Aging-dependent demethylation of regulatory elements correlates with chromatin state and improved insulin secretion by pancreatic β cells

Aging at the cellular level is driven by changes in gene activity and epigenetic state that are only partially understood. We performed a comprehensive epigenomic analysis of the pancreatic β cell, key player in glucose homeostasis and diabetes, in adolescent and very old mice. Globally, we observe a general methylation drift resulting in an overall more leveled methylome, suggesting that the maintenance of highly differential methylation patterns becomes compromised with advanced age. Importantly, we discover targeted changes in the methylation status of β cell proliferation and function genes that go against the global methylation drift, are specific to β cells, and correlate with repression of the proliferation program and activation of metabolic regulators. These targeted alterations frequently occur at distal cis-regulator elements, and are associated with specific chromatin marks and transcription factor occupancy in young β cells. Strikingly, we find the insulin secretory response to glucose much improved in mature β cells in mice, as predicted by the changes in methylome and transcriptome and in contrast to the decline in function observed in aged human β cells. Thus, aging of terminally differentiated cells in mammals is not always coupled to functional decline.