The Stress of Aging

Science Signaling  12 Feb 2008:
Vol. 1, Issue 6, pp. ec53
DOI: 10.1126/stke.16ec53

Laurent et al. present new evidence for a role of the transcription factor JunD in protection of cells against oxidative stress, which may in turn have effects on organismal aging. JunD, which functions as a subunit of the AP1 transcription factor, is thought to protect cells from oxidative damage by regulating transcription of genes whose products function in antioxidant defense or production of H2O2. The ability of cells to tolerate oxidative stress is thought to be an important factor that determines life span, and the insulin and insulin-like growth factor signaling pathways (inhibition of which can lead to enhanced life span) regulate Foxo transcription factors, which are linked to resistance to oxidative stress. With these connections in mind, Laurent et al. monitored life span of JunD–/– mice. The mice showed about a 15% decrease in mean or maximal life spans compared with those of wild-type littermates. Analysis of metabolic parameters showed that the mutant animals had enhanced insulin secretion and consequent hypoglycemia along with inactivation of FoxO1. Some of the authors had earlier shown that depletion of JunD could influence angiogenesis by altering expression of vascular endothelial growth factor A (VEGF-A), so they tested whether alterations in angiogenesis at the pancreas might contribute to the hyperinsulinemia of the mutant animals. Indeed, in JunD–/– pancreatic β cells, expression of hypoxia-inducible factor 1α was increased and led to increased production of VEGF-A, and the pancreatic islets of the mutant animals showed increased vascularization. The authors propose that increased oxidative stress in the JunD–/– animals may lead to these effects in the pancreas, an idea supported by an experiment in which long-term treatment of animals with the antioxidant N-acetylcysteine reduced pancreatic angiogenesis and restored normal blood concentrations of glucose and insulin in the mutant animals. The authors thus propose to have outlined a pathway by which the JunD protein may have a role in promoting longevity through protection from oxidative stress.

G. Laurent, F. Solari, B. Mateescu, M. Karaca, J. Castel, B. Bourachot, C. Magnan, M. Billaud, F. Mechta-Grigoriou, Oxidative stress contributes to aging by enhancing pancreatic angiogenesis and insulin signaling. Cell Metab. 7, 113-124 (2008). [PubMed]