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Many adults also struggle with understanding speech in noise despite having normal auditory thresholds, a condition termed \u201chidden\u201d hearing loss because it evades standard audiological assessments. Examination of animal models and postmortem human tissue suggests that hidden hearing loss is also associated with age\u2010related changes in the cochlea and may, therefore, precede overt age\u2010related hearing loss. Nevertheless, the pathological mechanisms underlying hidden hearing loss are not understood, which hinders the development of diagnostic biomarkers and effective treatments for age\u2010related hearing loss. To fill these gaps in knowledge, we leveraged a combination of tools, including transcriptomic profiling and morphological and functional assessments, to identify these processes and examine the transition from hidden to overt hearing loss. As a novel approach, we took advantage of a recently characterized model of hidden hearing loss: <jats:italic>Kcnt1\/2<\/jats:italic> double knockout mice. Using this model, we find that even before observable morphological pathology, hidden hearing loss is associated with significant alteration in several processes, notably proteostasis, in the cochlear sensorineural structures, and increased susceptibility to overt hearing loss in response to noise exposure and aging. Our findings provide the first insight into the pathophysiology associated with the earliest and, therefore, most treatable stages of hearing loss and provide critical insight directing future investigation of pharmaceutical strategies to slow and possibly prevent overt age\u2010related hearing loss.<\/jats:p>","DOI":"10.1111\/acel.14243","type":"journal-article","created":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T04:40:43Z","timestamp":1721882443000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pathophysiological processes underlying hidden hearing loss revealed in <i>Kcnt1\/2<\/i> double knockout mice"],"prefix":"10.1111","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3611-2939","authenticated-orcid":false,"given":"Nick M. A.","family":"Schubert","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology\/Head and Neck Surgery, University Medical Center Groningen University of Groningen  Groningen The Netherlands"},{"name":"Graduate School of Medical Sciences Research School of Behavioural and Cognitive Neurosciences University of Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dani\u00ebl O. 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