1. Overview of oxidative stress
Cellular function results in the production of oxygen-derived chemical species called reactive oxygen species (ROS), which have the ability to react with and damage different cellular structures, a process known as oxidation(1). The main site of production within cells is the mitochondria(2), the cellular structure responsible for energy production, but two enzymes are also capable of producing ROS: xanthine oxidase and NADPH oxidase(3). These have important functions within the human body:
- Xanthine oxidase, or xanthine oxidoreductase, enables the production of nitric oxide, necessary for the normal functioning of blood vessels(4).
- NADPH oxidase degrades bacteria within white blood cells (5) and participates in muscle adaptations to endurance training(6).
To limit the damage of ROS to cellular structures, the human body has numerous antioxidant defenses that are divided into enzymatic systems and non-enzymatic systems. Enzymatic systems consist of three enzymes: superoxide dismutase, glutathione peroxidase, and catalase, which transform ROS into harmless molecules for the body through a series of chemical reactions(7). Two stimuli allow an increase in these systems: an increase in chronic production of ROS(8) and training(9,10). However, these enzymatic systems do not have the capacity to handle all ROS produced by the body(3). These are then managed by non-enzymatic systems, primarily vitamins C and E(11,12), which will react with ROS and prevent them from reacting with other biological molecules. Unlike enzymatic systems, which can increase in response to increased ROS production, non-enzymatic systems can only increase through higher dietary intake and/or supplementation with supplements. Therefore, prooxidant and antioxidant systems work together to produce and maintain a concentration of ROS to ensure normal cellular function. An imbalance in this balance leads to oxidative stress in which ROS progressively damage cells. More precisely, oxidative stress is defined as a situation in which the concentration of ROS increases transiently or chronically, disrupting cellular metabolism, its regulation, and damaging various cellular components(13). The causes of this oxidative stress are multiple: 1) an increase in ROS production, 2) depletion of non-enzymatic antioxidant reserves, 3) inactivation of antioxidant enzymes, 4) a decrease in the production of enzymatic and non-enzymatic antioxidant systems, and 5) finally, a combination of at least two of these alterations(3).
2. Oxidative Stress in Chronic Pathologies
Oxidative stress contributes to the pathophysiology of numerous chronic diseases(14). Indeed, the physiological alterations of these diseases promote oxidative stress that will damage different cellular structures and thus significantly contribute to their pathophysiology. Furthermore, aging is also associated with high oxidative stress that actively participates in the physiological modifications observed in older individuals(15).
From a mechanistic standpoint, oxidative stress contributes to the pathophysiology of aging and many chronic diseases in several ways:
- Oxidative damage to different cellular structures triggers the activation of senescence mechanisms and programmed cell death (apoptosis) of organ-forming cells. This leads to cellular dysfunction and even cell death, resulting in organ function impairment.
Additionally, the activation of these mechanisms also leads to significant secretion of pro-inflammatory molecules, promoting low-grade inflammation that contributes to health degradation. - Produced ROS react with molecules involved in normal physiological functioning, disrupting these physiological processes.
To illustrate, some examples observed in various pathological conditions can be given. A prime example is the contribution of oxidative stress to the progressive onset of sarcopenia through the activation of protein degradation systems at the muscular level. Indeed, ROS will activate a molecule called NF-κB, which in turn is responsible for a series of chemical reactions ending with the activation of two molecules called MAFbx and MurF-1(16,17). Within the cell, these two molecules play a role in degrading dysfunctional proteins to maintain normal cellular function, and their activation leads to increased degradation of muscle proteins and thus a decrease in skeletal muscle mass. Besides sarcopenia, this mechanism is also responsible for the decrease in muscle mass observed in many chronic diseases including cancer(18), chronic obstructive pulmonary disease (COPD)(19), and heart failure(20). Oxidative stress is also strongly implicated in the pathophysiology of type II diabetes (T2D), especially in the dysfunction of β cells, which are responsible for insulin production, and in the muscles’ ability to absorb glucose(21). Specifically, the hyperglycemia present in T2D promotes ROS production at a systemic level, but also in β cells, activating apoptosis mechanisms. This leads to dysfunction or even death of β cells and altered insulin production, thus promoting hyperglycemia. Additionally, at the muscular level, oxidative stress also limits the production and expression of GLUT-4, a molecule whose function is to transport glucose into the muscle. In normal physiological functioning, GLUT-4 production is activated by insulin binding to the muscle so that it takes more glucose from the blood and reduces blood sugar. Therefore, in the presence of chronic oxidative stress, the ability of skeletal muscle to take up blood glucose is greatly reduced, also favoring hyperglycemia. In conclusion, oxidative stress significantly limits the body’s ability to control blood sugar and therefore promotes hyperglycemia, the main pathophysiological event in type 2 diabetes. Given this evidence, it seems necessary to monitor and quantify oxidative stress over time to avoid its harmful effects.
3. Measurement of Oxidative Stress
ROS are molecules that react extremely rapidly with other molecules in the human body, so it is not possible to directly measure ROS as done with blood tests. However, it is possible to assess indirect markers of oxidative stress either in blood or in different tissues, if a sample can be taken. These indirect markers include:
- The activity of the pro- and antioxidative enzymes described earlier, which can indicate the capacity to produce and protect against ROS, respectively.
- The concentration of non-enzymatic antioxidant systems, which also provides an indication of the body’s capacity to protect against ROS.
- The concentration of molecules produced by the oxidation of DNA, lipids, carbohydrates, and proteins, which allows estimating the amount of ROS not handled by antioxidant systems. Thus, the higher the concentration of these molecules, the higher the oxidative stress.
Although studying these markers allows estimating oxidative stress through an assessment of the pro/antioxidant balance, it is necessary to measure as many of these markers as possible to obtain an accurate evaluation. However, this method requires specific assays for each marker and an analysis time that may limit its use in common practice. Some laboratories offer to perform these analyses, but they are not covered by insurance, which also limits the monitoring of oxidative stress over time. Therefore, it is necessary to have measurement methods and/or markers that allow for chronic monitoring of oxidative stress.
4. Management of Oxidative Stress
The main objective of managing oxidative stress is to increase antioxidant systems, as it is easier to modulate antioxidant systems than prooxidant systems. This allows for compensating for increased ROS production and/or decreased antioxidant systems. Two main means can be used to increase antioxidant defenses: physical activity and nutrition.
In addition to its numerous beneficial effects, physical activity increases enzymatic antioxidant systems both systemically(10,22) and muscularly(23), allowing for better handling of ROS by the body. However, physical activity encompasses a wide range of activities, from walking to more intense resistance or strength training exercises, such as weightlifting. In a meta-analysis, de Sousa et al.(22) compiled 19 studies that measured the effects of different exercise modalities (Tai Chi/Pilates, resistance, and weightlifting) on enzymatic antioxidant systems and demonstrated that Tai Chi/Pilates-type activities and resistance exercises allowed for a significant increase in these systems. In contrast, weightlifting exercises did not allow for an increase in these systems. Therefore, with the aim of increasing enzymatic antioxidant systems, it is pertinent to propose moderate resistance physical activities or activities similar to Tai Chi and/or Pilates.
As mentioned earlier, non-enzymatic antioxidant systems are molecules that are not produced by the body and must be provided by diet. There are many molecules capable of reacting with ROS and having antioxidant activity in foods, with the two main ones being vitamin C(11) and vitamin E(24). Therefore, it may be interesting to favor foods rich in these two vitamins and/or other antioxidants in individuals with chronic diseases characterized by a limitation in exercise capacity and/or a decrease in enzymatic antioxidant systems.
However, in athletes, especially in endurance exercises, enzymatic antioxidant systems are highly developed, and although non-enzymatic systems remain indispensable, it is important to be careful not to have them too elevated. In fact, transient oxidative stress is necessary for training-related adaptations, and excessive supplementation could limit this transient stress and these adaptations.
Conclusion
Oxidative stress is a chemical phenomenon responsible for the degradation of numerous biological molecules and is implicated in the pathophysiology of many chronic diseases and aging. Although it is currently difficult to measure in common practice, it is still possible to limit it through physical activity and proper nutrition.
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