Oxidative stress and aging.

Free radical-derived reactive oxygen species (ROS) are constantly generated in most living tissue and can potentially damage DNA, proteins and lipids. "Oxidative stress" occurs if ROS reach abnormally high concentrations. Harman was the first to propose that the damaging effects of ROS may play a key role in the mechanism of aging. Genetic studies of such distantly related species as C. elegans, Drosophila melanogaster, and mice support this hypothesis. However, ROS are not only a cause of structural damage, but also physiologically important mediators in biological signaling processes. Abnormally high levels of ROS may therefore lead to dysregulation of redox-sensitive signaling pathways. The redox-sensitive targets in these pathways are often signaling proteins with redox-sensitive cysteine residues which are oxidized to sulfenic acid moieties and mixed disulfides, thereby altering the signaling function of the protein. Because the formation of these mixed disulfides can also occur through a prooxidative shift in the intracellular thiol/disulfide redox status (REDST), the respective signaling pathways respond not only to ROS but also to changes in REDST. Information about the concentration of ROS in living tissue is scarce, but aging-related changes in REDST are well documented. Several studies with cell cultures or experimental animals have shown that the oxidative shift in the intracellular glutathione REDST is typically associated with cellular dysfunction. Complementary studies in humans have shown that oxidative changes in the plasma (i.e., extracellular) REDST are correlated with aging-related pathophysiological processes. The available evidence suggests that these changes play a key role in various conditions which limit the human life span. Several attempts have been made to ameliorate the consequences of aging by thiol-containing antioxidants, but this approach requires a detailed knowledge of the effects of thiol-containing antioxidants on cysteine homeostasis, REDST, and redox-sensitive signaling pathways of the host.