Peripheral adaptive immune remodeling associated with severe hearing loss in older adults: a single-center flow-cytometry study with mouse cochlear transcriptomic context

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Objective To investigate the association between severe hearing loss and systemic immune aging in older adults using participant-level clinical immunophenotyping, and to explore potential inflammatory pathways and cellular contexts using public mouse cochlear transcriptomic data. Methods We analyzed a single-center cohort of 76 older adults, classified into normal hearing (NH), mild-to-moderate hearing loss (MMHL), or severe-to-profound hearing loss (SPHL) groups. Age- and sex-adjusted models were used to assess immune profiles. Prespecified sensitivity and diagnostic analyses evaluated age specification, overlap weighting, influential observations, and the stability of the inversion model. Additionally, public mouse cochlear bulk transcriptomics and single-nucleus RNA sequencing (snRNA-seq) data were examined to identify relevant inflammatory pathways and cell-type-specific immune-stress modules. Results SPHL was significantly associated with a higher T-cell/CD8 skew, increased CD4 differentiation, an elevated EM/naive CD4 balance, a lower CD8 activation/checkpoint score, and increased odds of CD4/CD8 inversion. These associations remained consistent across sensitivity analyses. Mouse bulk transcriptomics highlighted inflammatory response and IL6/JAK/STAT3 signaling pathways, while snRNA-seq localized immune-stress modules primarily to broad macrophage and perivascular macrophage-like cell populations. Conclusion Severe hearing loss in older adults is associated with distinct peripheral immune remodeling features indicative of systemic immune aging. These findings support an association-focused framework linking hearing loss severity with immune dysregulation, though validation in larger, clinically annotated cohorts is required.