Time flies faster in epilepsy

People with epilepsy have a significantly reduced life expectancy and an increased burden of age-related comorbidities, raising the possibility that epilepsy accelerates biological aging. Seizures trigger molecular and cellular hallmarks of aging, including telomere attrition, oxidative stress, and senescence, yet direct evidence for accelerated aging in epilepsy has been lacking. Here, we applied tissue-specific epigenetic clocks to DNA methylation profiles from brain and blood of 298 epilepsy patients and 25 controls. Across lesion types and age groups, epileptic brain tissue showed robust biological age acceleration, exceeding that observed in blood. Blood also exhibited accelerated aging, with effects varying by genotype and etiology. In a mouse model of somatic mTOR activation, mutant epileptic brains recapitulated this age acceleration, with epilepsy and aging-related signatures emerging before seizure onset. Seizure frequency and cumulative burden did not correlate with epigenetic age, establishing accelerated biological aging as a hallmark of epileptogenesis and potential therapeutic target.