Oxidative stress and aberrant signaling in aging and cognitive decline

Abstract

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.

Fig. 1

Oxidative upregulation of the insulin receptor signaling cascade in the absence of insulin. Akt, serine/threonine kinase PKB; IRS-1, insulin-receptor substrate; INS-RK, insulin receptor tyrosine kinase; PDK1, phosphoinositide-dependent protein kinase-1; PI3K, phosphatidylinositol-3 kinase; PTEN, phosphatase and tensin homolog on chromosome 10; PTP1B, protein tyrosine phosphatase 1B; PI(3,4)P₂, phosphatidylinositol(3,4) diphosphate; PI(4,5)P₂, phosphatidylinositol(4,5) diphosphate; PI(3,4,5)P₃, phosphatidylinositol (3,4,5) triphosphate; SHIP2, SH2-domain-containing inositol phosphatase; TOR/mTOR, (mammalian) target of rapamycin. The question mark indicates that H₂O as a product of this reaction has not been formally proven (for other details see text).

Fig. 2

Interrelated changes of insulin receptor signaling, autophagy, and sirtuin expression during the day (hypothetical scheme). The solid lines illustrate the temporal changes in young healthy subjects. During the night, that is, in the post-absorptive state, insulin receptor signaling is low and autophagy and sirtuin activity are accordingly high. In the aging organism (dashed lines), the age-related oxidative shift in redox status leads to an increased basic signaling activity from the insulin receptor in spite of low insulin levels; autophagy and sirtuin expression are accordingly suppressed.

Fig. 3

Oxidative activation of insulin receptor kinase and inactivation of phosphatases (schematic illustration). Upper panel: in the absence of insulin, basic insulin receptor kinase (Ins-RK) activity is relatively low. Hydrogen peroxide oxidizes cysteine sulfhydryl (SH) groups into sulfenic acid moieties (S-OH). This oxidative process allows adenosine 5’-triphosphate (ATP) to phosphorylate the insulin receptor kinase at its catalytic site and to render the kinase catalytically active. Lower panel: phosphatases typically contain an SH group at their catalytic center. Upon oxidation by hydrogen peroxide the phosphatase is converted into a catalytically inactive intermediate and other inactive derivatives. The question marks indicate that these reaction products have not been formally proven.

Fig. 4

Pathomechanisms of aging: deregulation at key ‘nodes’ in a network of interrelated physiological processes. AUPH, autophagic mechanism of proteolysis involved in the turnover of (damaged) mitochondria and other cellular constituents. Autophagy is negatively regulated by insulin. BIRS, basal activity of the insulin receptor signaling pathway, that is, in the post-absorptive state.Ca²⁺, mitochondrial calcium concentrations (calcium homeostasis); Cys, post-absorptive plasma cysteine concentration (cysteine homeostasis); Fe²⁺, nontransferrin iron concentration (iron homeostasis); GSH, intracellular glutathione concentrations; REDST, glutathione redox status; ROS, intracellular reactive oxygen species; SIRT, sirtuin proteins impact lifespan and are negatively regulated by insulin.