Free Radicals and the Oxygen ParadoxOxidative Stress in Biology, Aging and Disease

The unavoidable consequence of living in an aerobic environment, and utilizing oxygen for (mitochondrial) ATP production, is the accidental generation of reactive oxygen species. This is sometimes known as the ‘Oxygen Paradox’, which reminds us that oxygen is hard to live with, but even harder to live without! It has... read morebeen estimated that some 3-5% of all the oxygen we breathe each day is reduced by one electron, in the mitochondrial electron transport chain, to form the superoxide anion radical, O2* - (usually known as superoxide). Superoxide can be reduced by a second electron to form hydrogen peroxide (H2O2) and by a third electron to form the highly reactive hydroxyl radical (HO* ). The phagocyte enzyme myeloperoxidase combines H2O2 with chloride ions to form the caustic hypochlorous acid (HOCl), and the widely distributed enzyme nitric oxide synthase generates nitric oxide (NO*), which reacts with O2* - to form the even more reactive peroxynitrite (ONOO -).

Controlled free (and caged) radical reactions are utilized in mitochondrial electron transport to generate ATP and NO* is essential for vasodilation. Very low (nM) concentrations of H2O2 stimulate mitosis and slightly higher concentrations of reactive oxygen/nitrogen species are involved in numerous signal transduction pathways. The overall oxidation/reduction (redox) state of a cell may actually control several important metabolic pathways.

At higher (μM to mM) concentrations H2O2 and HOCl are necessary for the bactericidal activity of phagocytes such as neutrophils, macrophages and monocytes. Adventitious reactions of free radicals and other reactive oxygen/nitrogen species, however, are a constant source of damage to all living organisms. Antioxidant enzymes such as the superoxide dismutases and the glutathione peroxidases, are able to inactivate many of the biologically relevant reactive oxygen species.

Similarly, a diet rich in the antioxidant vitamin C is necessary in order to avoid scurvy and the antioxidant vitamin E is necessary in order to avoid extensive membrane lipid damage. Many researchers and clinicians are also exploring the possible health benefits of dietary supplements such as flavonoids, polyphenols, carotenoids and various components of wines, olive oils, fruits and vegetables. Although the antioxidant enzymes and compounds diminish the oxidant load to which cells and tissues are exposed, proteins, lipids, sugars, RNA and DNA are all still subject to oxidative damage and must be continually repaired, or the oxidized molecules degraded and replaced, in order to avoid decay. In addition to the antioxidant enzymes and compounds, and the oxidant repair/removal systems, our cells are also able to alter the expression of more than 30 defense and repair genes in order to adapt to ever changing levels of oxidative stress.

In aging, and in many diseases, the ability of cells and tissues to cope with reactive oxygen and nitrogen species, and to remove or repair the damage they do, is diminished or severely compromised. Thus, aging is accompanied by a significant decline in damage removal and repair capacities and adaptive responses. A number of diseases involve significant inflammation and extensive tissue damage from reactive oxygen/nitrogen species. Such diseases include (but are not limited to) rheumatoid arthritis, Alzheimer disease and Parkinson disease. The cardiac damage that occurs during a heart attack and much of the brain damage that occurs during a stroke, involve reactive oxygen/nitrogen species generated during ischemia and reperfusion of the affected tissues. The damage to lens proteins in the eye that characterizes cataract is caused by photo-oxidative reactions. Many degenerative liver diseases involve a significant oxidative component, as does diabetes. The devastating effects of certain infectious micro-organisms, such as trypanosomes, are partly mediated by oxidative stress.

Not all reactive oxygen and nitrogen species cause damage or disease. Mitochondrial electron transport and regulation of signal transduction pathways and mitosis have already been mentioned above. In addition, spermatozoa appear to use peroxides in membrane protein cross-linking reactions that are actually essential to normal function. Similarly, reactive oxygen and nitrogen species generated during endurance exercise training may actually mediate many of the positive physiological adaptations associated with exercise training. Finally, the vasodillatory effects of NO* have been successfully exploited in the treatment of male erectile dysfunction.