Comparative Cochlear–Vestibular Aging Reveals Age‐Aligned Mitochondrial Ultrastructural Burden, Mitophagy–Autophagy Remodeling, Synaptic Uncoupling, and Sensory Functional Decline

ABSTRACT

Age‐related hearing loss and balance decline are prevalent features of organismal aging, yet how the cochlea and vestibular organs converge on shared cellular liabilities remains insufficiently resolved. In particular, whether mitochondrial ultrastructural injury and mitochondrial quality‐control programs co‐vary with synaptic vulnerability and sensory functional decline across these systems within an age‐resolved framework has not been clearly delineated. Here, we compared cochlear and vestibular aging in SAMP8 mice of different ages using integrated functional assays, region‐resolved quantification of hair cells and CtBP2/GluA2 synapses, cochlear NF200+ fiber area fraction, transmission electron microscopy, and targeted qPCR of mitophagy/autophagy–lysosome genes. The results show that ABR thresholds rose progressively across 5.6–32 kHz. VsEP exhibited age‐dependent threshold shifts and prolonged P‐wave latency. Relative to the magnitude of synaptic and functional changes, cochlear hair‐cell numbers were broadly preserved, although regional OHC loss was observed in middle‐to‐basal turns, whereas vestibular macular hair‐cell density declined with age. Ultrastructurally, the proportion of pathological mitochondria increased with age, featuring electron‐lucent matrix, disrupted cristae organization, and rounded/swollen profiles. What's more, guided by an adult‐versus‐aged transcriptomic screen nominating the Ca ²⁺ extrusion gene Atp2b4, we derived z‐scored molecular indices, including a flux–burden signature (z(p62)–z(Lc3b)) and a TFEB–lysosome module. Descriptive coupling across age‐group means indicated that mitochondrial pathology burden aligned closely with high‐frequency ABR loss and basal synaptic uncoupling, and tracked the flux–burden signature more consistently than the TFEB–lysosome module. Together, these findings support age‐aligned associations among mitochondrial ultrastructural injury, molecular remodeling, synaptic vulnerability, and progressive sensory decline across cochlear and vestibular systems.