Stress

Oxidative stress occurs when highly reactive molecules called free radicals overwhelm the cell’s natural defenses against their attack. It is a battle that is fought in cells every day. Each cell in the body produces billions of free radicals a day, and some of them are used in physiological relevant reactions; oxygen itself is a free radical. Free radicals derived from oxygen are formed in the course of aerobic life when chemical bonds are broken during the production of energy in the mitochondria. Usually free radical reactions are controlled by free radical scavenging molecules that remove excess free radical scavenging molecules and antioxidants that neutralize free radicals. Chemical reactions with free radicals occur in all living organisms and can amplify their effects in the cell. Under conditions of oxidative stress, free radicals attack other molecules and form molecules that are foreign to cellular machinery (e.g., cross-linking of proteins makes them resistant to proteases), so they fail to turn over, accumulate, and eventually impair function by slowing down physiological processes. Free radicals are also produced in response to genotoxic stress by exposure to ionizing radiation from ultraviolet rays of the sun, chemical pollutants, and smoking.

Denham Harman first proposed the role of oxygen-derived free radicals in the aging process in 1956. An introduction to the concepts of free radical production and oxidative stress during aging is presented in a 1992 Scientific American article titled ‘‘Why Do We Age?’’ A more in-depth review by Toren Finkel and Nikki Holbrook appeared in Nature in 2000 as part of a series titled ‘‘Ageing.’’ During aging an imbalance occurs between production of free radicals and antioxidant defenses, resulting in an accumulation of free radicals and oxidative attack or damage to DNA, protein, lipids, membranes, and mitochondria. Although enzymes that repair proteins, lipids, and DNA are produced, the ability to repair cellular oxidative damage decreases with age, resulting in a reduced ability of old cells to withstand oxidative stress. The repair enzymes may be less efficient because they, too, are attacked or cross-linked and the whole system breaks down, resulting in impaired function and susceptibility to disease. Furthermore, free radicals build up over time and can damage the mitochondria, resulting in less energy production. The decrease in energy results in oxidative stress and a further increase in free radicals, which eventually damage other cellular components. Oxidative damage to organelles results in cellular injury and cell death. Free radical reactions with cellular components and cross-linking of proteins and DNA increase with aging. In addition, various types of stress, including injury and disease, amplify these reactions during aging. An effect of aging on oxidative damage to nuclear and mitochondrial DNA was first reported by Bruce Ames’s laboratory. Richardson’s group showed that the increase in DNA oxidative damage during aging was not due to inability to repair the damage but, rather, to increased sensitivity to oxidative stress. Richardson’s group also showed that caloric restriction could reduce the levels of DNA oxidative damage in aged rats, supporting the role of oxidative stress in the process of aging.

Evidence from mutants in fruit flies and nematodes, reviewed by Finkel and Holbrook, supports a role for molecules that are capable of scavenging free radicals or of decreasing the accumulation of free radicals and oxidative stress in extension of life span. Surprisingly, mutants with altered life span can have their normal life span restored by expression of the normal protein specifically in neurons, suggesting that neurons control how long an organism can live. Overexpression of superoxide dismutase, an enzyme that neutralizes the superoxide free radical, in motor neurons can extend life span by up to 48 percent in fruit flies that also exhibit resistance to oxidative stress, and partially rescues the normal life span of a short-lived superoxide dismutase null mutant in a dose-responsive manner. The long life span of age-1 and daf-2 mutants rescued with expression of these genes only in neurons is also associated with higher levels of free-radical scavenging enzymes and protection of neurons from oxidative damage. According to Gabrielle Bouliame, whose group performed the experiments on fruit fly motor neurons, it is possible that these neurons, through neuroendocrine signals, regulate the functional reserve or adaptive capacity of tissues in the organism, which in turn influences life span.