Accelerated Biological Aging and Genetic Pleiotropy in Age-Related Eye Diseases: A Population-Based Cohort and...

Age-related eye diseases (AREDs) are major causes of vision loss worldwide. Biological age acceleration (BAA) reflects systemic aging, but its relationship with AREDs and underlying genetic mechanisms remains unclear. This study investigated the combined effects of BAA and genetic risk on AREDs and blindness, and explored shared genetic pathways and potential anti-aging targets.

Biological age was measured using the Klemera-Doubal method for estimating biological age (KDM-BA) and PhenoAge algorithms. We assessed the cross-sectional and prospective associations between BAA and AREDs in 297,375 participants from the UK Biobank, followed by genetic pleiotropy analysis.

Participants with higher BAA were more likely to experience AREDs at baseline and had an increased risk of incident AREDs during follow-up. In participants with high genetic susceptibility to AREDs, accelerated biological aging was associated with an increased risk of disease onset. Notably, we observed a significant additive interaction between BAA and genetic risk. The multi-omics integrative analysis identified 115 genetic variants with pleiotropic effects and 512 candidate genes. Notably, we identified APOE, APOC1, TOMM40, PVRL2, and BCAM as shared genes between BAA and the three AREDs. Among ARED patients, accelerated biological aging was associated with a reduction in vision-healthy life expectancy, compared to those without accelerated biological aging.

Accelerated biological aging significantly increases ARED risk, especially in those with high genetic risk, and is linked to shorter vision-healthy life expectancy. Identifying individuals with accelerated aging may help reduce ARED risk and improve vision-healthy life expectancy. APOE, APOC1, TOMM40, PVRL2, and BCAM could be potential targets for ocular anti-aging interventions.