Drug-resistant epilepsy is associated with increased cumulative epigenetic ageing, and while cumulative age remained stable during modified ketogenic diet 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.
Adults with drug-resistant epilepsy showed substantial epigenetic age acceleration compared to expected values at baseline.
Cumulative epigenetic age acceleration did not change significantly during the 12-week modified ketogenic diet intervention.
DunedinPACE, a rate-based epigenetic clock, revealed two distinct ageing-rate trajectory clusters during the ketogenic diet intervention.
The 'up-down' DunedinPACE trajectory cluster showed significantly greater improvement in health-related quality of life compared to the 'down-up' cluster.
The quality of life differences between DunedinPACE trajectory clusters were independent of ketone levels, seizure frequency, and body weight changes.
The study design included 58 adults with drug-resistant epilepsy completing a 12-week modified ketogenic diet intervention with three time-point blood sampling.
This research suggests that people with drug-resistant epilepsy — epilepsy that doesn't respond well to medications — show signs of accelerated biological aging at the molecular level, as measured by patterns of chemical tags on their DNA (called DNA methylation). These biological age measurements, known as 'epigenetic clocks,' can estimate how fast a person's body is aging regardless of their actual chronological age. The study enrolled 58 adults with drug-resistant epilepsy who followed a modified ketogenic diet (a high-fat, low-carbohydrate diet) for 12 weeks, with blood samples taken at the start, after four weeks, and after 12 weeks. The research found that traditional 'cumulative' epigenetic clocks — which estimate a person's total biological age — did not show measurable change during the 12-week diet. However, a newer type of clock called DunedinPACE, which measures the current *rate* of aging rather than accumulated age, revealed two distinct patterns among participants: some people showed an initial speed-up in aging rate followed by a slowdown ('up-down'), while others showed an initial slowdown followed by a rebound ('down-up'). Crucially, the group whose aging rate ultimately slowed reported dramatically greater improvements in quality of life (average improvement of 18.8 versus 4.7 on a standard epilepsy quality-of-life scale), and this difference held even after accounting for ketone levels in the blood, changes in seizure frequency, and weight loss. This research suggests that rate-based epigenetic clocks may be sensitive enough to detect short-term biological adaptations to dietary treatment that traditional measures miss, and that these molecular patterns may reflect something meaningful about how individual patients benefit from the ketogenic diet beyond just seizure control. The findings could have implications for personalizing dietary therapies and for understanding why some epilepsy patients report broader improvements in energy, cognition, and well-being during ketogenic diet treatment, even when seizure outcomes are similar.
Gervin K, Kverneland M, Nakken K, Rudi K, Iversen P, Selmer K. (2026). Epigenetic ageing is accelerated in drug-resistant epilepsy and dynamically modulated during ketogenic diet therapy.. EBioMedicine. https://doi.org/10.1016/j.ebiom.2026.106449