褐藻寡糖通过TFEB相关自噬恢复减轻氧化应激和炎症，从而缓解年龄相关性听力损失

文献信息

中文摘要

年龄相关性听力损失（ARHL）是一种高度流行的感觉障碍，以进行性耳蜗退化为特征。迄今为止，临床上尚无有效的药物治疗。在本研究中，我们在体外D-半乳糖（D-gal）诱导的衰老模型和C57BL/6J小鼠年龄相关耳蜗功能障碍模型中，研究了褐藻寡糖（AOS）的耳保护功效及其潜在机制。多组学分析确定氧化应激、炎症、细胞衰老和自噬是与AOS治疗相关的核心靶向通路。在D-gal处理的HEI-OC1细胞和耳蜗外植体中，AOS处理显著降低了衰老相关β-半乳糖苷酶（SA-β-gal）活性，并下调了衰老标志物P16和P21。这些抗衰老效应伴随着氧化应激和促炎应激的改善，表现为活性氧（ROS）减少、线粒体功能得以保留以及核因子-κB/NOD样受体热蛋白结构域相关蛋白3（NF-κB/NLRP3）信号受到抑制。AOS还促进转录因子EB（TFEB）核转位，并减轻D-gal诱导的自噬相关失调。药理学抑制自噬和TFEB核进入可有效削弱AOS的这些细胞保护、抗氧化和抗炎益处，支持TFEB相关自噬信号参与AOS介导的保护作用。在C57BL/6J小鼠中，长期给予AOS显著降低了听性脑干反应（ABR）阈值，减轻了毛细胞和螺旋神经节神经元的年龄相关退化，并减少了耳蜗衰老标志物。此外，AOS在体内抑制MDA积累，提高SOD活性，抑制NF-κB/NLRP3激活，并恢复TFEB相关自噬稳态。总之，这些发现表明AOS可防止年龄相关耳蜗功能障碍和衰老，同时伴随氧化应激和炎症减少以及自噬相关稳态改善。TFEB相关信号可能参与这些保护效应，支持进一步研究AOS用于预防或延缓耳蜗衰老。

英文摘要

Age-related hearing loss (ARHL) is a highly prevalent sensory disorder characterized by progressive cochlear degeneration. To date, no effective pharmacological treatment is clinically available. In this study, we investigated the otoprotective efficacy and underlying mechanisms of alginate oligosaccharide (AOS) against D-galactose (D-gal)-induced senescence in vitro and age-associated cochlear dysfunction in C57BL/6J mice. Multi-omics analyses identified oxidative stress, inflammation, cellular senescence, and autophagy, as core targeted pathways associated with AOS treatment. In D-gal-treated HEI-OC1 cells and cochlear explants, AOS treatment markedly reduced senescence-associated β-galactosidase (SA-β-gal) activity and downregulated senescence markers P16 and P21. These anti-senescent effects were accompanied by ameliorated oxidative and pro-inflammatory stress, as reflected by decreased reactive oxygen species (ROS), preserved mitochondrial function, and suppressed nuclear factor-κB/NOD-like receptor pyrin domain-containing 3 (NF-κB/NLRP3) signaling. AOS also promoted transcription factor EB (TFEB) nuclear translocation and attenuated D-gal-induced autophagy-related dysregulation. Pharmacological inhibition of autophagy and TFEB nuclear entry effectively blunted these cytoprotective, antioxidant, and anti-inflammatory benefits of AOS, supporting the involvement of TFEB-associated autophagic signaling in AOS-mediated protection. In C57BL/6J mice, long-term AOS administration significantly lowered auditory brainstem response (ABR) thresholds, attenuated the age-related degeneration of hair cells and spiral ganglion neurons, and reduced cochlear senescence markers. Furthermore, AOS suppressed MDA accumulation, elevated SOD activity, inhibited NF-κB/NLRP3 activation, and restored TFEB-associated autophagic homeostasis in vivo. Collectively, these findings suggest that AOS protects against age-associated cochlear dysfunction and senescence, accompanied by reduced oxidative stress and inflammation and improved autophagy-related homeostasis. TFEB-associated signaling may contribute to these protective effects, supporting further investigation of AOS for the prevention or delay of cochlear aging.