Simple SummaryChronological aging has long been considered an immutable risk factor for cerebral small vessel disease, but recent studies have revealed the potential for biological aging to be modulated and possibly even slowed or reversed, offering a promising avenue for intervention. Emerging studies have reported that biological aging biomarkers, such as leukocyte telomere length and epigenetic clocks, are associated with the risk of cerebral small vessel disease. However, the results remain inconsistent and controversial. Hence, in this study, we sought to explicate the underlying causal relationship between biomarkers of aging and cerebral small vessel disease. The results show that genetically determined leukocyte telomere length and epigenetic clocks were not associated with the ten measures of cerebral small vessel disease. Our study did not provide evidence to support a causal association between cerebral small vessel disease and the aging biomarkers of leukocyte telomere length and epigenetic clocks; thus, more studies are needed to evaluate the potential of reverse-biological-aging therapy in cerebral small vessel disease.AbstractBiological 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 (IVWp> 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.