Senescent microglia limit remyelination through the senescence associated secretory phenotype

The capacity to regenerate myelin in the central nervous system (CNS) diminishes with age. This decline is particularly evident in multiple sclerosis (MS), which has been suggested to exhibit features of accelerated biological aging. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells (SCs) accumulate within demyelinated lesions after injury, and their elimination enhances remyelination in young mice but not in aged mice. In young mice, we observed the upregulation of senescence-associated transcripts primarily in microglia after demyelination, followed by their reduction during remyelination. However, in aged mice, senescence-associated factors persisted within lesions, correlating with inefficient remyelination. We found that SC elimination enhanced remyelination in young mice but was ineffective in aged mice. Proteomic analysis of senescence associated secretory phenotype (SASP) revealed elevated levels of CCL11/Eotaxin-1 in lesions, which was found to inhibit efficient oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS. Overall design: 3 months old and 18 months old mice were used. Focal demyelitation was induced by injecting 1% of L-a-Lysophosphatidylcholine (LPC) in PBS between the T11-12 vertebrae into the ventral white matter columns of the mouse spinal cord. To identify and dissect out the lesion, 500ul 1% neutral red dye in PBS was injected intraperitoneally 2 hours prior to cardiac perfusion with ice cold RNA-ase free 1X PBS. Spinal cords were flash frozen on dry ice.