{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:44:30Z","timestamp":1790793870821,"version":"4.1.0"},"reference-count":77,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T00:00:00Z","timestamp":1702598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation (NRF)","doi-asserted-by":"publisher","award":["NRF-2019R1A2C2002384"],"award-info":[{"award-number":["NRF-2019R1A2C2002384"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation (NRF)","doi-asserted-by":"publisher","award":["NRF-2019M3A9H1103737"],"award-info":[{"award-number":["NRF-2019M3A9H1103737"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Korean government (MSIT)","doi-asserted-by":"publisher","award":["NRF-2019R1A2C2002384"],"award-info":[{"award-number":["NRF-2019R1A2C2002384"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Korean government (MSIT)","doi-asserted-by":"publisher","award":["NRF-2019M3A9H1103737"],"award-info":[{"award-number":["NRF-2019M3A9H1103737"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cholesterol is a risk factor for age-related hearing loss (ARHL). However, the effect of cholesterol on the organ of Corti during the onset of ARHL is unclear. We established a mouse model for the ARHL group (24 months, n = 12) and a young group (6 months, n = 12). Auditory thresholds were measured in both groups using auditory brainstem response (ABR) at frequencies of 8, 16, and 32 kHz. Subsequently, mice were sacrificed and subjected to histological analyses, including transmission electron microscopy (TEM), H&amp;E, Sudan Black B (SBB), and Filipin staining, as well as biochemical assays such as IHC, enzymatic analysis, and immunoblotting. Additionally, mRNA extracted from both young and aged cochlea underwent RNA sequencing. To identify the mechanism, in vitro studies utilizing HEI-OC1 cells were also performed. RNA sequencing showed a positive correlation with increased expression of genes related to metabolic diseases, cholesterol homeostasis, and target of rapamycin complex 1 (mTORC1) signaling in the ARHL group as compared to the younger group. In addition, ARHL tissues exhibited increased cholesterol and lipofuscin aggregates in the organ of Corti, lateral walls, and spiral ganglion neurons. Autophagic flux was inhibited by the accumulation of damaged lysosomes and autolysosomes. Subsequently, we observed a decrease in the level of transcription factor EB (TFEB) protein, which regulates lysosomal biosynthesis and autophagy, together with increased mTORC1 activity in ARHL tissues. These changes in TFEB and mTORC1 expression were observed in a cholesterol-dependent manner. Treatment of ARHL mice with atorvastatin, a cholesterol synthesis inhibitor, delayed hearing loss by reducing the cholesterol level and maintaining lysosomal function and autophagy by inhibiting mTORC1 and activating TFEB. The above findings were confirmed using stress-induced premature senescent House Ear Institute organ of Corti 1 (HEI-OC1) cells. The findings implicate cholesterol in the pathogenesis of ARHL. We propose that atorvastatin could prevent ARHL by maintaining lysosomal function and autophagy by inhibiting mTORC1 and activating TFEB during the aging process.<\/jats:p>","DOI":"10.3390\/ijms242417513","type":"journal-article","created":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T08:12:57Z","timestamp":1702627977000},"page":"17513","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Abnormal Cholesterol Metabolism and Lysosomal Dysfunction Induce Age-Related Hearing Loss by Inhibiting mTORC1-TFEB-Dependent Autophagy"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6127-7415","authenticated-orcid":false,"given":"Yun Yeong","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungho","family":"Ha","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Republic of Korea"},{"name":"Department of Medical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Sun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9370-6552","authenticated-orcid":false,"given":"Sivasubramanian","family":"Ramani","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8745-8717","authenticated-orcid":false,"given":"Siung","family":"Sung","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Republic of Korea"},{"name":"Department of Medical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Sol","family":"Gil","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Republic of Korea"},{"name":"Department of Medical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oak-Sung","family":"Choo","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Hun","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Hoon","family":"Choung","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Republic of Korea"},{"name":"Department of Medical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,15]]},"reference":[{"key":"ref_1","first-page":"746","article-title":"Dysregulation of cholesterol balance in the brain: Contribution to neurodegenerative diseases","volume":"5","author":"Vance","year":"2012","journal-title":"Dis. 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