Methylation-enriched telomere length mediates the association between lead exposure and cognitive function in an aging population

This study investigated the mediating role of methylation-predicted telomere length (mTL) in the association between lead (Pb) exposure and cognitive decline among older adults, leveraging data from the National Health and Nutrition Examination Survey (NHANES). We analyzed 1661 participants aged ≥60 years, assessing blood Pb levels, Horvath-estimated mTL, and cognitive function. Linear regression models and causal mediation analyses were performed with sequential adjustments for demographics, comorbidities, and lifestyle factors. Pb exposure exhibited a dose-dependent association with cognitive impairment. In fully adjusted models, the highest Pb quartile (Q4) was associated with a significant cognitive deficit (β = −3.9, 95% CI: −6.9, −0.9) compared to Q1, and continuous Pb exposure was associated with reduced cognitive scores (β = −2.6, 95% CI: −4.3, −1.0) per standard deviation increase in Pb. Crucially, mTL mediated 30.8% of the total effect of continuous Pb exposure on cognition (total effect β = −2.6; direct effect β = −1.6, 95% CI: −3.7, 0.5; indirect effect β = −1.0, 95% CI: −1.6, 0.4). The mediation was particularly pronounced in higher-Pb groups (Q4 indirect effect β = −1.9), attenuating the Pb-cognition association from β = −3.9 (unmediated) to β = −2.0 after mTL adjustment. These results established mTL as a significant biological mediator, explaining approximately one-third of Pb-induced cognitive deficits in aging populations. Our findings suggest that Pb exposure was associated with increased epigenetic aging via telomere attrition. Interventions preserving telomere integrity may mitigate Pb-related cognitive decline.