Investigation of the Causal Association Between Biological Aging Indicators and Vascular Disease Through Two-Sample Mendelian Randomization Analysis

Objective This study used two-sample Mendelian Randomization to investigate the causal link between multiple biological aging indicators and vascular disease. Methods Summary genetic data was obtained from genome-wide association studies (GWAS) focusing on aging-related exposures and various vascular disease outcomes. The exposures included granulocyte proportions, PAI-1 (plasminogen activator inhibitor-1), telomere(definition) lengths, and the Frailty Index. The primary analysis employed the Inverse Variance Weighted (IVW) method to estimate causal relationships, supported by MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses, including Cochran’s Q test, MR-Egger regression, leave-one-out test, and the MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) test, were conducted to evaluate heterogeneity and pleiotropy. Results The analysis revealed distinct pathways after sensitivity adjustments. A higher genetically predicted Frailty Index was associated with an increased risk of abdominal aortic aneurysm (OR=2.5935, 95% CI: 1.3936–4.8268, P =0.0026, false discovery rate (FDR)=0.0475), atherosclerosis excluding cerebral and coronary sclerosis (OR=2.0262, 95% CI:1.5179–2.705, P =1.66×10 -6 , FDR=1×10 -4 ), and arterial thromboembolic events (OR = 4.0306, 95% CI: 1.7133–9.4818, P = 0.0014, FDR = 0.0337). Conversely, longer telomere length demonstrated a strong, specific protective effect against abdominal aortic aneurysm (OR=0.5008, 95% CI:0.4111–0.6100, P =6.42×10 -12 , FDR=9.25×10 -10 ), indicating that shorter telomere length is associated with an increased risk of AAA. Furthermore, a lower granulocyte proportion was causally linked to an increased risk of thoracic aortic aneurysm (OR=0.0181, 95% CI: 0.0014–0.2376, P =0.0023, FDR=0.0465). Conclusion This study identifies three genetic pathways linking biological aging to vascular disease, offering new molecular targets for its prevention and treatment.