Conceição Bettencourt

Aims Epigenetic clocks are widely applied as surrogates for biological age in different tissues and/or diseases, including several neurodegenerative diseases. Despite white matter (WM) changes often being observed in neurodegenerative diseases, no study has investigated epigenetic ageing in white matter. Methods We analysed the performances of two DNA methylation‐based clocks, DNAmClock Multi and DNAmClock Cortical , in post‐mortem WM tissue from multiple subcortical regions and the cerebellum, and in oligodendrocyte‐enriched nuclei. We also examined epigenetic ageing in control and multiple system atrophy (MSA) (WM and mixed WM and grey matter), as MSA is a neurodegenerative disease comprising pronounced WM changes and α‐synuclein aggregates in oligodendrocytes. Results Estimated DNA methylation (DNAm) ages showed strong correlations with chronological ages, even in WM (e.g., DNAmClock Cortical , r = [0.80–0.97], p < 0.05). However, performances and DNAm age estimates differed between clocks and brain regions. DNAmClock Multi significantly underestimated ages in all cohorts except in the MSA prefrontal cortex mixed tissue, whereas DNAmClock Cortical tended towards age overestimations. Pronounced age overestimations in the oligodendrocyte‐enriched cohorts (e.g., oligodendrocyte‐enriched nuclei, p = 6.1 × 10 −5 ) suggested that this cell type ages faster. Indeed, significant positive correlations were observed between estimated oligodendrocyte proportions and DNAm age acceleration estimated by DNAmClock Cortical (r > 0.31, p < 0.05), and similar trends were obtained with DNAmClock Multi . Although increased age acceleration was observed in MSA compared with controls, no significant differences were detected upon adjustment for possible confounders (e.g., cell‐type proportions). Conclusions Our findings show that oligodendrocyte proportions positively influence epigenetic age acceleration across brain regions and highlight the need to further investigate this in ageing and neurodegeneration.