Oxidative stress contributes to aging by enhancing pancreatic angiogenesis and insulin signaling.
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 beta 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.
Laurent
Gaëlle
G
Institut Curie, 26 Rue d'Ulm, 75248 Paris Cedex 05, France.
Solari
Florence
F
Mateescu
Bogdan
B
Karaca
Melis
M
Castel
Julien
J
Bourachot
Brigitte
B
Magnan
Christophe
C
Billaud
Marc
M
Mechta-Grigoriou
Fatima
F
D000375:Aging / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D007003:Hypoglycemia; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000209:etiology*; D018384:Oxidative Stress / Q000502:physiology*; D010179:Pancreas / Q000098:blood supply*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D015398:Signal Transduction
D000975:Antioxidants; D007328:Insulin; D016755:Proto-Oncogene Proteins c-jun