Chromatin and genomic instability in the cochlea contributing to age-related hearing loss: Insights from in vitro and in vivo models

  • Hear Res. 2026 Aug:478:109691. doi: 10.1016/j.heares.2026.109691.
Weiyi Huang  1 ,  Bing Kong  1 ,  Yiming Zhong  2 ,  Jinju Xu  2 ,  Jichang Wu  1 ,  Yimei Wang  1 ,  Hao Wang  1 ,  Haixia Hu  2 ,  Zhihong Yao  1 ,  Yilin Shen  3 ,  Bin Ye  4 ,  Mingliang Xiang  5
Affiliations
  • 1. Department of Otolaryngology & Head and Neck Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai 200025, China; Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 2. Department of Otolaryngology & Head and Neck Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Audiology & Speech-Language Pathology, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai 200025, China; Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 3. Department of Otolaryngology & Head and Neck Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Audiology & Speech-Language Pathology, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai 200025, China; Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: [email protected].
  • 4. Department of Otolaryngology & Head and Neck Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Audiology & Speech-Language Pathology, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai 200025, China; Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: [email protected].
  • 5. Department of Otolaryngology & Head and Neck Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Audiology & Speech-Language Pathology, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai 200025, China; Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: [email protected].
PMID: 42263393 DOI: 10.1016/j.heares.2026.109691
Abstract

Age-related hearing loss (ARHL) is one of the most common causes of hearing impairment in older adults. However, the cellular and molecular mechanisms underlying ARHL remain unclear. Chromatin and genomic instability, including DNA damage, heterochromatin loss, and telomere attrition, are hallmarks of aging. In the present study, we investigated DNA damage levels, chromatin accessibility, telomere length, and Telomerase changes in vitro and in vivo mouse models of ARHL. To further explore changes in outer hair cells (OHCs), one of the prominent auditory sensory cells in the cochlea, we constructed a transgenic mouse model with tdTomato-labeled OHCs and performed single-cell RNA Sequencing in vivo. We found increased DNA single-strand breaks, double-strand breaks, and oxidative damage in senescent HEI-OC1 cells and in the aged Corti's Organ, stria vascularis, and spiral ganglion neurons in the cochleae. Loss of constitutive heterochromatin and abnormal formation of facultative heterochromatin, known as senescence-associated heterochromatin foci, were also observed in both models. The cochleae also exhibited shortened telomere length and marked spatiotemporal differences in the distribution of telomerase Reverse Transcriptase during aging. We further confirmed that OHCs experienced chromatin and genomic instability during aging through single-cell RNA Sequencing. In particular, we verified changes in Alpha-thalassemia mental retardation X-linked (ATRX) expression in young and aged OHCs. In conclusion, chromatin and genomic instability participate in cochlear senescence, especially OHC senescence, and relevant genes may represent potential targets for ARHL intervention and treatment.

Keywords
Age-related hearing loss; DNA damage; Heterochromatin loss; Outer hair cell; Telomerase; Telomere attrition.
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