Mendelian randomization study implicates inflammaging biomarkers in retinal vasculature, cardiovascular diseases, and longevity
- Ana Villaplana-Velasco
- Nicolas Perrot
- Yu Hang
- Michael Chong
- Emanuele Trucco
- Muthu R. K. Mookiah
- Walter Nelson
- Jeremy Petch
- Hertzel C. Gerstein
- Parminder Raina
- Salim Yusuf
- Miguel O. Bernabeu
- Albert Tenesa
- Konrad Rawlik
- Guillaume Pare
- Alexander Doney
- Erola Pairo-Castineira
- Marie Pigeyre
2025-10-24
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.