Myelin density dictates region-specific vulnerability of oligodendrocyte lineage cells during aging

Abstract

Aging of the central nervous system (CNS) leads to a progressive decline in numerous physiological functions. This decline can be attributed in part to alterations within the oligodendrocyte lineage, which comprises myelinating oligodendrocytes (OLs) and their progenitors, NG2-glia, that play a central role in maintaining homeostasis and ensuring proper myelin turnover. While NG2-glia are distributed throughout the CNS, OLs are enriched in highly myelinated regions, implying spatially heterogeneous requirements for NG2-glia proliferation and differentiation. Consequently, age-related impairments in these progenitor functions may differentially compromise oligodendrogenesis and myelin maintenance across distinct CNS compartments. Yet, the spatial and temporal dynamics of aging-associated alterations within the oligodendrocyte lineage remains insufficiently characterized. To address this gap, we investigated the effects of aging across three age groups in two anatomically adjacent but functionally distinct CNS regions, the cortical gray matter (GM) and the corpus callosum (CC). We demonstrated that aging is accompanied by a marked decline in the NG2-glia population. Aging NG2-glia displayed cell cycle dysregulation, characterized by reduced proliferative and differentiative capacity and accompanied by increased expression of cyclin-dependent kinase inhibitors (CDKIs), indicating disrupted homeostatic regulation. These alterations were most pronounced in highly myelinated regions, which also exhibited a stronger shift toward an age-associated inflammatory milieu. In parallel, we observed substantial accumulation of myelin debris and impaired phagocytic clearance in these myelin-dense areas. Moreover, we identified a selective loss of myelinating OLs in the CC, a phenomenon not detected in the gray matter (GM). Together, our findings delineate a tight interdependence between regional myelin density, inflammatory status, and the vulnerability of oligodendrocyte lineage cells to aging. These highlight multiple entry points of potential therapeutic intervention to mitigate CNS aging.