
dc.date.accessioned2023-08-16T09:28:41Z
dc.date.accessioned2023-08-25T09:41:09Z
dc.date.available2023-08-16T09:28:41Z
dc.date.available2023-08-25T09:41:09Z
dc.date.issued2023-08
dc.identifier.citationVintila AR, Slade L, Cooke M et al (2023) Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegans. Proceedings of the National Academy of Sciences. 120(32): e2216141120.en_US
dc.identifier.urihttp://hdl.handle.net/10454/19564
dc.descriptionYesen_US
dc.description.abstractLiving 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.en_US
dc.description.sponsorshipA.R.V., M.W., and T.E. were supported by the US Army Research Office (W911NF-19-1-0235). L.S., M.W., and T.E. were supported by the United Mitochondrial Disease Foundation (PI-19-0985). L.S. was also supported by the University of Exeter Jubilee Scholarship. M.C., N.J.S., and T.E. were supported by the UK Space Agency (ST/R005737/1). N.J.S. and T.E. were supported by BBSRC (BB/N015894/1). S.A.V. was supported by NASA (NNX15AL16G). N.J.S. was supported by grants from NASA [NSSC22K0250; NSSC22K0278] and acknowledges the support of the Osteopathic Heritage Foundation through funding for the Osteopathic Heritage Foundation Ralph S. Licklider, D.O., Research Endowment in the Heritage College of Osteopathic Medicine.en_US
dc.language.isoenen_US
dc.rights© 2023 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).en_US
dc.subjectHealth Spanen_US
dc.subjectLongevityen_US
dc.subjectMitochondriaen_US
dc.subjectTranscriptomicsen_US
dc.subjectH2Sen_US
dc.titleMitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegansen_US
dc.status.refereedYesen_US
dc.date.Accepted2023-05-30
dc.date.application2023-07-31
dc.typeArticleen_US
dc.type.versionPublished versionen_US
dc.identifier.doihttps://doi.org/10.1073/pnas.2216141120
dc.rights.licenseCC-BYen_US
dc.date.updated2023-08-16T09:28:50Z
refterms.dateFOA2023-08-25T09:41:51Z
dc.openaccess.statusopenAccessen_US


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