膳食甘氨酸锌补充减轻衰老驱动的耳蜗毛细胞氧化损伤和听力损失

文献信息

中文摘要

背景： 微量营养素失衡现已被认为是驱动年龄相关性听力损失（ARHL）进展的可改变危险因素。锌是一种不可或缺的膳食微量营养素，作为广谱抗氧化酶的结构辅因子和转录调节因子，维持全身和细胞抗氧化防御能力。然而，锌营养补充的治疗价值及其对抗年龄依赖性耳蜗变性的精确分子机制在很大程度上仍未被阐明。方法：我们建立衰老小鼠模型，以观察耳蜗锌营养稳态破坏所致的表型变化，并应用口服生物可利用甘氨酸锌补充干预ARHL。采用体外D-半乳糖（D-gal）刺激诱导细胞氧化损伤，随后进行一系列机制实验以检测核心抗氧化分子的表达并确定线粒体功能。结果：耳蜗锌营养稳态破坏在衰老小鼠中诱导进行性听力损失和严重毛细胞变性。相反，口服甘氨酸锌补充显著缓解年龄相关听力下降并减少耳蜗毛细胞的氧化损伤。作为一种营养干预，甘氨酸锌显著提高关键细胞内抗氧化剂（SOD、GSH和GPX4）的水平，并挽救由D-半乳糖触发的活性氧积累所诱导的线粒体功能障碍。此外，甘氨酸锌的保护作用可能与金属响应转录因子1（MTF-1）的上调有关，后者进而抑制D-半乳糖诱导的促炎cGAS-STING通路的过度激活。结论：膳食甘氨酸锌补充对耳蜗衰老提供潜在保护。这种听觉益处可能涉及MTF-1上调和cGAS-STING通路抑制。总体而言，这些发现提供了临床前证据，支持进一步研究甘氨酸锌作为ARHL的潜在营养干预。

英文摘要

Background: Micronutrient imbalance is now recognized as a modifiable risk factor driving the progression of age-related hearing loss (ARHL). Zinc, an indispensable dietary trace nutrient, acts as a structural cofactor and transcriptional regulator of a broad panel of antioxidant enzymes to sustain systemic and cellular antioxidant defense capacity. Nevertheless, the therapeutic value of zinc nutritional supplementation and its precise molecular mechanisms against age-dependent cochlear degeneration remain largely uncharacterized. Methods: We established aging mouse models to observe the phenotypic changes caused by disrupted cochlear zinc nutritional homeostasis, and applied oral supplementation of bioavailable zinc glycinate to intervene in ARHL. In vitro D-galactose (D-gal) stimulation was adopted to induce cellular oxidative damage, followed by a series of mechanistic assays to detect the expression of core antioxidant molecules and determine mitochondrial function. Results: Disrupted cochlear zinc nutritional homeostasis induced progressive hearing loss and severe hair cell degeneration in aging mice. Conversely, oral zinc glycinate supplementation significantly relieved age-related hearing decline and reduced oxidative injury of cochlear hair cells. As a nutritional intervention, zinc glycinate significantly elevates the levels of key intracellular antioxidants (SOD, GSH, and GPX4) and rescues mitochondrial dysfunction induced by D-galactose triggered reactive oxygen species accumulation. Moreover, the protective effect of zinc glycinate may be associated with the upregulation of metal-responsive transcription factor 1 (MTF-1), which in turn suppresses the D-galactose-induced hyperactivation of the pro-inflammatory cGAS-STING pathway. Conclusions: Dietary zinc glycinate supplementation offers potential protection against cochlear aging. This auditory benefit may involve MTF-1 upregulation and inhibition of the cGAS-STING pathway. Collectively, these findings provide preclinical evidence supporting further investigation of zinc glycinate as a potential nutritional intervention for ARHL.