The crosstalk between CNS resident glial cells and peripheral immune cells is critical for age-dependent demyelination and subsequent remyelination.

White-matter diseases like multiple sclerosis begin in young adulthood. Aging, being a risk factor, contributes to the progression of these diseases and makes neurological disabilities worsen. Aging causes white matter alteration due to myelin loss, axonal degeneration, and hyperintensities, resulting in cognitive impairment and neurological disorders. Aging also negatively affects central nervous system resident glial cells and peripheral immune cells, contributing to myelin degeneration and diminished myelin renewal process. Restoration of myelin failure with aging accelerates the progression of cognitive decline. This review will mainly focus on how age-related altered functions of glial and peripheral cells will affect myelin sheath alteration and myelin restoration. This understanding can give us insights into the underlying mechanisms of demyelination and failure of remyelination with aging concerning altered glial and peripheral immune cell function and their crosstalk. Also, we will explain the therapeutic strategies to enhance the remyelination process of an aging brain to improve the cognitive health of an aging person.