The negative effect of reactive oxygen and nitrogen species (RONS) on human cells

Cellular Damage From RONS

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are sometimes collectively referred to as reactive oxygen and nitrogen species (RONS). RONS, and particularly the highly reactive hydroxyl radical, can react with many molecules in cells, including DNA, proteins, and lipids. The slow buildup of threats to mitochondrial and nuclear DNA over years of oxidative damage is thought to be a factor in aging. The relatively rapid turnover (breakdown and resynthesis) of proteins is also partly due to their susceptibility to oxidative damage and their need to ensure structural integrity to maintain optimal function. The free radical theory of aging was first proposed in the 1950s by the American scientist Denham Harman. It has continued to receive scientific support over the years, and it is now well established as an integral component of the aging process. Polyunsaturated fatty acids, which are important components of the phospholipids found in cell membranes, are particularly susceptible to damage by RONS. It has been known for more than 200 years that exposure of fats to air or oxygen will turn them rancid. This rancidity is caused by peroxidation of the fatty acids by RONS. During peroxidation, RONS such as the hydroxyl radical can react with the phospholipids by abstracting a hydrogen from one of the double bonded hydrogen molecules in the unsaturated fat, and in so doing, forming water. In the following equation, LH represents the lipid and OH* represents the hydroxyl radical, with the * representing the electron that is donated:

LH + OH* → L* + H2O

The lipid radical (L*) can then spontaneously propagate a chain reaction, which can result in peroxidation and breakdown of a number of phospholipids in a cell membrane and damage and disruption of cellular function. Similar damage also results from RONS-induced oxidation of proteins and DNA. As will be discussed in the following section, endogenous antioxidants (e.g., glutathione) and antioxidant vitamins (e.g., vitamin E) can help stop these reactions and prevent peroxidative damage to membranes and other cellular molecules, including proteins and DNA. Limiting oxidative stress may be important in limiting various conditions associated with aging (Pourova et al. 2010)

Protection From Reactive Oxygen and Nitrogen Species

Our bodies produce a number of endogenous oxidants that we have categorized as RONS. Added to this is a host of exogenous substances, such as pollution, ozone, automobile exhaust, solvents, pesticides, and cigarette smoke. Foreign molecules that may pose a hazard to us are generally categorized as xenobiotics. Some xenobiotics are free radicals or can produce RONS. Three approaches to maintaining control over RONS are principal. First, reducing the formation of or exposure to RONS and xenobiotics is an essential step. Second, our endogenous scavenging systems, including antioxidant enzymes and other antioxidant molecules, can scavenge those RONS already present. Finally, mechanisms in cells can upregulate antioxidant defenses in the face of persistent problems (Halliwell and Gutteridge 1999). A failure to maintain a balance between the formation of oxidants (e.g., RONS) and their removal by our various antioxidant systems produces a state known as oxidative stress. Powerful oxidants such as those just discussed can damage proteins, DNA, and the unsaturated fatty acid molecules in membranes. It is no wonder, then, that aging and a variety of diseases, such as cancers, heart disease, neurodegenerative diseases, and type 2 diabetes, have a relationship to oxidative
stress.

Figure 5.20 summarizes a number of important reactions that produce and remove ROS, such as SOD, catalase, and GPX. In addition to specific antioxidant enzymes, the body contains a number of nonprotein antioxidant molecules. For example, the essential nutrients vitamin C, vitamin E, and carotenoids such as b-carotene can by themselves scavenge free radicals. Minerals such as selenium, zinc, manganese, and copper are constituents of antioxidant enzymes. Finally, a host of non-nutrient antioxidants from a wide variety of foods of plant origin are important. The general name phytochemical is applied to those molecules that can function in our bodies as antioxidants. Fruits, vegetables, and grains, as well as common products derived from these such as tea and wine, are the major sources. Flavonoids, polyphenols, and lycopene are common examples of phytochemicals.

Exercise and Oxidative Stress

It is extremely difficult to directly measure free radical formation in a human being. Rather, we use indirect measures to point to increased or decreased ROS formation; from this, we make inferences. From a theoretical perspective, during exercise, we should expect a greater formation of superoxide, and therefore hydrogen peroxide and hydroxyl radicals, simply because of an increased flux through the electron transport chain with the increased need for ATP. Since we can greatly increase oxygen consumption and oxidative phosphorylation during exercise, it has been postulated that exercise can increase the generation of oxygen radicals and the possibility of oxidative damage or stress in muscles and other tissues.

Even though the proportion of oxygen that undergoes one- instead of four-electron reduction should decrease with increased activity of the electron transport chain, the fact that the overall flux may increase 10- to 20-fold above resting levels when we exercise should lead us to suspect an increase in superoxide formation. Bailey and colleagues (2003) were the first to actually measure increased formation of free radicals in venous blood of humans during a single-leg exercise task, using an expensive technique known as electron paramagnetic resonance spectroscopy. In this study, the researchers noted that the outflow of free radical species in the venous blood increased as exercise intensity increased.

The active muscle is not the only source of increased RONS formation during exercise. It has been observed that RONS production by white blood cells increases with exercise. However, the effect of RONS production by white blood cells is increasingly blunted the more trained the person is for the particular exercise activity (Mooren, Lechtermann, and Völker 2004). This is likely a consequence of increased antioxidant enzyme activity in white blood cells with training (Elosua et al. 2003). Some types of exercise, such as intense isometric or eccentric contractions, can create inflammation in muscle. Part of the inflammatory response is caused by neutrophils (white blood cell subset) accumulating in the muscle. As mentioned earlier, these cells produce superoxide that can cause damage within the muscle and can also produce other reactive species (Nguyen and Tidball 2003). Obesity, a major public health problem, is characterized by elevated markers of oxidative stress. When people who are obese perform either aerobic or resistance exercise, they produce higher levels of lipid peroxidation products than normal-weight individuals (Vincent, Morgan, and Vincent 2004). Acute feeding of high-fat diets also increases RONS production in rodents. Such a response suggests either an enhanced production or a reduced ability to scavenge free radicals, or both, in the obese state. Aging is also characterized by increased RONS production and oxidative stress, and increased RONS are associated with various diseases of senescence (Pourova et al. 2010).

Rested muscle produces RONS. When muscle becomes more active, formation of RONS increases. Having some RONS in muscle confers a benefit, since they are often important signaling agents that help regulate acute responses to exercise as well as positive adaptations to training in the muscles. Animal studies have demonstrated that inhibiting RONS production during exercise training actually blunts the signaling pathways that regulate adaptations to training, such as increasing mitochondria and aerobic capacity in skeletal muscle (Gomez-Cabrera et al. 2005). Important signaling pathways such as NFkB can help regulate antioxidant adaptations and mitochondrial synthesis consequent to endurance training. The inhibition of RONS production during exercise can blunt the response of these pathways and, consequently, positive training-induced adaptations (Powers et al. 2010). However, a study involving endurance training in humans failed to demonstrate a short-term negative effect of antioxidant supplements on endurance training adaptations (Yfanti et al. 2010).

Dietary antioxidants such as vitamin E and vitamin C have been touted as important for minimizing muscular damage from exercise. Athletes have often been encouraged to supplement their diets with a variety of antioxidants. While eating a diet high in antioxidants would likely have health benefits and could influence longer term effects of oxidative stress such as aging, studies have demonstrated that it is unlikely that large intakes of antioxidants will have significant physiological effects in diminishing exercise-induced muscle damage; instead, they may inhibit positive adaptations to training (McGinley, Shafat, and Donnelly 2009; Gomez-Cabrera et al. 2008). In addition, studies have demonstrated that antioxidant supplements taken during training may also suppress health-promoting benefits such as improved insulin resistance (Ristow et al. 2009).

Unaccustomed exercise and overtraining lead to muscle soreness, inflammation, and damage. This can be reduced by repeated exposure to the activity or through training. Attempts to limit the amount of stress by taking anti-inflammatory medication such as NSAIDs can potentially reduce oxidative stress in muscles that results from infiltration of white blood cells, such as neutrophils and macrophages. However, since the presence of white blood cells, particularly macrophages in muscle following exercise, is obligatory for the activation of muscle satellite cells and their role in stimulating muscle hypertrophy, reducing inflammation may also limit the amount of muscle repair, adaptation, and hypertrophy that would be induced by the training.

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