Abstract: Just over half of the weight of an entire adult human brain is attributed to myelin, which wraps around neuronal axons and is essential for superfast axonal conduction and neuronal integrity. In the central nervous system, it is the function of specialized cells called oligodendrocytes (OLs) to make myelin, which is made up of lipids and proteins. OLs are generated throughout life by a significant population of oligodendrocyte progenitor cells (OPCs) that are responsible for the lifelong generation of OLs and myelin, essential for learning, as well as repair following pathological insults (i.e. in demyelinating diseases that include multiple sclerosis) (Simons and Nave, 2015; Philips and Rothstein, 2017). Changes in myelin content in the human brain over the lifespan of individuals have been well documented, as well as evidence of myelin loss in rodent models using classical histological approaches (Bartzokis et al., 2012; Soreq et al., 2017). During the normal course of aging, degenerative alterations in myelin (myelin thinning, formation of myelin balloons, loss of myelinated tracts) have been shown to precede overt neuronal loss and ultimately lead to negative clinical outcomes, which manifest as the dramatic decline in the speed and efficiency of neuronal networks [reviewed in Rivera et al. (2021a)]. However, a gap in our knowledge was the precise changes in OL and myelin genes at the transcriptome level, which can inform the genetic programs for targeting rejuvenation (Neumann et al., 2019; Rivera et al., 2021b).