Abstract
With the increasing proportion of elderly individuals, understanding biological mechanisms of aging is critical. Retinal vascular complexity, measured as fractal dimension (Df) from fundus photographs, has emerged as a vascular aging indicator. We conducted a genome-wide association study of Df on 74,434 participants from the Canadian Longitudinal Study on Aging, Genetics of Diabetes Audit and Research in Tayside Scotland, and UK Biobank cohorts. We identified a novel locus near DAAM1. We found negative genetic correlations between Df and cardiovascular disease, stroke, and inflammation but a positive correlation with life span. By combining the genetic determinants of 1159 circulating proteins from the Prospective Urban and Rural Epidemiological cohort with those of Df using Mendelian randomization, we identified eight causal mediators, including MMP12 and IgG-Fc receptor IIb, which link higher inflammation to lower Df, increased cardiovascular disease risk, and shorter life span. These results extend our understanding of the biological pathways underlying aging processes and inform targets to prevention and treatment.