Epigenetic age acceleration in the brain and blood of people with epilepsy and in a mouse model of focal cortical dysplasia: a retrospective cross-sectional study

Abstract People with epilepsy have reduced life expectancy and increased age-related comorbidities, raising the possibility that epilepsy is associated with accelerated biological aging. Yet, direct and quantitative evidence for biological age acceleration in epilepsy has been limited. Here, we applied a tissue-specific DNA methylation-based epigenetic clock to brain and blood samples from 307 individuals with epilepsy across major etiologies (i.e., structural and genetic) and age groups, alongside 65 nonepileptic controls. Across lesion types and developmental stages, epileptic brain tissue exhibited robust epigenetic age acceleration. In blood, age acceleration was not consistently detected at the group level after controlling for cell composition, chronological age, and sex, although subtle or subgroup-specific effects could not be excluded. Cross-tissue comparisons in structural epilepsies suggested higher age acceleration in brain than in blood overall; however, this pattern was not uniform. Notably, focal cortical dysplasia was the only subgroup showing significant age acceleration in both brain and blood, with no difference between tissues, precluding a general conclusion that the brain universally ages faster than peripheral blood in epilepsy. To assess temporal dynamics, we analyzed an in utero electroporation mouse model of somatic mTOR pathway activation. Mutant epileptic mouse brains recapitulated the human brain aging signatures, with minimal effects in blood and evidence that age acceleration emerged prior to seizure onset. Together, our findings identify epigenetic age acceleration as a core feature of epileptic brain tissue and potential novel treatment target, while highlighting etiological heterogeneity and leaving open the contribution of systemic aging processes in epilepsy.