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Oxidative stress and aberrant signaling in aging and cognitive decline


  • Wulf Dröge,

    1. Immunotec Research Ltd., 300 Joseph-Carrier, Vaudreuil-Dorion, Quebec, Canada J7V 5V5
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  • Hyman M. Schipper

    1. Department of Neurology and Neurosurgery and Department of Medicine (Geriatrics), McGill University, Centre for Neurotranslational Research, Lady Davis Institute for Medical Research, S.M.B.D. Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2
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Wulf Dröge, Immunotec Research Ltd., 300 Joseph-Carrier, Vaudreuil-Dorion, Quebec, Canada J7V 5V5. Tel.: 450 510 4459; fax: 450 424 9993; e-mail: w.droege@immunotec.com


Brain aging is associated with a progressive imbalance between antioxidant defenses and intracellular concentrations of reactive oxygen species (ROS) as exemplified by increases in products of lipid peroxidation, protein oxidation, and DNA oxidation. Oxidative conditions cause not only structural damage but also changes in the set points of redox-sensitive signaling processes including the insulin receptor signaling pathway. In the absence of insulin, the otherwise low insulin receptor signaling is strongly enhanced by oxidative conditions. Autophagic proteolysis and sirtuin activity, in turn, are downregulated by the insulin signaling pathway, and impaired autophagic activity has been associated with neurodegeneration. In genetic studies, impairment of insulin receptor signaling causes spectacular lifespan extension in nematodes, fruit flies, and mice. The predicted effects of age-related oxidative stress on sirtuins and autophagic activity and the corresponding effects of antioxidants remain to be tested experimentally. However, several correlates of aging have been shown to be ameliorated by antioxidants. Oxidative damage to mitochondrial DNA and the electron transport chain, perturbations in brain iron and calcium homeostasis, and changes in plasma cysteine homeostasis may altogether represent causes and consequences of increased oxidative stress. Aging and cognitive decline thus appear to involve changes at multiple nodes within a complex regulatory network.