Aging and inflammation contribute to oligodendroglial dysfunction in multiple sclerosis (MS). The study used directly converted oligodendrocytes (dchiOL) from young, adult, and old human donors to investigate age-related changes. dchiOL from all age groups differentiated into O4+ immature oligodendrocytes, but the proportion of MBP+ mature dchiOL decreased with increasing donor age. Old dchiOL showed increased ROS production and upregulation of senescence markers like CDKN1A and CDKN2A. Transcriptomic analysis revealed 1324 differentially regulated genes in old dchiOL, with limited overlap with other cell types. Epigenetic analysis showed that chronological and epigenetic age correlate in CNS white matter and dchiOL, with an age-specific epigenetic signature. MS patients' normal appearing white matter (NAWM) showed accelerated epigenetic aging compared to healthy individuals. In vitro, young dchiOL exposed to pro-inflammatory microglial supernatants showed impaired differentiation and increased senescence markers. These findings suggest that physiological aging and inflammation-induced cellular senescence contribute to oligodendroglial pathology in MS. The study highlights the importance of understanding age-related changes in oligodendrocytes and their role in MS pathology.Aging and inflammation contribute to oligodendroglial dysfunction in multiple sclerosis (MS). The study used directly converted oligodendrocytes (dchiOL) from young, adult, and old human donors to investigate age-related changes. dchiOL from all age groups differentiated into O4+ immature oligodendrocytes, but the proportion of MBP+ mature dchiOL decreased with increasing donor age. Old dchiOL showed increased ROS production and upregulation of senescence markers like CDKN1A and CDKN2A. Transcriptomic analysis revealed 1324 differentially regulated genes in old dchiOL, with limited overlap with other cell types. Epigenetic analysis showed that chronological and epigenetic age correlate in CNS white matter and dchiOL, with an age-specific epigenetic signature. MS patients' normal appearing white matter (NAWM) showed accelerated epigenetic aging compared to healthy individuals. In vitro, young dchiOL exposed to pro-inflammatory microglial supernatants showed impaired differentiation and increased senescence markers. These findings suggest that physiological aging and inflammation-induced cellular senescence contribute to oligodendroglial pathology in MS. The study highlights the importance of understanding age-related changes in oligodendrocytes and their role in MS pathology.