老年听力障碍药物靶点的研究进展

doi:10.3969/j.issn.1003-9198.2026.02.002

摘要/Abstract

摘要： 老年听力障碍也称年龄相关性听力损失(age-related hearing loss, ARHL),是全球范围内最普遍的慢性退行性疾病之一,严重影响老年人的生活质量及心理健康,然而目前临床上尚无有效的预防及治疗药物。本文从ARHL发生发展的三大核心机制(氧化应激、线粒体功能障碍及慢性炎症)角度,系统介绍相关药物靶点的最新研究进展。虽然基于这些靶点研发的药物已在基础实验中展现出耳蜗保护及延缓听力损失的潜在疗效,但仍存在实验模型多脱离人类自然衰老进程、药物耳蜗靶向递送效率低、候选药物长期安全性与老年生理环境下的疗效尚未充分验证的局限性。

Abstract: Age-related hearing loss (ARHL), also known as presbycusis, is one of the most prevalent chronic degenerative diseases worldwide, seriously affecting the quality of life and mental health of the elderly. However, there are currently no effective preventive or therapeutic drugs in clinical practice. This review systematically summarizes the latest research progress on potential drug targets from the perspective of three core mechanisms underlying the occurrence and development of ARHL: oxidative stress, mitochondrial dysfunction, and chronic inflammation. Finally, it proposes that although drugs developed based on these targets have demonstrated potential efficacy in protecting the cochlea and delaying hearing loss in preclinical studies, there are still limitations such as most experimental models being divorced from the natural human aging process, low efficiency in targeted drug delivery to the cochlea, and insufficient validation of the long-term safety of candidate drugs and their efficacy in the elderly physiological environment.

Key words: age-related hearing loss, hearing impairment, drug target, aged, oxidative stress, hair cells, inflammation

中图分类号:

R 764

金晶晶, 谷秋丽, 雷佳炜, 王佳贺. 老年听力障碍药物靶点的研究进展[J]. 实用老年医学, 2026, 40(2): 111-115.

JIN Jingjing, GU Qiuli, LEI Jaiwei, WANG Jiahe. Research progress on drug targets for age-related hearing loss[J]. Practical Geriatrics, 2026, 40(2): 111-115.

参考文献

[1] 贺祖宏, 李明, 邹圣宇, 等. 老年性聋的发病机制及干预研究进展[J]. 中华耳鼻咽喉头颈外科杂志, 2020, 55(11): 1105-1110.
[2] TSAI DO B S, BUSH M L, WEINREICH H M, et al. Clinical practice guideline: age-related hearing loss[J]. Otolaryngol Head Neck Surg, 2024, 170(Suppl 2):S1-S54.
[3] AMIEVA H, OUVRARD C. Does treating hearing loss in older adults improve cognitive outcomes？ A review[J]. J Clin Med, 2020, 9(3): 805.
[4] THOMAS J P, VÖLTER, C. Update on surgical and nonsurgical treatment options for age-related hearing loss[J]. Z Gerontol Geriatr, 2023, 56(4): 276-282.
[5] KISHIMOTO-URATA M, URATA S, FUJIMOTO C, et al. Role of oxidative stress and antioxidants in acquired inner ear disorders[J]. Antioxidants: Basel, 2022, 11(8):1469.
[6] XING Y, PENG K, YI Q, et al. TMEM30A is essential for hair cell polarity maintenance in postnatal mouse cochlea[J]Cell Mol Biol Lett, 2023, 28(1): 23.
[7] TAN W J T, SONG L. Role of mitochondrial dysfunction and oxidative stress in sensorineural hearing loss[J]Hear Res, 2023, 434: 108783.
[8] TAWFIK K O, KLEPPER K, SALIBA J, et al. Advances in understanding of presbycusis[J]. J Neurosci Res, 2020, 98(9): 1685-1697.
[9] LI D, ZHAO H, CUI Z K, et al. The role of Nrf2 in hearing loss[J]. Front Pharmacol, 2021, 12: 620921.
[10] 姚娟, 吴平安, 李芸, 等. Keap1-Nrf2-ARE信号通路及其激活剂的研究进展[J]. 中国药理学通报, 2019, 35(10): 1342-1346.
[11] ZHANG M, AN C, GAO Y, et al. Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection[J]. Prog Neurobiol, 2013, 100: 30-47.
[12] UL-HAQ I, KHAN S, AWAN K A, et al. Sulforaphane as a potential remedy against cancer: comprehensive mechanistic review[J]. J Food Biochem, 2022, 46(3): e13886.
[13] MAZARAKIS N, SNIBSON K, LICCIARDI P V, et al. The potential use of l-sulforaphane for the treatment of chronic inflammatory diseases: a review of the clinical evidence[J]. Clin Nutr, 2020, 39(3): 664-675.
[14] SCHIAVONI V, DI CRESCENZO T, MEMBRINO V, et al. Bardoxolone methyl: a comprehensive review of its role as a Nrf2 activator in anticancer therapeutic applications[J]. Pharmaceuticals: Basel, 2025, 18(7): 966.
[15] CHEN Y, LUO X, DENG Y, et al. Isoliquiritigenin attenuates cisplatin-induced hearing loss and ototoxicity by activating the Keap1-Nrf2-ARE pathway[J]. Free Radic Biol Med, 2025, 241: 599-616.
[16] YANG W, ZHAO X, CHAI R,et al. Progress on mechanisms of age-related hearing loss[J]. Front Neurosci, 2023, 17:1253574.
[17] LU Y, LI Z, ZHANG S, et al. Cellular mitophagy: mechanism, roles in diseases and small molecule pharmacological regulation[J]. Theranostics, 2023, 13(2): 736-766.
[18] KAPAHI P, ZID B M, HARPER T, et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway[J]. Curr Biol, 2004, 14(10): 885-890.
[19] KAMADA Y, FUNAKOSHI T, SHINTANI T, et al. Tor-mediated induction of autophagy via an Apg1 protein kinase complex[J]. J Cell Biol, 2000, 150(6): 1507-1513.
[20] EGE T, TAO L, NORTH B J. The role of molecular and cellular aging pathways on age-related hearing loss[J]. Int J Mol Sci, 2024, 25(17): 9705.
[21] PANWAR V, SINGH A, BHATT M, et al. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease[J]. Signal Transduct Target Ther, 2023, 8(1): 375.
[22] FU X, LI P, ZHANG L, et al. Activation of Rictor/mTORC2 signaling acts as a pivotal strategy to protect against sensorineural hearing loss[J]. Proc Natl Acad Sci USA, 2022, 119(10): e2107357119.
[23] LIU H, LI F, LI X, et al. Rapamycin ameliorates age-related hearing loss in C57BL/6J mice by enhancing autophagy in the SGNs[J]. Neurosci Lett, 2022, 772: 136493.
[24] VERSCHUUR C, AGYEMANG-PREMPEH A, NEWMAN T A. Inflammation is associated with a worsening of presbycusis: evidence from the MRC national study of hearing[J]. Int J Audiol, 2014, 53(7): 469-475.
[25] VERSCHUUR C A, DOWELL A, SYDDALL H E, et al. Markers of inflammatory status are associated with hearing threshold in older people: findings from the Hertfordshire Ageing Study[J]. Age Ageing, 2012, 41(1): 92-97.
[26] WANG Y, ZHAO H, ZHAO K, et al. Chronic inflammation and age-related hearing: based on mendelian randomization[J]. J Inflamm Res, 2024, 17: 8921-8934.
[27] WU T, ZHOU J, QIU J, et al. Tumor necrosis factor-α mediated inflammation versus apoptosis in age-related hearing loss[J]. Front Aging Neurosci, 2022, 14: 956503.
[28] WATSON N, DING B, ZHU X, et al. Chronic inflammation-inflammaging–in the ageing cochlea: a novel target for future presbycusis therapy[J]. Ageing Res Rev, 2017, 40: 142-148.
[29] LIU J, CHEN H, LIN X, et al. Melatonin suppresses cyclic GMP-AMP synthase-stimulator of interferon genes signaling and delays the development of hearing loss in the C57BL/6J presbycusis mouse model[J]. Neuroscience, 2023, 517: 84-95.
[30] ZHANG X, CAO R, LI C, et al. Caffeine ameliorates age-related hearing loss by downregulating the inflammatory pathway in mice[J]. Otol Neurotol, 2024, 45(3):227-237.
[31] ZHAO W, MA L, CAI C, et al. Caffeine inhibits NLRP3 inflammasome activation by suppressing MAPK/NF-κB and A2aR signaling in LPS-induced THP-1 macrophages[J]. Int J Biol Sci, 2019, 15(8): 1571-1581.