Przyspieszenie biologicznego starzenia się w opornej na leki epilepsji i jego zmiana podczas terapii dietą ketonową

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.