biostudies-literatureGuo QXiangya Hospital Central South UniversityCentral South UniversityChina Postdoctoral Science FoundationNational Natural Science Foundation of ChinaHunan Provincial Natural Science Foundation113285https://www.ebi.ac.uk/biostudies/studies/S-EPMC12424239biostudies-literatureUnknown28(9)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, whileiScienceMetabolic shifts in murine inner ears mimicking erythrocytes and plasma reveal diagnostics and early predictors for age-related hearing loss.PMC1242423982401827823015142023JJ409192209090555464GZB202408662025JJ60551824008732023JJ410182023M74396882230023Kellems REXia YLi ZQiang QLong XZhang YYu FLuo CChen CWang YGuo QLiu WfalseMetabolic shifts in murine inner ears mimicking erythrocytes and plasma reveal diagnostics and early predictors for age-related hearing loss.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, while2025-01-01T00:00:00Z2025 Sep2026-06-03T07:44:28.942Z2026-04-26T03:09:49.327ZS-EPMC124242394094910310.1016/j.isci.2025.113285