Systemic Regulation of the Age-Related Decline of Pancreatic β-Cell Replication

The frequency of pancreatic beta-cell replication declines dramatically with age, potentially contributing to the increased risk of type 2 diabetes in old age. Previous studies have shown the involvement of cell-autonomous factors in this phenomenon, particularly the decline of polycomb genes and accumulation of p16/INK4A. Here, we demonstrate that a systemic factor found in the circulation of young mice is able to increase the proliferation rate of old pancreatic beta-cells. Old mice parabiosed to young mice have increased beta-cell replication compared with unjoined old mice or old mice parabiosed to old mice. In addition, we demonstrate that old beta-cells transplanted into young recipients have increased replication rate compared with cells transplanted into old recipients; conversely, young beta-cells transplanted into old mice decrease their replication rate compared with young cells transplanted into young recipients. The expression of p16/INK4A mRNA did not change in heterochronic parabiosis, suggesting the involvement of other pathways. We conclude that systemic factors contribute to the replicative decline of old pancreatic beta-cells.