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With the increasing proportion of elderly individuals, understanding biological mechanisms of aging is critical. Retinal vascular complexity, measured as fractal dimension (D_f) from fundus photographs, has emerged as a vascular aging indicator. We conducted a genome-wide association study of D_f 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 D_f 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 D_f using Mendelian randomization, we identified eight causal mediators, including MMP12 and IgG-Fc receptor IIb, which link higher inflammation to lower D_f, 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.