Transposable elements (TEs) comprise over half of our genome and are important gene regulators, yet their impact on brain function is unclear. My research has shown that TEs and their epigenetic repressor affect gene expression in the healthy and diseased brain. Interestingly, these epigenetic repressors are altered genome-wide upon aging, posing one of my main research questions: how do these age-related changes alter the impact of TEs in the elderly brain? My preliminary data and recent studies suggest that oligodendrocytes in our brain undergo significant age-related transcriptional and functional changes, potentially influenced by TEs. However, how these mechanisms work, and the extent of TE influence remain unclear. The overall aim of this project is to understand the age-related alterations in oligodendrocytes and the contribution of TEs to this process. The first aim will explore TE-mediated transcriptome alterations in oligodendroglia during aging using human post-mortem brain tissue and long-read Oxford Nanopore Sequencing. The second aim will focus on determining the functional consequences of these alterations by using a directly reprogrammed oligodendrocyte model and CRISPR gene editing. Finally, in the third aim we will develop a CRISPR-based epigenome editing approach to mitigate the impact of TEs. Overall, this project will further our understand of brain aging and will aid in developing therapies for aging related brain disorders affecting oligodendrocytes.