Oxidative Stress Contributes to Aging by Enhancing Pancreatic Angiogenesis and Insulin Signaling

• Published in: Cell metabolism 2008-02, Vol.7 (2), p.113-124
• Main Authors: Laurent, Gaëlle, Solari, Florence, Mateescu, Bogdan, Karaca, Melis, Castel, Julien, Bourachot, Brigitte, Magnan, Christophe, Billaud, Marc, Mechta-Grigoriou, Fatima
• Format: Article
• Language: English
• Subjects: Aging - physiology; Animals; Antioxidants - administration & dosage; Antioxidants - pharmacology; HUMDISEASE; Hypoglycemia; Insulin - metabolism; Mice; Mice, Knockout; Neovascularization, Pathologic - etiology; Oxidative Stress - physiology; Pancreas - blood supply; Proto-Oncogene Proteins c-jun - genetics; Signal Transduction
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2007.12.010

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.