Oxidative stress can be described as an imbalance between pro- and antioxidant forces in favor of the former. Although acute oxidant production is likely necessary for cell signaling and inflammatory processes, as well as cellular adaptation, there are also deleterious consequences of chronic oxidative stress in many tissues. Indeed, oxidative stress has been implicated in the etiology and pathophysiological processes of diseases such as heart failure and chronic obstructive pulmonary disease (COPD). In addition, normal healthy aging is associated with a pro-inflammatory, pro-oxidant phenotype, which likely plays a role in the detrimental consequences of the aging process for many organ systems. Consequently, research examining the impact of oxidative stress on physiological function, and how the role of oxidative stress may change in pathophysiological conditions, is of utmost importance.
There are many sources of oxidant, or free radical production that may be dysregulated and contribute to oxidative stress. Perhaps most notably, free radicals are produced by electron leak from complexes within the mitochondrial electron transport chain. Here, the leaked electrons reduce molecular oxygen, producing the free radical superoxide in several physiological and pathophysiological states. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and xanthine oxidase have also been documented to contribute, via superoxide production, to oxidative stress, to varying degrees depending on the tissue examined. Numerous nonenzymatic and enzymatic antioxidants, including superoxide dismutase and catalase, exist within the mitochondria and cytosol to neutralize radical species and protect the cell. However, excessive oxidant formation can overwhelm these antioxidant defenses and lead to a chain of oxidation-reduction reactions, whereby additional radical species are generated, and cellular constituents, such as lipids, proteins, and DNA, are damaged.
Interestingly, acute exercise is associated with a transient increase in free radical production, and this pro-oxidant state is likely necessary for optimal contractile function of skeletal muscle, and is thought to confer beneficial adaptations following exercise. In health, therefore, upsetting the normal oxidant/antioxidant balance can attenuate exercise-training induced adaptations and may actually be detrimental to physiological function. Excessive oxidant production during exercise, however, has been linked to skeletal muscle dysfunction, increased fatigability, and may adversely impact exercise-induced hyperemia. Thus, the normally favorable pro-oxidant potential of exercise in health, may have deleterious consequences in populations predisposed to oxidative stress, such as patients with COPD and aged individuals.
Healthy aging is associated with a decline arterial function, primarily manifested as vascular endothelial dysfunction. Oxidative stress has been documented to contribute to this process, and as such, circulating markers of oxidative stress are inversely related to brachial artery flow-mediated dilation (FMD), an assessment of endothelial cell mediated vascular function. As a result, antioxidant administration has been documented to improve FMD in older individuals. Within the vasculature, mitochondria-derived free radicals as well as the upregulation of NADPH oxidase contribute to elevated superoxide production. Superoxide, in turn, reacts with endothelial cell-derived, vasodilatory nitric oxide, producing peroxynitrite; the resulting decrease in NO bioavailability impairs endothelially-mediated vasodilation. Furthermore, peroxynitrite may oxidize tetrahydrobyopterin, an essential cofactor for endothelial nitric oxide synthase (eNOS), causing eNOS uncoupling and additional superoxide production. Collectively, these processes, among others, are responsible for the observed impairment in vascular responsiveness with age to physiological and pharmacological stimuli that target the NO pathway.