The cochlear macrophage in presbycusis: inflammaging, neuroinflammation, and targets for therapeutic modulation.

Age-related neurodegenerative diseases and age-related hearing loss are increasing in prevalence globally. Immune cells are novel mediators linking these diseases through shared mechanisms of chronic inflammation and maladaptive repair. In the cochlea, resident macrophages and infiltrating immune cells respond to injury, noise exposure, and aging by adopting activated phenotypes that disrupt synaptic integrity, impair myelination, and promote hair cell and neuronal loss. Similarly, in the central nervous system, microglia, the resident immune cells of the brain undergo age- and disease-associated priming, characterized by exaggerated inflammatory responses, complement activation, and impaired clearance of cellular debris. Emerging evidence suggests that cochlear macrophages and CNS microglia share transcriptional programs and signaling pathways. Importantly, these immune cells also serve as key regulators of repair and regeneration when appropriately modulated, adopting pro-regenerative phenotypes that promote tissue recovery rather than injury. As hearing loss is increasingly recognized as a contributing risk factor for neurodegenerative disease, deepening our understanding of age-related immune responses within the inner ear and the mechanisms governing immune cell modulation may help mitigate this risk while uncovering shared therapeutic targets across these related disease processes.