Dynamic imbalance of autophagy: A molecular link between age-related hearing loss and cognitive dysfunction.

Abstract

Age-related hearing loss (ARHL) and cognitive dysfunction are established comorbidities, yet their molecular links remain unclear. This study employed a D-galactose-induced ARHL guinea pig model, along with multimodal analysis, to elucidate the bridging role of autophagy. ARHL animals exhibited significantly elevated hearing thresholds (>65 dB SPL) and spatial memory deficits (Morris Water Maze escape latency increased 0.77-fold). PET/CT revealed a 28.57 % reduced hippocampal glucose metabolism (SUV), negatively correlating with cognitive impairment. Molecular analysis revealed that the autophagic marker LC3B was initially upregulated (0-8 weeks) and then declined (12-16 weeks), while P62 paradoxically mirrored the dynamics of LC3B, indicating an imbalance in autophagy homeostasis. Transmission electron microscopy identified mitochondrial cristae dissolution, postsynaptic density thinning, and widened synaptic clefts, linking ultrastructural damage to metabolic compromise via autophagy dysregulation. We establish an evidence chain: "ARHL-autophagy imbalance-hippocampal hypometabolism-cognitive decline". Autophagy initially exerts neuroprotection by clearing damage but transitions to neurotoxicity under chronic dysregulation, causing neuronal energy insufficiency. These findings reveal novel mechanisms connecting ARHL and cognitive impairment, providing a foundation for autophagy-targeted therapies.