Assessing the Causal Association between Biological Aging Biomarkers and the Development of Cerebral Small Vessel Disease: A Mendelian Randomization Study

Abstract

Biological aging biomarkers, such as leukocyte telomere length (LTL) and epigenetic clocks, have been associated with the risk of cerebral small vessel disease (CSVD) in several observational studies. However, it is unclear whether LTL or epigenetic clocks play causal roles as prognostic biomarkers in the development of CSVD. We performed a Mendelian randomization (MR) study of LTL and four epigenetic clocks on ten subclinical and clinical CSVD measures. We obtained genome-wide association (GWAS) data for LTL from the UK Biobank (N = 472,174). Data on epigenetic clocks were derived from a meta-analysis (N = 34,710), and CSVD data (N cases =1293–18,381; N controls = 25,806–105,974) were extracted from the Cerebrovascular Disease Knowledge Portal. We found that genetically determined LTL and epigenetic clocks were not individually associated with ten measures of CSVD (IVW p > 0.05), and this result was consistent across sensitivity analyses. Our findings imply that LTL and epigenetic clocks may not help in predicting CSVD development as causal prognostic biomarkers. Further studies are needed to illustrate the potential of reverse biological aging in serving as an effective form of preventive therapy for CSVD.