Age-related hearing loss (AHL) is a progressive sensorineural hearing loss in elderly people. Although no prevention or treatments have been established for AHL, recent studies have demonstrated that oxidative stress is closely related to pathogenesis of AHL, suggesting that suppression of oxidative stress leads to inhibition of AHL progression. NRF2 is a master transcription factor that regulates various antioxidant proteins and cytoprotection factors. To examine whether NRF2 pathway activation prevents AHL, we used Keap1-knockdown (Keap1^FA/FA) mice, in which KEAP1, a negative regulator of NRF2, is decreased, resulting in the elevation of NRF2 activity. We compared 12-month-old Keap1^FA/FA mice with age-matched wild-type (WT) mice in the same breeding colony. In the Keap1^FA/FA mice, the expression levels of multiple NRF2 target genes were verified to be significantly higher than the expression levels of these genes in the WT mice. Histological analysis showed that cochlear degeneration at the apical and middle turns was ameliorated in the Keap1^FA/FA mice. Auditory brainstem response (ABR) thresholds in the Keap1^FA/FA mice were significantly lower than those in the WT mice, in particular at low–mid frequencies. Immunohistochemical detection of oxidative stress markers suggested that oxidative stress accumulation was attenuated in the Keap1^FA/FA cochlea. Thus, we concluded that NRF2 pathway activation protects the cochlea from oxidative damage during aging, in particular at the apical and middle turns. KEAP1-inhibiting drugs and phytochemicals are expected to be effective in the prevention of AHL.

与年龄有关的听力损失（AHL）是老年人的进行性感觉神经性听力损失。尽管尚未建立针对AHL的预防或治疗方法，但最近的研究表明氧化应激与AHL的发病机理密切相关，这表明氧化应激的抑制导致AHL进程的抑制。NRF2是一个主转录因子，可调节各种抗氧化剂蛋白和细胞保护因子。为了检查NRF2途径的激活是否能阻止AHL，我们使用了Keap1- knockdown（Keap1 ^{FA / FA}）小鼠，其中的KEAP1（NRF2的负调节剂）减少，导致NRF2活性升高。我们比较了12个月大的Keap1 ^{FA / FA}在同一繁殖群体中具有年龄匹配的野生型（WT）小鼠的小鼠。在Keap1 ^{FA / FA}小鼠中，证实了多个NRF2靶基因的表达水平显着高于WT小鼠中这些基因的表达水平。组织学分析表明，Keap1 ^{FA / FA}小鼠的耳尖和中弯处的耳蜗变性得到改善。Keap1 ^{FA / FA}小鼠的听性脑干反应（ABR）阈值显着低于WT小鼠，特别是在中低频时。免疫组化检测氧化应激标志物表明，Keap1 ^{FA / FA}中氧化应激积累被减弱耳蜗。因此，我们得出的结论是，NRF2途径的激活可保护衰老过程中的耳蜗免受氧化损伤，特别是在心尖和中匝处。KEAP1抑制药物和植物化学物质有望有效预防AHL。