3.1. Physical Exercise and Oxidative Stress
Physical exercise (EXR) is widely acknowledged for its extensive benefits on human health, positively influencing multiple body systems and thereby reducing the risk of mortality associated with various chronic diseases, including cardiovascular diseases, cancer, metabolic disorders, and conditions of the central nervous system [
13]. This crucial health intervention significantly improves cardiovascular capacity, cognitive function, immune activity, endocrine balance, and musculoskeletal health, providing a solid foundation for promoting well-being in individuals of all ages.
The beneficial effects of EXR are partly mediated through the body’s adaptation to redox homeostasis, neutralizing the sudden increase in reactive oxygen species [ROS]—a key element in the pathogenesis of many chronic diseases. Furthermore, physical exercise initiates the release of a variety of humoral factors, such as proteins, microRNAs (miR), and DNA, transported via extracellular vesicles (EVs). These EVs exhibit changes in their load in response to oxidative stress and physical activity, indicating a pathway through which EXR can positively influence antioxidant enzyme pathways and mitigate the oxidative stress environment [
13].
Divided into endurance and resistance exercise categories, EXR represents a source of voluntary body movement generated by skeletal muscles that leads to energy consumption. This type of activity demands the body to quickly adapt to increased metabolic and physiological requirements, demonstrating the flexibility and responsiveness of the cardiovascular and muscular system to effort [
14].
Following exercise, cardiomyocytes and skeletal muscle cells undergo adaptive hypertrophy, thereby improving oxygen utilization capacity and reflecting an increase in cardiorespiratory fitness (CRF). This adaptation is measured through the increase in maximal oxygen consumption (VO2max), which can rise by 40–50% in response to EXR, offering significant benefits for cardiovascular health and serving as prevention for individuals at increased risk of developing cardiovascular diseases and for patients with pathological conditions such as heart failure [
15,
16,
17].
Beyond cardiovascular improvements, EXR has a remarkable positive impact on cognitive function, enhancing working memory, attention, processing speed, and inhibitory control. These cognitive benefits, affirmed by multiple studies, are attributed to the increase in aerobic capacity induced by exercise, which favors cognitive improvement through enhanced synaptic plasticity, highlighting the essential role of EXR in supporting mental health and preventing cognitive decline [
18,
19].
High-intensity physical exercises have been shown to modulate the response of the hypothalamic–pituitary–adrenal (HPA) axis, crucial in stress regulation. This modulation includes inhibiting cortisol release, a critical hormone in the stress response that, under normal conditions, mobilizes glucose to provide energy to the body. Inhibiting this mechanism at the end of exercise activities suggests a protective effect against additional stress, thus underlining the therapeutic role of exercise in stress management and in improving metabolic health, including in the context of disorders related to obesity and insulin resistance, precursors of type 2 diabetes [
20,
21].
Furthermore, physical exercise stimulates immune function through the release of anti-inflammatory cytokines, with variations determined by the intensity and duration of the exercise [
22]. This ability of exercise to regulate the immune response and promote an anti-inflammatory state underscores its importance in maintaining health and preventing diseases.
Exercise also contributes to improving muscular endurance and increasing cells’ capacity to resist oxidative stress. By enhancing the contractile properties of muscles and promoting angiogenesis, physical exercise supports positive muscular adaptations, essential for physical performance and resilience to injuries [
23,
24].
The increased energy demand during exercise is met by optimizing mitochondrial function, which, under the influence of exercise, enhances its biogenesis and cellular metabolism. This adaptation increases ATP availability, thereby supporting performance and endurance to effort [
25,
26]. In this context, mitochondria, along with NADPH oxidase and xanthine oxidase, serve as endogenous sources of reactive oxygen species (ROS), essential for cellular signaling and maintaining homeostasis [
27].
The reactive oxygen species generated during exercise can also originate from external sources to muscle cells, including immune cells and the endothelium. The increase in ROS concentration can induce oxidative stress, negatively affecting cellular function and metabolic balance [
28]. However, regular exercise induces adaptations to redox-sensitive pathways, known as “redox homeostasis”, which contribute to protection against the harmful effects of oxidative stress [
29].
These adaptations include the activation of complex signaling pathways and antioxidant defense mechanisms, among them the increased transcription of genes encoding key antioxidant enzymes, such as catalase, superoxide dismutase, heme oxygenase-1, and NAD(P)H quinone dehydrogenase 1, crucial in neutralizing ROS [
30,
31]. Nuclear factor erythroid 2 (NRF2), a central element in the regulation of antioxidant pathways, is activated by exercise, promoting the increased expression of antioxidant enzymes and, therefore, a beneficial adaptation to oxidative stress [
32].
Recent studies have revealed that training periods in athletes are associated with an increase in the body’s antioxidant capacity and activation of detoxification processes, suggesting a positive impact of physical exercises on redox homeostasis [
33]. For instance, a study conducted on a group of elderly and overweight individuals who performed aerobic dance training demonstrated a significant decrease in serum levels of malondialdehyde (MDA), a well-known marker of oxidative stress [
34].
Research indicates that regular physical activity promotes redox homeostasis through the activation of complex antioxidant pathways, leading to a decrease in oxidative stress markers [
13]. This adaptation to redox homeostasis has the potential to bring various health benefits in different health contexts and diseases.
Tissue crosstalk, essential for triggering adaptive effects in multiple tissues, is not yet fully understood in terms of the specific molecular mechanisms that facilitate communication between organs and coordinate the positive effects of physical exercises [
35]. However, it is known that, during exercise, skeletal muscles and other cell types can release peptides and nucleic acids that can be taken up by other organs.
These effort-induced factors, collectively termed “exerkines”, mediate systemic adaptations to exercise [
36]. Unlike myokines and adipokines, which are peptides and miRNAs produced and secreted by skeletal muscles and fat deposits, “exerkines” include all exercise-induced humoral factors (peptides and RNA species) that are expressed, produced, and secreted by all tissues and organs into the bloodstream to promote inter-organ communication and enhance the systemic benefits of physical exercises [
37].
It is important to note that proteins without a canonical secretion-targeting sequence, proteins whose secretion depends on external stimuli, and molecules that may be unstable in the extracellular environment are preferentially secreted through extracellular vesicles (EVs) [
38]. EVs are small membranous structures secreted by various cells as information vehicles and can transport diverse biomolecules, including proteins, lipids, and nucleic acids [
39]. Recently, it has been shown that EVs play a significant role in the beneficial effects mediated by physical exercise [
40].
Produced extracellular vesicles (EVs) are introduced into the biological fluid (peripheral blood, saliva, and amniotic fluid) to reach their specific target where they release their load [
41]. EVs are typically defined by specific surface markers. In this review, we highlight the role of EVs in the response to oxidative stress and the modulation of redox homeostasis, with a particular focus on the role of EXR. The latter has been shown to have beneficial effects on various organs and tissues by attenuating oxidative stress and promoting the adaptation of redox homeostasis. This adaptive process involves the activation of complex molecular pathways, including transcription factors (NRF2), antioxidant enzymes [AOEs], and non-enzymatic molecules, resulting in a reduction in oxidative stress levels.
The collective evidence from these studies strongly supports the positive impact of EXR on redox homeostasis at both the cellular and molecular levels. The EV load, modulated by EXR, appears to enhance antioxidant capacity, reduce oxidative stress, and activate detoxification processes, all contributing to maintaining a balanced redox state. Understanding the effects of the reduced oxidative stress environment mediated by regular EXR is crucial for preventing various diseases and aging processes. Indeed, an increase in ROS can lead to a reduction in nitric oxide (NO) availability, causing vasoconstriction and promoting hypertension [
42].
Furthermore, the imbalance in redox homeostasis is a key hallmark of many diseases, such as cancer, Alzheimer’s, and metabolic disorders. Therefore, understanding the effects of exercise on redox homeostasis may have significant implications for optimizing exercise interventions, as well as for promoting general health and well-being. Various types of exercises, such as HIIT, have shown considerable effects on redox homeostasis in various human cohorts [
43].
The complex interaction between EXR, EVs, and their load is highlighted. The evidence reported in this review suggests that EVs released into circulation during physical activity have an interesting antioxidant role, warranting further investigation. Additional research is needed to elucidate the specific mechanisms underlying these effects and to explore the potential therapeutic applications of the effort-induced modulation of EV load. Furthermore, these studies can help us discover additional interconnections and expand our understanding of the complex relationship between EVs and oxidative stress and how interventions, such as EXR, can lead to a more effective response.
Regular exercise enhances endurance and strength, which are essential for meeting physical demands in combat situations or extended missions. Additionally, physical exercise plays a crucial role in maintaining mental health by reducing the impact of psychological stress encountered in combat conditions [
44]. Weight management, improving insulin sensitivity, and regulating glucose levels are vital aspects in preventing and managing metabolic syndrome and type 2 diabetes. Studies have shown that physical fitness programs can significantly reduce risk factors for metabolic syndrome among military personnel [
45].
Structured workouts and organized sports activities, forms of group physical exercise, can significantly improve communication and cooperation among unit members. These activities not only support physical fitness but also create opportunities for team members to work together towards common goals, essential for unit cohesion [
46]. Increased cohesion in military units, stimulated through joint exercises, can provide significant protection against the adverse effects of military stress. Soldiers in units with strong cohesion report improved physical and psychological well-being and greater satisfaction with their military careers compared to those in less cohesive units [
47].
Enhancing cohesion during Basic Combat Training is associated with reduced psychological stress and improved stress management, contributing to the promotion of positive morale [
48]. In the infantry, the ability to perform long marches under full gear is crucial, and endurance training is essential. A study highlighted the importance of integrating endurance training with strength training to optimize soldiers’ overall physical performance, demonstrating the superiority of these combined training methods [
49].
Special units, which often perform tasks requiring rapid strength and agility, can greatly benefit from training programs that emphasize explosive strength and speed. A recent study examined the effects of linear periodized resistance training on cadets at a naval academy, revealing significant improvements in muscular strength, agility, and reaction time, underlining the efficacy of this type of training for improving specific conditioning needs [
50].
Wireless distributed sensor systems, such as body sensor networks, play a crucial role in the continuous monitoring of stress and physiological responses during intense training, providing a detailed perspective on the impact of stress on the body [
51]. Modern technology, including wearable devices and biometric sensors, enables the real-time monitoring of oxidative stress biomarkers and other physiological parameters [
52]. This technological approach facilitates the dynamic adaptation of training programs, optimizing both physical performance and oxidative stress management, allowing military trainers and doctors to customize workouts to maximize benefits and minimize risks [
51].
Improving physical mobility and functionality: A recent study on older veterans with PTSD demonstrated that participation in a physical exercise program significantly enhances physical function and reduces clinical risk factors for chronic diseases. Participants in the exercise group showed notable improvements in aerobic endurance and physical performance, highlighting long-term positive effects on health and quality of life [
53]. For a summary of the relevant studies and findings discussed in this chapter, see
Table 2.
3.2. Diet and Oxidative Stress
The ketogenic diet, characterized by high fat, low to moderate protein, and low carbohydrate intake, adheres to a macronutrient ratio of approximately 3–4:1, with the distribution being 90% fats, 6% proteins, and 4% carbohydrates. This nutritional approach was initially developed as a non-pharmacological therapy for epilepsy in 1923 [
54]. The central mechanism of the ketogenic diet aims to optimize mitochondrial metabolism, demonstrating a link between its practice and the improvement of mitochondrial function, as well as a significant reduction in oxidative stress [
55].
At the heart of the ketogenic diet is the production of ketone bodies, such as beta-hydroxybutyrate (bHB) and acetoacetate (AA), resulting from enhanced fatty acid oxidation in the liver. These precursors to acetyl CoA mark the initial stage of the citric acid cycle. Beta-hydroxybutyrate, the most studied ketone body, is recognized for its ability to reduce the production of reactive oxygen species (ROS), enhance mitochondrial respiration, and stimulate the cell’s endogenous antioxidant system [
54].
Oxidative stress is defined as a chemical imbalance between the production of free radicals and the antioxidant system’s capacity to neutralize these reactive compounds. This imbalance is characterized by the excessive production of free radicals and reactive oxygen species (ROS) as cells use oxygen to generate energy, with antioxidants serving to counteract and protect against these harmful species [
56]. The primary endogenous sources of free radicals include mitochondria, while sunlight exposure and smoking are relevant external sources.
Damage to biomolecules and cells, including deoxyribonucleic acid (DNA), lipids, and proteins, is a direct consequence of the imbalance between antioxidants and free radicals, leading to sustained oxidative stress and potential critical injuries to cellular structure. This can facilitate the onset of somatic mutations and neoplastic transmutations due to long-term ROS production in a state of prolonged oxidative stress.
Oxidative stress results from the interaction between the production of free radicals and the body’s antioxidant defense mechanisms, leading to excessive production of reactive oxygen species. This imbalance leads to oxidative stress and triggers a wide range of diseases [
57]. Thus, the ketogenic diet, by promoting an efficient energy metabolism and reducing oxidative stress, offers an interesting framework for studying dietary interventions in the context of managing oxidative stress, highlighting its therapeutic potential in various pathological states and in enhancing general health.
The pathogenesis of oxidative stress is closely linked to inflammation, which can have multiple sources, including microbial and viral infections, exposure to toxic chemicals, autoimmune diseases, chronic obesity, and alcohol and tobacco consumption. It is observed that the risk of developing cancer increases as inflammation persists over long periods [
56].
Inflammation can be classified into two phases: acute and chronic. Acute inflammation represents the initial phase, characterized by a short duration and often beneficial to the body, initiated by the activation of the immune system. On the other hand, chronic inflammation is long-lasting and can increase one’s susceptibility to various chronic diseases, including cancer [
58].
During the inflammatory process, mast cells and leukocytes are recruited to the site of injury, leading to a “respiratory burst” by increasing oxygen uptake and, consequently, the release and increased accumulation of reactive oxygen species (ROS) in the affected area [
59].
Reactive oxygen species (ROS) are naturally produced as a result of cellular metabolism; however, oxidative stress is described as a pathological condition when the balance between the production of oxidants and detoxification processes favors a pro-oxidant state, overwhelming antioxidant defense and resulting in the accumulation of reactive species that can damage nucleic acids, proteins, and membrane lipids [
60].
The DNA repair system contributes to maintaining the balance between the generation and elimination of ROS. In the context of cellular protection against radicals, antioxidants prove to be more specific and efficient. These antioxidants can be of endogenous or exogenous origin, enzymatic or non-enzymatic, forming a complex and multifunctional antioxidant system [
56].
The action mechanism of the ketogenic diet leads to a decrease in blood glucose levels and an increase in blood ketone levels, thus contributing to the inhibition of tumor development in both humans and animals. This effect is partly due to the fact that ketone body metabolism protects cells against oxidative damage by inhibiting the production of reactive oxygen species (ROS) and by enhancing the cell’s endogenous antioxidant capacity [
61]. A study on healthy women highlighted that adopting a ketogenic diet for 14 days, involving dietary restrictions, resulted in weight loss and a marked improvement in total antioxidant status, without inducing oxidative stress in the blood [
62].
Although this study utilized the ketogenic diet without a control group, making it challenging to determine whether the antioxidant effects were directly attributed to the diet or the weight loss resulting from caloric restriction, it was observed that the ketogenic diet favored the production of the antioxidant glutathione (GSH) [
63]. The beneficial effects of the ketogenic diet also extend to the reduction in inflammation and thermal nociception, considering its ability to limit the production of reactive oxygen species (ROS) and to improve the expression and activity of mitochondrial uncoupling proteins [
63].
A crucial aspect of the ketogenic diet is related to the improvement of mitochondrial function, facilitated by ketogenic metabolic activity and the reduction in oxidative stress [
56]. Specifically, the activity of beta-hydroxybutyrate (β-HB), the most studied ketone body, is known for reducing ROS production [
64]. Β-Hydroxybutyrate also stimulates mitochondrial respiration by activating the nuclear factor erythroid 2-related factor [Nrf2], which in turn initiates the cell’s endogenous antioxidant system. Nrf2 plays an essential role in promoting the synthesis of vital enzymes for regenerating active endogenous antioxidants, such as glutathione reductase, thioredoxin, and peroxiredoxin [
65].
Furthermore, β-HB acts as an endogenous inhibitor of class I and IIa histone deacetylases (HDACs), facilitating the transcription of genes responsible for detoxification, including catalase, mitochondrial superoxide dismutase (mn-SOD), and metallothionein, providing protection against oxidative stress [
66]. The ketogenic diet also modulates the intracellular NAD+/NADH ratio, recognized for its protective effects against ROS, constituting another mechanism through which the ketogenic diet exerts a protective effect against oxidative stress [
67].
By limiting glucose availability for glycolysis and, thus, the synthesis of pyruvate and glucose-6-phosphate, which could fuel the pentose phosphate pathway for the production of essential NADPH in reducing hydroperoxides, the ketogenic diet restricts glucose metabolism. This restriction encourages cells to generate energy through mitochondrial lipid metabolism, thereby forcing cancer cells to experience oxidative stress [
54].
Studies have highlighted the ketogenic diet’s potential to improve mitochondrial antioxidant status, providing protection to mitochondrial DNA (mtDNA) against oxidative damage. mtDNA, being highly sensitive to reactive oxygen species (ROS), can benefit from protection in the context of the ketogenic diet, as demonstrated in an animal study led by Yang et al. In this study, rats fed a ketogenic diet did not show significant mtDNA damage, while in the control group, the frequency of oxidative lesions was significantly higher at all time points assessed (
p < 0.0001) [
68].
Moreover, ketogenic diets have been associated with decreased levels of DNA damage and rapid changes in the activity of PARP-1 enzymes and sirtuin, suggesting that these diets could provide effective protection to healthy cells against oxidative and metabolic damage [
69]. It was observed that the ketogenic diet exerts specific effects on malignant brain tissue, influencing the expression of genes related to ROS level regulation [
70].
The specific ketone bodies of the ketogenic diet, beta-hydroxybutyrate and acetoacetate, contribute to reducing ROS production, thus demonstrating the diet’s ability to modulate oxidative stress in a beneficial manner [
71].
This diet also has a positive impact on antioxidant capacity, promoting the enhanced biosynthesis of the antioxidant glutathione (GSH). The findings obtained by Stafford et al. indicate that the ketogenic diet could be considered a promising strategy for the prevention and treatment of certain pathological conditions, including cancer. However, due to current limitations regarding the availability of controlled studies exploring the effects of the ketogenic diet on oxidative stress and cancer, further research is essential to solidify the evidence base on the anticancer benefits of this dietary approach [
71].
Oxidative stress levels in the body are influenced by both individual and environmental factors, where diet plays a significant role and represents an easily modifiable aspect [
72]. The importance of diet in the development and progression of chronic diseases is underscored by its direct association with oxidative stress, a common pathogenic mechanism of these diseases [
73]. A study conducted by Kong et al. on 335 Chinese citizens, aged over 60 years and without major conditions or recent treatments that could influence the measurement of oxidative stress, explored this link [
74], and the participants’ dietary diversity scores showed a preference for cereals over fish, reflecting similar findings from other regional research [
75].
The analysis highlighted that a higher-quality diet is associated with improved Total Antioxidant Capacity (T-AOC), suggesting that healthier eating can enhance antioxidant levels in the body. The results confirm that a high-quality diet corresponds with better levels of oxidative stress markers. Participants who followed a higher-quality diet presented a higher T-AOC, indicating a better balance of oxidative stress. This underscores the importance of dietary diversity and quality in managing oxidative stress, especially among the elderly population [
74].
The connection between diet and oxidative stress is strengthened by findings such as the beneficial effects of cherry juice on inflammation and oxidative stress biomarkers, highlighting the diet’s capacity to modulate these processes [
76]. Previous studies have indicated oxidative stress markers as early indicators of the risk for chronic diseases, and the Mediterranean diet has been associated with a reduction in this risk, unlike diets high in fats [
73,
77].
Research conducted on mice has indicated that the ketogenic diet may reduce mid-life mortality and enhance memory performance in old age through mechanisms including decreased insulin levels and protein synthesis, as well as increased mitochondrial efficiency. These effects could have significant implications for human resilience in survival scenarios [
78]. Another study on mice demonstrated that the ketogenic diet improves mitochondrial function and reduces oxidative stress, contributing to better energy efficiency and the maintenance of muscular integrity under conditions of prolonged physical stress [
79].
The ketogenic diet (KD) has been successfully applied among military personnel, showing promising results in managing energy and endurance—crucial elements for long-term missions or extreme conditions. LaFountain and colleagues observed that military personnel who adopted a KD experienced significant reductions in weight, body fat, and particularly visceral fat, without compromising the essential physical performance adaptations necessary for their training. These findings suggest that KD could improve overall health and readiness without negatively affecting the physical capabilities required for fulfilling their roles [
80].
KD supports the maintenance of physical performance and cognitive function in challenging conditions through its stable and efficient energy source derived from ketone bodies. This is particularly valuable in situations where traditional high-carbohydrate diets may be impractical [
81]. In scenarios of limited access to food, simplifying the diet by focusing on fat consumption can facilitate the management of food resources, making the ketogenic diet a practical and sustainable option. For a summary of the relevant studies and findings discussed in this chapter, see
Table 3.
3.3. Antioxidants
Over the years, the perception of antioxidant supplements in the field of nutrition associated with physical exercise has significantly fluctuated, spanning a wide spectrum from being considered essential to being labeled as potentially harmful. Initially, about 35 years ago, in the context of discoveries regarding the production of reactive oxygen, nitrogen, and sulfur species during physical activity, antioxidant supplements were seen as a crucial element for combating the harmful effects of exercise-induced oxidative stress [
82]. However, over the last decade, this opinion has radically changed, with numerous studies and review articles arguing against antioxidant supplementation during training, highlighting that it could inhibit beneficial molecular, biochemical, and physiological adaptations [
83].
In research conducted by Merry and colleagues, a considerable interindividual redox variability was observed, both at rest and in response to acute exercise. This heterogeneity was highlighted through the analysis of antioxidant biomarkers, such as glutathione and vitamin C, and oxidative stress markers, like F2-isoprostanes and carbonylated proteins [
84]. This diversity among individuals provides a new perspective on the mixed results obtained in studies on the effectiveness of antioxidants as ergogenic aids. It was found that antioxidant treatments were usually administered to young and healthy individuals with normal levels of antioxidants or oxidative stress markers, which may explain why some participants did not experience significant benefits from these treatments [
85].
Building on this finding, Michailidis adopted an innovative approach in biomedical research, known as stratified purposive sampling, to identify subgroups of individuals who might benefit most from antioxidant treatments. This strategy proposes a “stratified” approach to supplementation, personalizing the administration of antioxidants based on the specific redox profile of each individual [
86]. Thus, the deficient antioxidant would be administered individually, contrary to the conventional practice of the unselective administration of antioxidants, whether it is a single type of antioxidant or a combination.
This “data-focused” methodology suggests that the impact of antioxidant supplements on adaptations and responses to exercise varies depending on the initial redox state of the individual. Therefore, the ergogenic benefits of antioxidant supplements become evident only in individuals with initially low levels of antioxidants or with high levels of oxidative stress [
86]. This perspective not only balances the discussion around antioxidant supplements but also provides a clear direction for future research and for optimizing nutrition strategies in the context of physical exercise, highlighting the importance of personalizing nutritional interventions based on individual redox needs.
A relevant study in the military context explores the impact of training on oxidative stress and the role of antioxidant supplementation in this process. One specific example is research that investigates how antioxidant supplementation influences oxidative stress induced by physical training, concluding that although antioxidants can reduce oxidative stress, they may also interfere with some beneficial physiological adaptations to training, such as the enhancement of endogenous antioxidant capacity [
87].
Antioxidants neutralize free radicals and protect against oxidative stress, reducing the potential for cellular damage and improving recovery. This is crucial in challenging environmental conditions where physical and chemical stress is intensified. A recent study examined oxidative stress markers and muscle damage in military cadets after an intensive 10-day training course followed by a one-month recovery period. The results showed an increase in myoglobin levels and a higher glutathione index, with significant improvements after the recovery period, highlighting a positive impact of the antioxidant system before and after training [
88].
Antioxidant supplements are often used to mitigate negative responses to oxidative stress induced by intense training. However, it is important to note that while antioxidants can reduce oxidative stress biomarkers, they can also interfere with certain desired training adaptations, such as increased endogenous antioxidant capacity and mitochondrial biogenesis, as suggested by research published in
The Journal of Physiology [
84].
More research is necessary to produce evidence-based guidelines regarding the use of antioxidant supplements during training. The current recommendation is that an adequate intake of vitamins and minerals through a varied and balanced diet remains the best approach for maintaining optimal antioxidant status among physically active individuals [
87].
The use of wearable devices and other advanced technologies allows for the continuous monitoring of oxidative stress biomarkers, facilitating the adjustment of antioxidant supplementation according to individual needs, and offering a personalized and dynamic approach to oxidative stress management [
51].
Nutritional education is essential in promoting the correct and effective use of antioxidant supplements. Informing military personnel about the benefits and potential risks of antioxidant supplementation is crucial for adopting a balanced and well-informed approach. One study reveals that the use of antioxidant supplements is widespread among military personnel, highlighting the need to provide adequate education to ensure their safe and effective use [
89].
A relevant example is the study conducted on military firefighters in Brazil, which investigated the metabolic response and certain oxidative stress markers in plasma and erythrocytes of firefighters supplemented or not with resveratrol (RES) for 90 days (100 mg/day). Analyses conducted before and after a typical physical fitness test used to induce oxidative stress showed that RES supplementation had no liver consequences compared to the placebo group. Although supplementation reduced levels of IL-6 and TNF-α after the fitness test, the effect on other oxidative stress biomarkers was not significant, suggesting that an antioxidant regimen might have an anti-inflammatory effect but not necessarily a major impact on antioxidant defense systems under conditions of moderate stress [
90].
A study investigated the long-term effects of antioxidant supplementation, highlighting that antioxidants can influence the process of “intrinsic” aging as well as various pathological processes associated with aging. Long-term supplementation with vitamin E, for example, was associated with improvements in immune function in older subjects and the reduction of atherosclerosis risk, these benefits having direct implications for the long-term health of military personnel [
91]. For a summary of the relevant studies and findings discussed in this chapter, see
Table 4.
3.4. Antioxidant Supplements: Panacea, Harmful, or Neutral?
In recent decades, the role of reactive oxygen species produced during physical exercise has been profoundly re-evaluated. Initially seen as harmful by-products, these molecules are now recognized as essential signals that promote positive adaptations to exercise, such as mitochondrial biogenesis, angiogenesis, and neurogenesis, thereby contributing to the enhancement of physical performance. This new perspective highlights the complexity of the mechanisms through which exercise influences health and performance [
92,
93].
In this context, antioxidant supplements have traversed a controversial path, from being considered essential for combating the harmful effects of oxidative stress to being viewed as potentially inhibitory of the beneficial adaptations induced by exercise. The majority of relevant studies, including in vivo ones, have explored the use of antioxidant agents, reaching a consensus that supplementation either does not influence physical exercise adaptations or could even obstruct the beneficial effects of reactive species, resulting in a more reductive state than optimal and impeding adaptations to effort [
94,
95].
Similar observations regarding the neutral or even negative effects of antioxidant supplementation have been made in the context of the progression of diseases such as cancer and diabetes, as well as in increased mortality, contributing to the negative reputation of antioxidant supplements in the field of nutrition and biomedicine [
96].
Research conducted by Sayin and colleagues revealed significant interindividual variability in redox responses both to antioxidant stress and to oxidative stress after acute exercise, in a sample of 100 participants. This heterogeneity was partially attributed to the baseline values of the measured biomarkers, suggesting that individual differences in redox state might play a key role in determining the effectiveness of antioxidants as ergogenic aids [
97].
Furthermore, a study by Margaritelis and colleagues found that this redox individuality, assessed through exercise-induced changes in oxidative stress biomarkers such as F2-isoprostanes, could partially predict an individual’s aerobic and anaerobic trainability [
98]. Based on this documented redox variability, it was proposed that baseline levels of antioxidants could also influence the physiology of physical exercise and nutritional outcomes. Therefore, Margaritelis and colleagues investigated in another study the impact of antioxidant supplementation, such as vitamin C and N-acetylcysteine (NAC), on exercise adaptations, finding that the ergogenic benefits of antioxidant supplements are evident only in individuals with specific deficiencies or with initially high levels of oxidative stress [
99].
The exploration of the relationship between antioxidant supplements and oxidative stress in the context of physical exercise has evolved significantly, involving a reconsideration of the role of these supplements not only in the field of sports nutrition but also in general health. Recent research emphasizes that the effectiveness of antioxidant supplements in reducing oxidative stress and promoting health is significantly influenced by the individual’s initial redox state. This finding was exemplified by the study of Block and colleagues, which demonstrated that the benefits of supplementation with vitamin C or E on plasma levels of F2-isoprostane are limited exclusively to individuals with initially high levels of oxidative stress. Based on these results, the authors suggested a threshold of 50 μg F2-isoprostanes/mL in plasma as a benchmark for participant eligibility in studies targeting the use of antioxidants. This perspective underscores the importance of a more personalized approach in the research and application of antioxidant supplements, indicating that the response to antioxidant treatment can vary significantly depending on the person’s initial redox profile. Thus, to effectively assess the potential benefits of personalized nutrition, examining individual variability in responses to nutritional interventions is crucial. However, conducting such an assessment presents significant challenges, as precision nutrition, a pillar of personalized medicine, largely relies on identifying how an individual’s genetic characteristics influence the response to various nutritional interventions or supplements, such as nutrigenetics [
100,
101].
In this context, it is essential to consider factors such as dietary habits, physical activity level, and microbiome, which can significantly influence how an individual responds to nutritional intake [
102]. In practice, nutritional advice based on detailed assessments of an individual’s diet or phenotypic markers, such as anthropometric measures and clinical variables, continues to form the foundation of personalized nutrition [
103].
Studies have highlighted that specific deficiencies, such as low intake of vitamin C or sulfur-containing nutrients, could play a decisive role in an individual’s redox profiles, thus influencing the response to antioxidant supplementation. Identifying these deficiencies in groups with low antioxidant characteristics has enabled the application of targeted supplementation, which has effectively reversed these insufficiencies [
104,
105,
106].
It is important to note that the current strategy focuses on applying personalized antioxidant treatments at the group level, based on the common identification of phenotypic or metabolic profiles, rather than on granular individual adjustments [
107]. This approach, rooted in the concept of metabotyping, offers a promising path towards the broader implementation of personalized nutrition, in line with current trends in precision medicine. This evolution in understanding and applying antioxidant supplements reflects a move towards a more nuanced and individualized approach to nutrition, recognizing the complexity and diversity of human responses to nutritional interventions.
The development of understanding the role of antioxidant supplements in combating oxidative stress has been marked by significant evolution, especially in the context of physical exercise. The recognition that reactive oxygen species produced during physical activity are crucial for cellular signaling and inducing positive adaptations, such as mitochondrial biogenesis, angiogenesis, and neurogenesis, has shifted the paradigm regarding antioxidant supplements [
92,
93]. In this regard, it has been found that antioxidant supplementation can have varied effects, from neutral to even inhibitory of physiological adaptations to exercise, suggesting that their benefits or detriments largely depend on the individual’s initial redox state [
94,
95].
Recent explorations in personalized nutrition have highlighted that a more nuanced approach is needed to understand the impact of antioxidant supplementation. A specific clinical tool for identifying individual antioxidant deficiencies could optimize the effectiveness of antioxidant therapies, offering a promising route towards personalizing treatment based on each patient’s unique needs [
100]. This perspective is supported by the discovery that the beneficial effects of supplements, such as vitamins C and E, are limited to individuals with initially high levels of oxidative stress, proposing a specific threshold of F2-isoprostane for identifying eligible candidates for such interventions [
108].
Studies have drawn attention to significant interindividual redox variability in responses to exercise and supplementation, showing that groups with low levels of antioxidants exhibit initially inferior physical performance compared to those with moderate or high levels of antioxidants [
107,
109]. This observation underscores that the redox balance plays a crucial role in physical performance, and targeted supplementation can ameliorate specific deficiencies, significantly improving physical capacity and reducing oxidative stress.
It is essential to understand that antioxidant molecules do not act in isolation but are part of a complex defense system that includes both enzymatic and non-enzymatic mechanisms. Deficiencies in one of these components can affect the entire biochemical network, highlighting the importance of a holistic approach in assessing and treating oxidative stress [
85]. Moreover, Paschalis and colleagues discovered that dysregulation in redox metabolism, such as in the GSH pathway, can lead to disruptions in the entire antioxidative machinery, with significant repercussions on systemic oxidative stress and physical performance [
109].
The mechanisms through which the redox balance influences performance include regulating cellular signaling and energy metabolism through antioxidant enzymes, which act as key nodes in the redox network, selectively modulating signaling triggered by reactive species [
85,
110]. These enzymes exhibit high selectivity for signaling species and are kinetically favored over other antioxidants, highlighting the complexity and specificity of redox control over cellular functions [
111,
112,
113,
114,
115].
Therefore, understanding how antioxidant enzymes and redox mechanisms regulate cellular signaling and energy metabolism opens the path to new strategies for enhancing physical performance and managing oxidative stress. This conceptual framework not only highlights the importance of redox balance in cellular health but also provides a basis for exploring personalized nutritional and supplemental interventions aimed at optimizing health and performance.
In the context of oxidative stress and the response to physical exercise, understanding the mechanisms through which energy metabolism is regulated becomes essential. One of the most relevant signaling pathways involved in this process is the regulation of glucose uptake, particularly through the glucose transporter 4 (GLUT4). This pathway is especially important during physical exertion when the body’s energy demand significantly increases [
116].
Reactive oxygen species [ROS] and reactive nitrogen species (RNS), including nitric oxide (NO), play a crucial role in regulating this process. An increasing body of evidence underscores the influence of NO on muscle contraction-stimulated glucose uptake. Similarly, in vitro and ex vivo studies indicate a similar effect of ROS on glucose uptake, though this has not yet been confirmed under in vivo conditions [
117,
118,
119]. This highlights the complex and nuanced role of reactive species in the metabolic regulation of muscle cells during physical activity.
Besides these signaling mechanisms, it is well established that the functionality of many enzymes is directly influenced by their oxidation state. This is particularly relevant for enzymes involved in energy metabolism, such as creatine kinase, which plays an essential role in maintaining and recycling ATP in muscle cells [
120]. A disturbed redox state can, therefore, have significant implications for energy production capacity during physical exercises, underscoring the importance of redox balance for optimal energy metabolism functioning.
The importance of finely regulating these signaling pathways and energy metabolism through the antioxidant defense system becomes evident. Antioxidants, especially antioxidative enzymes, play a vital role in maintaining this balance, counteracting the potentially harmful effects of an imbalanced redox state [
121]. This balance is crucial not only for preventing oxidative damage but also for ensuring adequate cellular signaling and energy metabolism, especially under the increased physical stress encountered during physical exercises.
A study on antioxidant protection against cosmic radiation at commercial flight altitudes suggests that cosmic radiation can affect the human body and induce oxidative stress. This highlights the importance of prophylactic antioxidant treatment for individuals exposed to such conditions, including military personnel deployed in areas with intense solar exposure or at high altitudes [
122].
Research on volunteers from the Marine Firefighters Corps has shown that antioxidant supplementation can significantly reduce oxidative stress markers at moderate altitudes, although the effects varied depending on the specific biomarkers assessed. This underscores the need for well-tuned supplementation strategies to maximize benefits and minimize any potential negative effects [
123].
There is evidence that antioxidant supplementation, such as with vitamins C and E, might inhibit certain beneficial physiological adaptations to endurance training, such as mitochondrial biogenesis, essential for enhancing endurance performance and overall health. For instance, a study demonstrated that supplementation with vitamins C and E attenuated the increase in mitochondrial proteins induced by endurance training, suggesting that supplements might interfere with the cellular signals necessary for beneficial exercise adaptations [
124].
Another study investigated the effects of combining vitamin C and E supplementation on various measures of exercise performance after endurance training. The results suggest that administering vitamins C and E to healthy individuals without prior vitamin deficiencies had no effect on physical adaptations to intense endurance training, indicating that supplements did not enhance physical performance and might even limit beneficial adaptations [
125].
Education on antioxidants should cover both their benefits in protecting against oxidative stress and the potential risks of inhibiting physiological adaptations to intense physical exercise. Integrating case studies and the latest research into courses can provide military personnel with a deeper understanding of the complexity of antioxidant effects [
87].
Initiating longitudinal studies to track the long-term effects of antioxidant use on military health and performance is essential to determine the real benefits and risks associated with antioxidant supplements. A notable example of a longitudinal study that assessed the impact of daily supplementation with antioxidant vitamins and minerals is the SU.VI.MAX (Supplémentation en Vitamines et Minéraux AntioXydants) Study. Participants received a daily mix of vitamin C, beta-carotene, vitamin E, selenium, and zinc, or a placebo, over a period of 8 years. The results indicated potential benefits of antioxidant supplementation on cognitive performance but require further evaluation in the context of military stress and long-term physical performance [
126]. For a summary of the relevant studies and findings discussed in this chapter, see
Table 5.
3.5. Nutritional Supplements: Synergies and Divergences with Antioxidants
In discussing the efficacy of antioxidant supplementation, an emerging viewpoint suggests that the benefits of these supplements might be best realized by individuals who exhibit specific deficiencies or have low baseline levels of antioxidants. This perspective extends not only to antioxidants but also to other nutritional supplements, including vitamins E and D, recognized for their capacity to counteract molecular and biochemical disorders and to alleviate adverse physiological conditions [
127].
Vitamin E, particularly known in the literature as α-tocopherol, is valued for its lipophilic antioxidant properties and its role in regulating cellular metabolism. However, studies indicate that a significant percentage of the adult population does not achieve the recommended intake of vitamin E through diet, with estimates showing that between 80 and 90% of adults consume insufficient quantities of this vitamin [
128]. This nutritional deficit is associated with a variety of negative symptoms, from anemia and increased vulnerability to infections, to cognitive dysfunctions and developmental problems [
129].
Mechanistic research, mostly conducted on animal models such as rats and zebrafish, has discovered that long-term deficiencies in vitamin E can lead to a range of complications, including the dysregulation of energy metabolism, neurological dysfunctions, suboptimal lipid profiles of tissues, compromised mitochondrial function, and extensive tissue damage caused by the peroxidation of polyunsaturated fatty acids (PUFAs) in membranes [
130,
131]. Additionally, it has been observed that long-lasting disruptions in redox homeostasis and cellular metabolism induced by the lack of vitamin E can persist even after dietary or supplemental correction, and in extreme cases, severe deficiency has been linked to embryonic mortality [
132,
133].
Optimistically, supplementation with higher doses of vitamin E can significantly increase its concentrations in the body, succeeding in reversing multiple comorbidities and providing tangible health benefits [
131]. However, the effects of the long-term consumption of vitamin E in doses far exceeding optimal levels remain a subject of controversy [
134,
135]. This underscores the need to carefully balance the intake of vitamins and antioxidant supplements to support cellular and metabolic health without risking the potential negative effects of nutritional excess. Thus, understanding and correctly applying nutritional supplementation requires a personalized approach that considers the specific nutritional state and individual needs of each person, highlighting the importance of careful assessment and appropriate clinical monitoring.
Exploring the role of vitamins D and E in the context of health and physical performance has revealed that deficiencies in these essential nutrients are surprisingly common, both among athletes and in the general population. This underscores the importance of a careful approach to dietary supplementation, considering that deficiencies can have serious consequences on muscle function, immunity, bone health, and cardiovascular function. In particular, vitamin D has garnered attention in recent years due to its association with a wide range of comorbidities related to its deficit. Studies have shown that maintaining optimal levels of vitamin D is crucial for muscle regeneration and can improve recovery capacity and hypertrophic response after eccentric exercises [
136,
137,
138,
139].
Interestingly, similar to the approach to antioxidants, the efficacy of supplementation with vitamins D and E is seen to be greatest in individuals with initially low levels of these nutrients. Despite the vital role of vitamin E as a lipophilic antioxidant and regulator of cellular metabolism, a large number of adults do not meet the dietary requirements for this vitamin, leading to various negative symptoms [
127,
128]. Studies on animal models have indicated that long-term deficiencies in vitamin E can lead to serious issues, including the dysregulation of energy metabolism and disturbed mitochondrial function, highlighting the necessity of careful supplementation to counter these effects [
130,
131].
However, it is crucial to note that chronic supplementation with high doses of vitamins D and E does not always yield additional benefits and, in some cases, may even be counterproductive [
140]. This emphasizes a need for balance and personalization in the use of supplements, indicating that personalized nutritional interventions, which consider the individual’s specific deficiencies, can provide significant improvements in physical performance and the redox profile [
108,
109].
This perspective is reinforced by the observation that a stratified nutritional approach, focusing on the individual phenotype rather than the genotype, can offer a promising pathway to optimizing health and performance. This involves using personalized antioxidant supplementation strategies and other essential nutrients to ensure optimal levels during sports competitions or to support recovery in clinical contexts [
141].
In conclusion, the attempt to refine the approach suggested by Halliwell, which proposes testing antioxidants on individuals “more susceptible” to disease risk, urges us to identify and address specific antioxidant deficiencies for each individual. This underscores the potential of personalized nutrition, based on identifying individual nutritional needs and applying targeted interventions to maximize health and performance benefits [
142].
Tailoring nutritional supplements, including antioxidants, to meet the specific needs of military personnel is crucial as they often face intense physical and psychological stress. Personalizing supplementation can optimize performance and resilience under varying mission conditions. Nutritional supplements, including antioxidants, can be adapted to support specific needs of military personnel such as enhancing resistance to physical stress and rapid recovery from injuries. For example, supplementation with magnesium and vitamin B12 for protection against loud noises, glutamine and omega-3 for improving trauma recovery, beta-alanine for intense physical activity, and caffeine for enhancing mental function are all beneficial [
87].
Recent studies indicate that antioxidants, such as vitamins C and E, can help maintain physical performance even under conditions of intense oxidative stress, typical of pro-longed physical exercises or military operations. For instance, a study demonstrated that antioxidant supplementation could reduce oxidative stress induced by intense exercise, although the impact on physical performance is still a subject of debate [
143].
Vitamin E, due to its strong antioxidant properties, plays a crucial role in protecting against UV-induced injuries, which can accelerate oxidative stress and contribute to skin and other exposed tissues’ deterioration. Supplementation with vitamin E has been associated with a reduction in the harmful effects of UV radiation, reducing the potential for skin cancer and other dermatological conditions exacerbated by sun exposure.
Regular nutritional assessments can identify specific needs of soldiers, such as vitamin and mineral deficiencies or increased antioxidant needs due to heightened oxidative stress in military exercises. For example, a study demonstrated the importance of regular assessments to tailor supplementation to operational requirements and the specific stress of each mission [
144].
Education on the importance and correct use of nutritional supplements is crucial for military personnel. Training modules about supplements, including when and how to use them effectively, can prevent misuse and maximize the benefits of supplementation. A relevant example is the development of a web-based educational module for military healthcare providers, teaching them how to assess and communicate the evidence-based literature about supplements [
145].
Studies must evaluate the safety of supplements, ensuring there are no long-term adverse effects and that supplements do not interfere with natural physiological adaptations to stress and training. A study assessed the effect of antioxidants in diet and supplementation, pharmaco-nutritional support, and the use of an anti-inflammatory in a group of patients with advanced cancer and associated anorexia–cachexia. The results indicated a significant improvement in nutritional status and quality of life, suggesting that an integrated treatment including antioxidants can be effective and safe [
146].
Integrating training modules into the curriculum of military academies and continuing education programs. These modules should cover topics such as the mechanisms of action of supplements, proper dosing, and management of side effects.
It’s important to develop and distribute educational materials, like brochures and online tutorials, that offer accessible, evidence-based information on supplement use.
Another important aspect is conducting periodic assessments of nutrition and supplement knowledge among military personnel to keep the information relevant and current. For a summary of the relevant studies and findings discussed in this chapter, see
Table 6.