**Background:** Telomeres are repetitive DNA sequences at chromosome ends that shorten with each cell division, triggering cellular senescence. Leukocyte telomere length (LTL) is a biomarker of biological aging and has been linked to cardiovascular diseases (CVDs), but associations with preclinical vascular phenotypes—especially microvascular and hemodynamic function—have been inconsistent. This study aimed to investigate associations of measured LTL, genetically predicted LTL (using polygenic risk scores, PRS), and the difference between them (ΔLTL) with a comprehensive set of vascular function markers in a general population.
**Methods:** The study used cross-sectional baseline data from the Rhineland Study, a population-based cohort in Bonn, Germany, including 4,180 participants (56.2% women, mean age 55.5 years, range 30–95) with genetic and vascular phenotype data; a subset of 1,828 had measured LTL. LTL was measured by qPCR (T/S ratio). Genetically predicted LTL was calculated using weighted PRS based on two GWAS: primary analyses used PRS_GWSCodd (150 genome-wide significant variants) and PRS_MRCodd (130 non-pleiotropic MR instruments) from Codd et al. (2021); sensitivity analyses used PRS_FDRLi (47 variants) and PRS_GWSLi (20 genome-wide significant variants) from Li et al. (2020). ΔLTL was defined as the residual from regressing measured LTL on PRS. Vascular phenotypes included microvascular function (reactive skin hyperemia via laser Doppler flowmetry), hemodynamics (cardiac index, systemic vascular resistance index, stroke index via impedance cardiography), arterial stiffness (total arterial compliance index, pulse wave velocity, ankle-brachial index), and blood pressure (systolic, diastolic, mean arterial pressure, pulse pressure). Multiple linear regression models adjusted for age, sex, smoking, BMI, and genetic principal components. Epigenome-wide association studies (EWAS) were performed for each LTL measure, followed by gene enrichment and KEGG pathway analyses.
**Key Results:** Longer measured LTL was associated with better microvascular function (0.20 SD increase in reactive skin hyperemia per SD increase in LTL; 95% CI: 0.03, 0.37) and higher cardiac index (0.19 SD; 95% CI: 0.01, 0.37). Genetically predicted LTL (PRS_GWSCodd and PRS_MRCodd) was associated only with cardiac index (0.04 SD increase per SD increase in PRS; 95% CI: 0.01, 0.07). ΔLTL was associated with better microvascular function (0.07 SD increase in reactive skin hyperemia; 95% CI: 0.02, 0.12), higher cardiac index (0.08 SD; 95% CI: 0.02, 0.13), and lower systemic vascular resistance index (−0.06 SD; 95% CI: −0.12, −0.01). No significant associations were found with arterial stiffness or blood pressure traits. EWAS identified 5 CpGs associated with measured LTL, 8 with genetically predicted LTL, and 27 with ΔLTL at p<1e-05. Genes linked to ΔLTL were enriched in pathways related to vascular endothelial growth factor signaling, phospholipid metabolism, and toll-like receptor 4 signaling. KEGG analysis suggested involvement of vascular smooth muscle contraction.
**Clinical Implications:** This study provides evidence that telomere shortening, independent of genetic predisposition, is associated with microvascular and cardiac dysfunction in the general population. The consistent associations of measured and ΔLTL with microvascular function and cardiac index, but not with arterial stiffness or blood pressure, suggest that telomere length may be particularly relevant to early vascular aging processes. The EWAS findings linking ΔLTL to environmental exposures and lifestyle factors imply that non-genetic interventions (e.g., nutrition, physical activity, sleep) could mitigate telomere shortening and improve cardiovascular health. The association of genetically predicted LTL with cardiac index supports a causal role for telomere biology in cardiac function. These findings highlight potential targets for lifestyle and pharmacological strategies to prevent CVDs and age-related disorders.