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dc.contributor.authorVintila, AR
dc.contributor.authorSlade, L
dc.contributor.authorCooke, M
dc.contributor.authorWillis, CRG
dc.contributor.authorTorregrossa, R
dc.contributor.authorRahman, M
dc.contributor.authorAnupom, T
dc.contributor.authorVanapalli, SA
dc.contributor.authorGaffney, CJ
dc.contributor.authorGharahdaghi, N
dc.contributor.authorSzabo, C
dc.contributor.authorSzewczyk, NJ
dc.contributor.authorWhiteman, M
dc.contributor.authorEtheridge, T
dc.date.accessioned2023-08-03T12:25:11Z
dc.date.issued2023-07-31
dc.date.updated2023-08-03T10:33:58Z
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_GB
dc.description.sponsorshipUS Army Research Officeen_GB
dc.description.sponsorshipUnited Mitochondrial Disease Foundationen_GB
dc.description.sponsorshipUniversity of Exeteren_GB
dc.description.sponsorshipUK Space Agencyen_GB
dc.description.sponsorshipBiotechnology and Biological Sciences Research Council (BBSRC)en_GB
dc.description.sponsorshipNASAen_GB
dc.description.sponsorshipOsteopathic Heritage Foundationen_GB
dc.format.extente2216141120-
dc.identifier.citationVol. 120 (32), article e2216141120en_GB
dc.identifier.doihttps://doi.org/10.1073/pnas.2216141120
dc.identifier.grantnumberW911NF-19-1-0235en_GB
dc.identifier.grantnumberPI-19-0985en_GB
dc.identifier.grantnumberST/R005737/1en_GB
dc.identifier.grantnumberBB/N015894/1en_GB
dc.identifier.grantnumberNNX15AL16Gen_GB
dc.identifier.grantnumberNSSC22K0250en_GB
dc.identifier.grantnumberNSSC22K0278en_GB
dc.identifier.urihttp://hdl.handle.net/10871/133695
dc.identifierORCID: 0000-0003-2081-3466 (Cooke, Michael)
dc.identifierScopusID: 57210453209 (Cooke, Michael)
dc.identifierORCID: 0000-0002-6583-6779 (Whiteman, Matthew)
dc.identifierORCID: 0000-0002-3588-8711 (Etheridge, Timothy)
dc.language.isoenen_GB
dc.publisherNational Academy of Sciencesen_GB
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pubmed/37523525en_GB
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/bioproject/en_GB
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_GB
dc.subjectH2Sen_GB
dc.subjecthealth spanen_GB
dc.subjectlongevityen_GB
dc.subjectmitochondriaen_GB
dc.subjecttranscriptomicsen_GB
dc.titleMitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegansen_GB
dc.typeArticleen_GB
dc.date.available2023-08-03T12:25:11Z
dc.identifier.issn0027-8424
exeter.place-of-publicationUnited States
dc.descriptionThis is the final version. Available on open access from the National Academy of Sciences via the DOI in this recorden_GB
dc.descriptionData, Materials, and Software Availability: All study data are included in the article and/or supporting information. The raw RNA sequencing data can be found within the NCBI BioProject database (https://www.ncbi.nlm.nih.gov/bioproject/) under the Sequence Read Archive (SRA) accession PRJNA996496 (93).en_GB
dc.identifier.eissn1091-6490
dc.identifier.journalProceedings of the National Academy of Sciences (PNAS)en_GB
dc.relation.ispartofProc Natl Acad Sci U S A, 120(32)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_GB
dcterms.dateAccepted2023-05-30
rioxxterms.versionVoRen_GB
rioxxterms.licenseref.startdate2023-07-31
rioxxterms.typeJournal Article/Reviewen_GB
refterms.dateFCD2023-08-03T12:19:14Z
refterms.versionFCDVoR
refterms.dateFOA2023-08-03T12:25:19Z
refterms.panelAen_GB
refterms.dateFirstOnline2023-07-31


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© 2023 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Except where otherwise noted, this item's licence is described as © 2023 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).