[PDF][PDF] Oxidative stress contributes to aging by enhancing pancreatic angiogenesis and insulin signaling

G Laurent, F Solari, B Mateescu, M Karaca, J Castel… - Cell metabolism, 2008 - cell.com
G Laurent, F Solari, B Mateescu, M Karaca, J Castel, B Bourachot, C Magnan, M Billaud
Cell metabolism, 2008cell.com
JunD, a transcription factor of the AP-1 family, protects cells against oxidative stress. Here,
we show that junD−/− mice exhibit features of premature aging and shortened life span.
They also display persistent hypoglycemia due to enhanced insulin secretion.
Consequently, the insulin/IGF-1 signaling pathways are constitutively stimulated, leading to
inactivation of FoxO1, a positive regulator of longevity. Hyperinsulinemia most likely results
from enhanced pancreatic islet vascularization owing to chronic oxidative stress. Indeed …
Summary
JunD, a transcription factor of the AP-1 family, protects cells against oxidative stress. Here, we show that junD−/− mice exhibit features of premature aging and shortened life span. They also display persistent hypoglycemia due to enhanced insulin secretion. Consequently, the insulin/IGF-1 signaling pathways are constitutively stimulated, leading to inactivation of FoxO1, a positive regulator of longevity. Hyperinsulinemia most likely results from enhanced pancreatic islet vascularization owing to chronic oxidative stress. Indeed, accumulation of free radicals in β cells enhances VEGF-A transcription, which in turn increases pancreatic angiogenesis and insulin secretion. Accordingly, long-term treatment with an antioxidant rescues the phenotype of junD−/− mice. Indeed, dietary antioxidant supplementation was protective against pancreatic angiogenesis, hyperinsulinemia, and subsequent activation of insulin signaling cascades in peripheral tissues. Taken together, these data establish a pivotal role for oxidative stress in systemic regulation of insulin and define a key role for the JunD protein in longevity.
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