We observe that β-cell regeneration is severely and abruptly restricted by middle age in our cohort of mice. Fifty percent partial pancreatectomy stimulated a massive amount of β-cell proliferation in young mice. However, partial pancreatectomy had little effect on β-cell proliferation in aged mice. Similarly, the β-cell toxin streptozotocin greatly increased β-cell replication in young mice but failed to stimulate β-cell regeneration in aged mice. Moreover, β-cell proliferation was stimulated by exendin-4 in young but not in aged mice. Taken together, these results reveal that adaptive β-cell proliferation is severely restricted with advanced age.
In this study, we advance the hypothesis that age is a major factor limiting human β-cell regeneration. Basal β-cell proliferation was severely reduced as a function of age in our mice, consistent with our previous observations (17
). We further this observation to show that adaptive β-cell proliferation is also severely restricted with age. In support of this concept, basal replication rates in human pancreata and cultured human islets decline with donor age (29
). Similarly, islets from young donors have been reported to perform better when transplanted into type 1 diabetic patients (32
). Notably, type 2 diabetes is typically a disease of the elderly, most commonly diagnosed during middle age or beyond. Similarly, gestational diabetes mellitus is much more frequent with advanced maternal age (33
). This would imply that human patients of advanced age could have little regenerative capacity to increase β-cell mass. Indeed, there is indirect evidence to support this concept of an age-dependent decline in β-cell regeneration. For instance, increased rates of diabetes have been reported in patients after shock-wave lithotripsy for renal stones (35
). Similarly, minimal β-cell regeneration is observed in patients after partial pancreatectomy (15
). Thus, β-cell regeneration could be constrained in advanced age in humans, similar to that in the aged rodents in our study. Restricted β-cell mass expansion could have severe consequences in elderly patients with type 2 diabetes, limiting compensatory β-cell mass expansion to cope with increased insulin requirements. Interestingly, several of the recently discovered risk loci for type 2 diabetes have been implicated in cell cycle control of β-cells and could theoretically influence adult β-cell mass or alter the timing of cell cycle exit of adult β-cells (36
Discrepancies between rodent and human β-cell regeneration capacity have confounded diabetes researchers for many years. Regeneration of β-cell function in experimental animal models has been widely observed in rodents but remains elusive and controversial in humans (13
). Notably, islets from human cadaveric donors are typically in the 4th–6th decade of life and are therefore much more mature (32
). Because our results in rodents indicate that β-cell regeneration capacity declines with age, we hypothesize that young rodents may not faithfully model the regenerative capacity of mature adult human β-cells.
Our studies reveal that the regenerative capacity of adult β-cells becomes limited by early middle age (12 months of age [~40% of the mouse life span]) (23
). As such, aging β-cells may not be comparable with hematopoietic stem cells, which gradually lose replicative capacity during the normal aging process (40
). Under this schema, β-cells could have a developmental program that allows them to replicate early in adulthood to match insulin secretion capacity to peripheral insulin requirements. β-Cell replication might then become fully restricted when adult insulin requirements are established in middle age.