Reversing epigenetic changes in aged microglia via young circulatory factors

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Project Summary/Abstract Aging leads to a progressive decline in brain function and is the greatest risk factor for the development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. While myriad studies have focused on the genes that impact aging, the nongenetic regulation of aging is gaining increasing attention. Several recent studies have demonstrated chromatin-based epigenetic changes that occur during aging, and have highlighted the role of chromatin modifiers in regulating lifespan. Specifically, aging is associated with profound changes to the epigenome, resulting in alterations of gene expression and broad disturbances in genome architecture. Delineating the environmental, nongenetic regulation that occurs as a hallmark of aging could open new avenues that ‘reverse’ epigenetic changes to alter the trajectory of age-related diseases. One of the most intriguing aspects of the nongenetic control of aging is the ‘reversal’ of aging in muscle, brain, and heart by heterochronic parabiosis (fusion of the blood circulation between an old animal and a young animal). Recent studies from our group demonstrate that exposure of an aged mouse to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive levels and that microglia may play a role in this rejuvenation effect. This study will utilize the epigenetic assays ChIP-seq and ATAC-seq to provide a comprehensive understanding of how aging alters microglial chromatin accessibility genome-wide. Using these complimentary epigenomic read- outs, this application will determine 1) the epigenetic changes that occur in microglia with aging and 2) whether changes to the microglial epigenome can be reversed by young circulatory factors.