Epigenetic ageing is accelerated in drug-resistant epilepsy and dynamically modulated during ketogenic diet therapy

Abstract

Background The ketogenic diet (KD) is an established treatment for drug-resistant epilepsy. Beyond seizure reduction, many patients report improved energy, cognition, and well-being. DNA methylation (DNAm)–based epigenetic clocks provide molecular indices of biological ageing and may capture short-term adaptations induced by dietary therapy. Methods Fifty-eight adults with drug-resistant epilepsy completed a 12-week modified KD intervention with blood sampling at baseline, four weeks, and 12 weeks. Whole-blood DNAm was profiled using the Illumina EPIC array. Epigenetic ageing was estimated using cumulative clocks (Horvath, Hannum, Levine) and the rate-based DunedinPACE clock. Longitudinal changes were assessed using linear mixed-effects models. DunedinPACE trajectories were clustered using k-means. Associations with β-hydroxybutyrate, seizure frequency, body weight, and health-related quality of life were assessed using correlations and between-cluster comparisons. Findings At baseline, participants showed substantial epigenetic age acceleration on cumulative clocks. Cumulative age acceleration did not change during the intervention. In contrast, DunedinPACE revealed two marked ageing-rate trajectories: an initial increase followed by slowing ("up–down") and an initial slowing followed by rebound ("down–up"). Mean ageing rate did not change at the group level (p = 0.18). However, the "up–down" cluster exhibited significantly greater improvement in quality of life compared with the "down–up" cluster (ΔQOLIE 18.8 versus 4.7; p=0.007) independent of ketosis, seizure reduction, or weight change. Interpretation Drug-resistant epilepsy is associated with increased cumulative epigenetic ageing. While cumulative age remained stable during modified KD therapy, dynamic ageing-rate patterns were linked to patient-reported benefit, suggesting that rate-based DNAm clocks capture short-term systemic adaptation to metabolic treatment. Funding This study was funded by the Dam Foundation, the Norwegian Epilepsy Association's Research Fund, the Novo Nordisk Foundation, and the National Advisory Unit on Rare Disorders.