β-cell regeneration remains a fundamental challenge for diabetes research. Consequently, major research initiatives towards β-cell regeneration have been launched over the past decades. A general consensus of β-cell mass expansion has emerged from this work. Several putative mechanisms have been invoked to explain adult β-cell mass expansion, including neogenesis from pancreatic ducts or hematopoietic tissues, replication of specialized β-cell progenitors and self-renewal by β-cells.1
However, recent studies by several groups (including ours) indicate that normal β-cell growth primarily occurs by division of cells with insulin promoter activity, not by replication of specialized progenitors.2,3
β-cell mass also appears to be dynamically regulated, at least in young rodents. β-cell mass expansion can accelerate in response to increased insulin requirements4
or during pregnancy.5
These observations have led to speculation that β-cell regeneration therapies for diabetes patients might someday become a reality. However, human β-cell regeneration is an ambitious long-term goal, and has yet to be convincingly demonstrated in vitro nor in vivo.6,7
Aging has emerged over the past few years as a key factor to limit β-cell regeneration. In the past rodent β-cells were reported to undergo frequent turnover (every 1–3 months) and assumed to have a relatively short lifespan.8
This observation implied that β-cell mass expansion could highly responsive to metabolic stimuli and that small changes in β-cell turnover might result in large changes in β-cell mass expansion. However, we discovered that mice have very little evidence of β-cell turnover at one year of age (approximately 1:1400 BrdU positive β-cells per 24 hours).9
Given that β-cell mass continues to expand into the second year, our observation implies that β-cells could be very long lived. Indeed, Clark and colleagues have recently reported that human β-cells are extremely long lived, as estimated by lipofuscin accumulation in cadaveric β-cells.10
Similarly, Perl and colleagues recently reported that β-cell turnover is limited to the first three decades of life as determined by in vivo thymidine analog incorporation and radiocarbon dating.11
Minimal β-cell turnover also implies that cell cycle entry of β-cells might be restricted with age. Consequently, we recently analyzed the effect of aging upon β-cell regeneration.12
We found that β-cell regeneration is severely and abruptly restricted by middle age in our cohort of mice. 50% partial pancreatectomy potently stimulated β-cell proliferation in young mice (2 or 8 months of age). But, partial pancreatectomy had little effect upon β-cell proliferation at 12 months, and no effect by 14 months or 19 months of age. Moreover, β-cell proliferation was stimulated by low dose streptozotocin (a β-cell toxin) in young mice but not in aged mice. Similarly, β-cell proliferation was stimulated by exendin-4 in young mice but not in aged mice. Taken together, these results reveal that adaptive β-cell proliferation is severely restricted with advanced age. Independent experiments by Bhushan and colleagues also showed that aged mice had little proliferative response to high fat diet, low dose streptozotocin or exendin-4.13
Thus, aging seems to be a previously unrealized factor that limits adaptive β-cell proliferation.
Much remains to be learned regarding the role of aging in β-cell proliferation. We recently studied the effect of aging upon islet gene expression using a candidate gene approach to measure mRNAs of cell cycle components.12
Several negative regulators of cell cycle progression were increased in aged islets compared to young islets, including p21, p16Ink4a
. These results suggest that genomic studies could identify unique ageregulated genes or signals in islets. Moreover, truly important genes would be predicted to follow a pattern that correlates with the ability for β-cell regeneration. Consequently, we set out to interrogate the role of aging in β-cell proliferation using genomic expression studies in mice of various ages. Here we show that aging imparts a distinct gene expression program in aging mouse islets, with many genes that are differentially expressed in young vs. old islets. Partial pancreatectomy induces distinct gene expression patterns in both young and old islets. Surprisingly, Reg family genes were induced by partial pancreatectomy in mice of all ages, despite the lack of β-cell regeneration in aged mice. Still, few other genes were induced by partial pancreatectomy in both young and old mice.