Aging and β-Cell Proliferation, Molecular and Signaling Changes and What This Means for Targeted Regeneration
Pp. 20-41 (22)
Aaron R. Cox
Increased age confers a greater risk for the development of type 2 diabetes
(T2D), and also has significant consequences for β-cell growth and regeneration.
Pancreatic insulin-producing β-cells are long-lived, and exhibit very little turnover in
adult life. The severe decline in β-cell proliferation contributes to a decreased capacity
for β-cell regeneration with age. β-cell regeneration is dependent on mitogenic signals,
receptor and downstream signal transduction, cell cycle progression, and epigenetic
regulation of gene expression, all of which are significantly affected by increasing age.
Studies suggest that circulating growth factors and their receptors are decreased with
age, along with important intracellular signaling molecules, such as Pdx-1 and FoxM1.
Cell cycle progression is inhibited by an increased expression of cell cycle inhibitors
and a reduction in cell cycle kinase complexes (Cyclin/Cdks). Moreover, decreased
expression of epigenetic silencers, such as polycomb group proteins, results in derepression
of the cell cycle inhibitor p16, and a significant reduction in β-cell
proliferation. Collectively, these age-induced changes present obstacles for the design
of β-cell regenerative therapies for diabetes; however, some reports suggest that even
very old β-cells can re-enter cell cycle. Future studies will further define the effects of
aging on β-cell proliferation and elucidate new drug targets for diabetes therapy.
Aging, β-cell regeneration, Cell cycle, Diabetes, Epigenetics,
Molecular signals, Proliferation.
McNair Medical Institute, Baylor College of Medicine, Houston, Texas, U.S.A.