Aging-Dependent Demethylation of Regulatory Elements Correlates with Chromatin State and Improved β Cell Function

Aging is driven by changes of the epigenetic state that are only partially understood. We performed a comprehensive epigenomic analysis of the pancreatic beta cell, key player in glucose homeostasis, in adolescent and very old mice. We observe a global methylation drift resulting in an overall more leveled methylome in old b cells. Importantly, we discover targeted changes in the methylation status of b cell proliferation and function genes that go against the global methylation drift, are specific to b cells, and correlate with repression of the proliferation program and activation of metabolic regulators. These targeted alterations are associated with specific chromatin marks and transcription factor occupancy in young b cells. Strikingly, we find b cell function improved in aged mice, as predicted by the changes in methylome and transcriptome. Thus, aging of terminally differentiated cells in mammals is not always coupled to functional decline.