Przyspieszane starzenie się na poziomie epigenetycznym w mózgu i krwi osób chorych na epilepsję oraz w zwierzęcym modelu ogniskowej dysplazji kory mózgowej - badanie retrospektywne przekrojowe
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
W skrócie
Badacze zbadali próbki mózgu i krwi osób z epilepsją oraz myszy z epilepsją, aby sprawdzić, czy ich tkanki starzą się szybciej na poziomie molekularnym. Okazało się, że mózgi osób z epilepsją wykazywały oznaki przyspieszającego się starzenia się (średnio o 7,3 lat szybciej), podczas gdy w krwi tego zjawiska prawie nie zaobserwowano. Wyniki sugerują, że epilepsja może powodować przyspieszane starzenie się mózgu, co mogłoby wyjaśniać, dlaczego osoby z epilepsją mają krótszą przeciętną długość życia i więcej chorób związanych z wiekiem.
Oryginalny abstract (angielski)
BACKGROUND: People with epilepsy have reduced life expectancy and more age-related comorbidities, suggesting a link to faster biological ageing. Direct molecular evidence has been scarce. METHODS: We applied DNA-methylation-based epigenetic clocks to brain and blood samples from 324 unique individuals with structural or genetic epilepsy and 65 non-epilepsy controls, and to an in utero electroporation mouse model of somatic mTOR pathway activation (etiocopy of human FCD type 2) sampled before and after seizure onset. Epigenetic age acceleration was defined as the residual from a robust regression on chronological age, sex, cell-type composition, and array type. Relative telomere length was measured in the mouse model to independently validate biological ageing. FINDINGS: In brain, epigenetic age acceleration was consistent across structural lesion types (median +7.3 years, p < 0.0001), most pronounced in GG (+10 years, adj. p < 0.0001), followed by MOGHE (+8.1 years, adj. p < 0.0001), TLE (+6.6 years, adj. p < 0.001), and FCD (+5.6 years, adj. p < 0.001). In blood, age acceleration was not significant after adjustment for cell composition, age, and sex (median +0.7 years, p = 0.20), except in FCD (+2.3 years, adj. p < 0.05). Across structural epilepsies, acceleration was greater in brain than in blood (median +7.3 vs. + 1.4 years, p < 0.0001). Available VPA-exposure data (n = 175) was not significantly associated with age acceleration. In a drug-naïve mTOR mouse model, mutant epileptic brains, but not blood, showed epigenetic age acceleration (adj. p < 0.05). Ageing signatures were already detectable in brains of animals in the pre-seizure latency phase and were independently supported by shortened relative telomere length (adj. p = 0.05), indicating that biological ageing can precede overt epilepsy. INTERPRETATION: Accelerated epigenetic ageing is a consistent feature of the epileptic brain in drug-resistant structural epilepsies and a candidate pathway for disease modification. The contribution of systemic ageing remains unresolved, and generalisability to other aetiologies will need to be further tested. FUNDING: Else Kröner Fresenius Stiftung, German Science Foundation, L'Institut pour la Recherche en Santé Publique, Interdisziplinäres Zentrum für Klinische Forschung, Czech Science Foundation, Ministry of Health of the Czech Republic, Ministry of Education, Youth and Sports of the Czech Republic, Research Foundation-Flanders FWO.