Epigenetic aging is associated with hearing loss and multi-system disease risk independently of chronological age

ARHL (Age-related hearing loss) affects over one-third of people aged 65 and older worldwide. It is often viewed as an isolated sensory deficit, but whether it is associated with systemic biological aging remains unclear.

We analyzed NHANES (n = 2530) and HRS (n = 2849) cohorts. GrimAgeAcc (GrimAge acceleration) was used to assess biological aging. GO/KEGG (Gene Ontology/Kyoto Encyclopedia of Genes and Genomes) and disease association analyses were performed on GrimAge-related proteins. Prospective associations between ARHL and dementia, CVD (Cardiovascular Disease), and diabetes were examined in HRS. Murine cochlear data (GEO: GDS5624, n = 5-6 per group) were analyzed as a preliminary exploratory dataset. Network pharmacology and molecular docking were used for in silico screening. An exploratory risk prediction model based on GrimAgeAcc and clinical covariates was developed for hypothesis generation.

After adjustment for chronological age, GrimAgeAcc was independently associated with ARHL in both cohorts. GrimAge-related proteins showed enrichment in endoplasmic reticulum function, endocytosis, and inflammatory pathways. Prospective analysis in HRS indicated time-dependent associations between ARHL and dementia (HR = 2.94), CVD (HR = 1.43), and diabetes (HR = 1.14) after age adjustment. However, mediation analysis showed that chronological age explained 28-50% of these associations. In murine cochlear data, ADM expression was higher in adult vs. young mice (4-5% increase), but the effect size was small and no significant reversal was observed. In silico screening suggested that selumetinib (a MEK inhibitor) was associated with expression changes in several GrimAge-related genes. An exploratory risk prediction model showed preliminary calibration in HRS but requires external validation.

Based on our data, GrimAgeAcc is associated with ARHL and systemic age-related diseases (dementia, CVD, diabetes), potentially through shared biological pathways (e.g., endocytosis, lysosomal, inflammatory). Chronological age explains 28-50% of these associations, yet ARHL remains independently associated with all three outcomes after age adjustment. The cochlea may be vulnerable, but causal evidence is lacking. All findings are hypothesis-generating and require experimental validation.