Guo Qi, Li Zhenjiang, Luo Cheng, Chen Changhan, Long Xi, Wang Yidan, Qiang Qingfen, Yu Fang, Liu Wuping, Zhang Yujin, Kellems Rodney E, Xia Yang
Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
National Medical Metabolomics International Collaborative Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
iScience. 2025 Aug 5;28(9):113285. doi: 10.1016/j.isci.2025.113285. eCollection 2025 Sep 19.
Age-related hearing loss (ARHL) is a major public health concern, driven by the interplay of multiple factors. Here, we reveal spatiotemporal metabolic shifts in murine inner ears mirroring erythrocytes and plasma. Isotope-labeled glucose tracing demonstrates a metabolic rerouting favoring glycolysis over the pentose phosphate pathway, alongside downregulation of the tricarboxylic acid cycle, indicating impaired energy production and redox homeostasis. Accumulation of medium- and long-chain acylcarnitines further exacerbates lipotoxicity. Notably, age-dependent depletion of arginine, lysine, proline, and glycine disrupts the arginine-polyamine-urea cycle. Translationally, UK Biobank plasma metabolomics links omega-6 fatty acids, linoleic acid, glycine, and albumin to ARHL resilience, while branched-chain amino acids, tyrosine, creatinine, glycoprotein acetyls and urea confer risk. Sex differences in ARHL were linked to fatty acid metabolism divergence. These bioenergetic disruptions in the inner ear are mirrored in erythrocytes and plasma, highlighting potential biomarkers for early ARHL diagnosis and treatment.
年龄相关性听力损失（ARHL）是一个重大的公共卫生问题，由多种因素相互作用所致。在此，我们揭示了小鼠内耳中反映红细胞和血浆的时空代谢变化。同位素标记的葡萄糖追踪显示，代谢途径发生重排，糖酵解优于磷酸戊糖途径，同时三羧酸循环下调，表明能量产生和氧化还原稳态受损。中链和长链酰基肉碱的积累进一步加剧了脂毒性。值得注意的是，精氨酸、赖氨酸、脯氨酸和甘氨酸的年龄依赖性消耗会破坏精氨酸-多胺-尿素循环。在转化层面，英国生物银行的血浆代谢组学研究表明，ω-6脂肪酸、亚油酸、甘氨酸和白蛋白与ARHL恢复力相关，而支链氨基酸、酪氨酸、肌酐、糖蛋白乙酰化物和尿素则带来风险。ARHL中的性别差异与脂肪酸代谢差异有关。内耳中的这些生物能量紊乱在红细胞和血浆中也有体现，突出了早期ARHL诊断和治疗的潜在生物标志物。
