Suggestive genetic association between age-related biomarkers and hearing impairment: a mendelian randomization study

Objective Observational studies suggest links between biological aging biomarkers and hearing impairment, but causal inference remains limited. Mendelian Randomization (MR) offers a genetic epidemiological approach to explore potential causal relationships. We used MR to evaluate potential causal associations between various aging biomarkers and five subtypes of hearing impairment. Methods We conducted a two-sample MR study using summary data from large-scale, European-ancestry genome-wide association studies. Biological aging biomarkers, including epigenetic clocks, overall and cell-specific telomere length, were used as exposures. Outcomes were age-related hearing impairment and four other subtypes. The inverse variance weighted method was our primary analysis, supported by comprehensive sensitivity analyses to assess result stability. Results Our analysis observed nominal associations related to immune cell subtypes. Genetically predicted longer granulocyte telomere length was nominally associated with lower odds of mixed hearing loss (OR = 0.84, 95% CI 0.74‒0.96, p = 0.009), whereas longer leukocyte telomere length was nominally associated with higher odds of mixed hearing loss (OR = 1.21, 95% CI: 1.03–1.42, p = 0.02). Furthermore, a higher proportion of granulocytes was nominally associated with lower odds of age-related hearing impairment (OR = 0.72, 95% CI: 0.55‒0.95, p = 0.02). Although sensitivity analyses did not indicate substantial heterogeneity and horizontal pleiotropy, these associations should be interpreted with caution due to the lack of robust FDR-corrected evidence. Conclusion Our findings suggest a complex landscape of cell-type specific and paradoxical associations. This may help shift attention from general anti-aging interventions towards dissecting specific cellular pathways for hearing health. Level of Evidence This two-sample Mendelian randomization study provides genetic evidence suggesting potential associations between age-related biomarkers and hearing impairment, complementing findings from conventional observational studies.