Therapeutic Timing at Mitochondrial Redox-Autophagy-Mitophagy Checkpoints in Age-Related Hearing Loss.

Age-related hearing loss (ARHL) is common, disabling, and still managed largely with compensatory devices rather than mechanism-modifying therapy. The major weakness in the current translational pipeline is not the absence of candidate pathways, but the lack of a timing framework that links cochlear phenotype, mitochondrial injury state, and intervention intensity. This revised Review therefore focuses on a staged mitochondrial redox-quality-control model. We argue that ARHL emerges when high-energy cochlear compartments-outer and inner hair cells, spiral ganglion neurons, and the lateral wall/stria vascularis-cross a threshold at which mitochondrial reactive oxygen species (ROS), impaired mitochondrial DNA and transfer RNA integrity, lysosomal insufficiency, and incomplete mitophagy reinforce each other. Three checkpoints are emphasized because they are mechanistically actionable and experimentally measurable: NAD+-SIRT3-dependent mitochondrial deacetylation and antioxidant stabilization, NRF2-dependent redox and detoxification buffering, and PINK1-Parkin-dependent selective mitophagy. We also expand the sidewall perspective, highlighting that strial and spiral ligament redox instability can reduce endocochlear-potential reserve and modify the apparent sensory-neural phenotype. A practical therapeutic sequence is proposed: early substrate reinforcement through NAD+-SIRT3 and NRF2; mid-stage restoration of autophagy-lysosome competence; and selective mitophagy enhancement only when flux, not merely marker accumulation, is demonstrably limiting. Finally, we define a biomarker and detection framework that distinguishes cochlear tissue endpoints from blood or perilymph proxies and separates mouse proof-of-mechanism from human trial stratification. This approach clarifies which evidence is sufficient for prevention studies, which remains missing, and how future ARHL trials can be aligned with mechanism and timing.