Migraine is the most frequent primary disorder of medication overuse headache (MOH). As MOH progresses, patients tend to increase medication doses, which paradoxically results in more frequent headaches and reduced efficacy of analgesics. Epigenetic age, which can be evaluated by DNA methylation (DNAm)-based models, has been associated with disease risk, morbidity, and mortality in several health conditions. The principal aim of this work was to study epigenetic aging-related mechanisms in MOH. This study is part of Epimode project in which MOH (n = 23), episodic migraineurs (EM, n = 18) and healthy controls (HC, n = 13) were recruited. MOH group received therapy including education and detoxification. Responsiveness to MOH intervention was evaluated based on a reduction in headache frequency from chronic to episodic, consistent with established diagnostic thresholds, and did not imply complete cure of MOH. Six subsets of biomarkers derived from DNA methylation were calculated to evaluate changes in epigenetic aging: DNAm clocks, PC-clocks, components of GrimAge and FitAge clocks, DNAm-estimated blood cell composition measures and EpiScores. We used two‑stage residual‑outcome regression (2SR) approach to perform disease-related analysis comparing MOH patients with HC, and intervention-related analysis comparing non-responders (NR) with responders (R) before and after the treatment. We observed epigenetic age deceleration (GrimAge, HannumAge and ZhangAge) in MOH. Compared to controls, MOH showed decreased DNAm-based surrogates of PAI1 and CCL11, and increased estimates of VO2max, B2M, cystatin C and C9. At baseline, there were no differences in epigenetic clocks between R and NR but increased estimated levels of cystatin C, ADM and GDF15, and decreased NEP and CXCL10 were found in MOH NR group. After detoxification, intervention-related differences were observed in DNAmAge, DunedInPoAm, GrimAge, surrogates of ADM, GDF15, TARC, OSM, VCAM1 and estimated counts of natural killer cells (NK). Longitudinal exploration of three timepoints (baseline, after 5 and 9 months) demonstrated that alterations tended to be preserved over time. Our findings indicate that the DNA methylation aging-related mechanisms may be involved in the MOH pathology as well as in MOH treatment.
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