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This progressive pathology often has psychological and medical comorbidities, including social isolation, depression, and cognitive decline. Despite ARHL's enormous societal and economic impact, no therapies to prevent or slow its progression exist. Loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs), a.k.a. IHC synaptopathy, is an early event in cochlear aging, preceding neuronal and hair cell loss. To determine if age\u2010related IHC synaptopathy can be prevented, and if this impacts the time\u2010course of ARHL, we tested the effects of cochlear overexpression of neurotrophin\u20103 (Ntf3) starting at middle age. We chose <jats:italic>Ntf3<\/jats:italic> because this neurotrophin regulates the formation of IHC\u2010SGN synapses in the neonatal period. We now show that triggering Ntf3 overexpression by IHC supporting cells starting in middle age rapidly increases the amplitude of sound\u2010evoked neural potentials compared with age\u2010matched controls, indicating that Ntf3 produces a positive effect on cochlear function when the pathology is minimal. Furthermore, near the end of their lifespan, Ntf3\u2010overexpressing mice have milder ARHL, with larger sound\u2010evoked potentials along the ascending auditory pathway and reduced IHC synaptopathy compared with age\u2010matched controls. Our results also provide evidence that an age\u2010related decrease in cochlear Ntf3 expression contributes to ARHL and that Ntf3 supplementation could serve as a therapeutic for this prevalent disorder. Furthermore, these findings suggest that factors that regulate synaptogenesis during development could prevent age\u2010related synaptopathy in the brain, a process involved in several central nervous system degenerative disorders.<\/jats:p>","DOI":"10.1111\/acel.13708","type":"journal-article","created":{"date-parts":[[2022,9,11]],"date-time":"2022-09-11T14:24:55Z","timestamp":1662906295000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Cochlear Neurotrophin\u20103 overexpression at mid\u2010life prevents age\u2010related inner hair cell synaptopathy and slows age\u2010related hearing loss"],"prefix":"10.1111","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2965-6826","authenticated-orcid":false,"given":"Luis R.","family":"Cassinotti","sequence":"first","affiliation":[{"name":"Kresge Hearing Research Institute and Department of Otolaryngology\u2010Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingchao","family":"Ji","sequence":"additional","affiliation":[{"name":"Kresge Hearing Research Institute and Department of Otolaryngology\u2010Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7525-3924","authenticated-orcid":false,"given":"Beatriz C.","family":"Borges","sequence":"additional","affiliation":[{"name":"Kresge Hearing Research Institute and Department of Otolaryngology\u2010Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2654-2812","authenticated-orcid":false,"given":"Nathan D.","family":"Cass","sequence":"additional","affiliation":[{"name":"Kresge Hearing Research Institute and Department of Otolaryngology\u2010Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditi S.","family":"Desai","sequence":"additional","affiliation":[{"name":"Kresge Hearing Research Institute and Department of Otolaryngology\u2010Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6888-6889","authenticated-orcid":false,"given":"David C.","family":"Kohrman","sequence":"additional","affiliation":[{"name":"Kresge Hearing Research Institute and Department of Otolaryngology\u2010Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1973-1730","authenticated-orcid":false,"given":"M. Charles","family":"Liberman","sequence":"additional","affiliation":[{"name":"Eaton\u2010Peabody Laboratories, Massachusetts Eye &amp; Ear, and Department of Otolaryngology, Head and Neck Surgery Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5412-9473","authenticated-orcid":false,"given":"Gabriel","family":"Corfas","sequence":"additional","affiliation":[{"name":"Kresge Hearing Research Institute and Department of Otolaryngology\u2010Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,9,11]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.168.14.1522"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010publhealth\u2010032013\u2010182510"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896\u20106273(95)90263\u20105"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/369658a0"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-012369454-6\/50074-1"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2021.12.037"},{"key":"e_1_2_10_8_1","unstructured":"Hagan C. 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