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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,8,8]]},"abstract":"<jats:p>\n                    Living longer without simultaneously extending years spent in good health (\u201chealth span\u201d) is an increasing societal burden, demanding new therapeutic strategies. Hydrogen sulfide (H\n                    <jats:sub>2<\/jats:sub>\n                    S) can correct disease-related mitochondrial metabolic deficiencies, and supraphysiological H\n                    <jats:sub>2<\/jats:sub>\n                    S concentrations can pro health span. However, the efficacy and mechanisms of mitochondrion-targeted sulfide delivery molecules (mtH\n                    <jats:sub>2<\/jats:sub>\n                    S) administered across the adult life course are unknown. Using a\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    aging model, we compared untargeted H\n                    <jats:sub>2<\/jats:sub>\n                    S (NaGYY4137, 100 \u00b5M and 100 nM) and mtH\n                    <jats:sub>2<\/jats:sub>\n                    S (AP39, 100 nM) donor effects on life span, neuromuscular health span, and mitochondrial integrity. H\n                    <jats:sub>2<\/jats:sub>\n                    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\n                    <jats:sub>2<\/jats:sub>\n                    S donor-mediated health span. Developmentally administered mtH\n                    <jats:sub>2<\/jats:sub>\n                    S (100 nM) improved life\/health span vs. equivalent untargeted H\n                    <jats:sub>2<\/jats:sub>\n                    S doses. mtH\n                    <jats:sub>2<\/jats:sub>\n                    S preserved aging mitochondrial structure, content (citrate synthase activity) and neuromuscular strength. Knockdown of H\n                    <jats:sub>2<\/jats:sub>\n                    S metabolism enzymes and FoxO\/\n                    <jats:italic>daf-16<\/jats:italic>\n                    prevented the positive health span effects of mtH\n                    <jats:sub>2<\/jats:sub>\n                    S, whereas DCAF11\/\n                    <jats:italic>wdr-23<\/jats:italic>\n                    \u2013 Nrf2\/\n                    <jats:italic>skn-1<\/jats:italic>\n                    oxidative stress protection pathways were dispensable. Health span, but not life span, increased with all adult-onset mtH\n                    <jats:sub>2<\/jats:sub>\n                    S treatments. Adult mtH\n                    <jats:sub>2<\/jats:sub>\n                    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\n                    <jats:italic>elt-6<\/jats:italic>\n                    \/\n                    <jats:italic>elt-3<\/jats:italic>\n                    transcription factor circuit. H\n                    <jats:sub>2<\/jats:sub>\n                    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\n                    <jats:sub>2<\/jats:sub>\n                    S doses required for health span extension, combined with efficacy in adult animals, suggest mtH\n                    <jats:sub>2<\/jats:sub>\n                    S is a potential healthy aging therapeutic.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2216141120","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T15:07:46Z","timestamp":1690816066000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":25,"title":["Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated\n                    <i>Caenorhabditis elegans<\/i>"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7956-7904","authenticated-orcid":false,"given":"Adriana Raluca","family":"Vintila","sequence":"first","affiliation":[{"name":"Public Health and Sport Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter EX1 2LU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7660-7392","authenticated-orcid":false,"given":"Luke","family":"Slade","sequence":"additional","affiliation":[{"name":"Public Health and Sport Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter EX1 2LU, United Kingdom"},{"name":"University of Exeter Medical School, Faculty of Health and Life Sciences, University of Exeter, Exeter EX1 2LU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2081-3466","authenticated-orcid":false,"given":"Michael","family":"Cooke","sequence":"additional","affiliation":[{"name":"Public Health and Sport Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter EX1 2LU, United Kingdom"},{"name":"Medical Research Council Versus Arthritis Centre for Musculoskeletal Ageing Research, Nottingham Biomedical Research Center, School of Medicine, Royal Derby Hospital, University of Nottingham, Derby DE22 3DT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig R. G.","family":"Willis","sequence":"additional","affiliation":[{"name":"School of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1809-7029","authenticated-orcid":false,"given":"Roberta","family":"Torregrossa","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School, Faculty of Health and Life Sciences, University of Exeter, Exeter EX1 2LU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mizanur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Texas Tech University, Lubbock, TX 79409"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taslim","family":"Anupom","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering, Texas Tech University, Lubbock, TX 74909"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6036-1949","authenticated-orcid":false,"given":"Siva A.","family":"Vanapalli","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Texas Tech University, Lubbock, TX 79409"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7990-2792","authenticated-orcid":false,"given":"Christopher J.","family":"Gaffney","sequence":"additional","affiliation":[{"name":"Lancaster University Medical School, Lancaster University, Lancaster LA1 4YW, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nima","family":"Gharahdaghi","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School, Faculty of Health and Life Sciences, University of Exeter, Exeter EX1 2LU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3110-4235","authenticated-orcid":false,"given":"Csaba","family":"Szabo","sequence":"additional","affiliation":[{"name":"Chair of Pharmacology, Section of Medicine, University of Fribourg, Fribourg CH-1700, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4425-9746","authenticated-orcid":false,"given":"Nathaniel J.","family":"Szewczyk","sequence":"additional","affiliation":[{"name":"Medical Research Council Versus Arthritis Centre for Musculoskeletal Ageing Research, Nottingham Biomedical Research Center, School of Medicine, Royal Derby Hospital, University of Nottingham, Derby DE22 3DT, United Kingdom"},{"name":"Ohio Musculoskeletal and Neurologic Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6583-6779","authenticated-orcid":false,"given":"Matthew","family":"Whiteman","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School, Faculty of Health and Life Sciences, University of Exeter, Exeter EX1 2LU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3588-8711","authenticated-orcid":false,"given":"Timothy","family":"Etheridge","sequence":"additional","affiliation":[{"name":"Public Health and Sport Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter EX1 2LU, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,7,31]]},"reference":[{"key":"e_1_3_4_1_2","unstructured":"E. 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