The aim of this study was to elucidate whether age plays a role in the expansion or regeneration of β-cell mass.

We analyzed the capacity of β-cell expansion in 1.5- and 8-month-old mice in response to a high-fat diet, after short-term treatment with the glucagon-like peptide 1 (GLP-1) analog exendin-4, or after streptozotocin (STZ) administration.

Young mice responded to high-fat diet by increasing β-cell mass and β-cell proliferation and maintaining normoglycemia. Old mice, by contrast, did not display any increases in β-cell mass or β-cell proliferation in response to high-fat diet and became diabetic. To further assess the plasticity of β-cell mass with respect to age, young and old mice were injected with a single dose of STZ, and β-cell proliferation was analyzed to assess the regeneration of β-cells. We observed a fourfold increase in β-cell proliferation in young mice after STZ administration, whereas no changes in β-cell proliferation were observed in older mice. The capacity to expand β-cell mass in response to short-term treatment with the GLP-1 analog exendin-4 also declined with age. The ability of β-cell mass to expand was correlated with higher levels of Bmi1, a polycomb group protein that is known to regulate the Ink4a locus, and decreased levels of p16^Ink4aexpression in the β-cells. Young Bmi1^−/− mice that prematurely upregulate p16^Ink4afailed to expand β-cell mass in response to exendin-4, indicating that p16^Ink4alevels are a critical determinant of β-cell mass expansion.

β-Cell proliferation and the capacity of β-cells to regenerate declines with age and is regulated by the Bmi1/p16^Ink4apathway.