Age-dependent decline in remyelination capacity is mediated by apelin–APJ signaling

Age-related regeneration failure in the central nervous system can occur as a result of a decline in remyelination efficacy. The responsiveness of myelin-forming cells to signals for remyelination is affected by aging-related epigenetic modification; however, the molecular mechanism is not fully clarified. In the present study, we report that the apelin receptor (APJ) mediates remyelination efficiency with age. APJ expression in myelin-forming cells is correlated with age-associated changes in remyelination efficiency, and the activation of APJ promotes remyelination through the translocation of myelin regulatory factor. APJ signaling activation promoted remyelination in both aged mice with toxin-induced demyelination and mice with experimental autoimmune encephalomyelitis. In human cells, APJ activation enhanced the expression of remyelination markers. Impaired oligodendrocyte function in aged animals can be reversibly reactivated; thus, the results demonstrate that dysfunction of the apelin–APJ system mediates remyelination failure in aged animals, and that their myelinating function can be reactivated by APJ activation. Ito et al. show that regeneration in the aging brain is impaired due to reduced expression of the apelin receptor APJ. Circulating apelin signals oligodendrocytes via APJ to support remyelination, and this pathway can be restored in older mice with an APJ agonist.