OBJECTIVE: Regeneration of the insulin-secreting beta-cells is a fundamental research goal that could benefit patients with either type 1 or type 2 diabetes. beta-Cell proliferation can be acutely stimulated by a variety of stimuli in young rodents. However, it is unknown whether this adaptive beta-cell regeneration capacity is retained into old age. RESEARCH DESIGN AND METHODS: We assessed adaptive beta-cell proliferation capacity in adult mice across a wide range of ages with a variety of stimuli: partial pancreatectomy, low-dose administration of the beta-cell toxin streptozotocin, and exendin-4, a glucagon-like peptide 1 (GLP-1) agonist. beta-Cell proliferation was measured by administration of 5-bromo-2'-deoxyuridine (BrdU) in the drinking water. RESULTS: Basal beta-cell proliferation was severely decreased with advanced age. Partial pancreatectomy greatly stimulated beta-cell proliferation in young mice but failed to increase beta-cell replication in old mice. Streptozotocin stimulated beta-cell replication in young mice but had little effect in old mice. Moreover, administration of GLP-1 agonist exendin-4 stimulated beta-cell proliferation in young but not in old mice. Surprisingly, adaptive beta-cell proliferation capacity was minimal after 12 months of age, which is early middle age for the adult mouse life span. CONCLUSIONS: Adaptive beta-cell proliferation is severely restricted with advanced age in mice, whether stimulated by partial pancreatectomy, low-dose streptozotocin, or exendin-4. Thus, beta-cells in middle-aged mice appear to be largely postmitotic. Young rodents may not faithfully model the regenerative capacity of beta-cells in mature adult mice.