Possible effect of exercise with anti-fatigue nutrition on ROS-induced depression and suicide risk: a review

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Abstract

INTRODUCTION

Suicide is a significant public health issue worldwide, and a 2012 survey observed that the prevalence of suicide was 11.4 per 100,000 people [1]. Every country aims to reduce the suicide rate by 10% according to disease management guidelines [2]. Depression is classified as a serious mental illness that has undesirable effects on cognitive ability and behavior and is a risk factor for suicidal impulses [3]. In terms of suicide prevention methodology, various studies have been conducted to relieve depression, which is the main cause of suicide [4]. In epidemiological studies of depression-related suicide, a high suicide rate is often caused by factors such as nutritional status, physical activity, physiological phenomena, and stress [5].

The onset and accelerated progression of depression may be due to genetic, environmental, or biochemical factors (e.g., changes in serotonin levels, immune status, and nutritional changes) [6]. For example, a correlation among hypoalbuminemia, elevated ferritin levels, and depressive symptoms has been reported in patients undergoing dialysis, suggesting the need for further research on malnutrition and inflammatory conditions [7]. Therefore, treating depression requires a research approach that considers the antioxidant mechanisms from a nutritional perspective. According to epidemiological evidence, exercise and nutrition help overcome depression [8,9]. However, there is still a lack of understanding regarding the use of exercise and nutrition to overcome depression. Therefore, there is a need for discussion on which exercise and type of nutrition are appropriate.

The pathophysiological threat of depression increases suicide risk [10]. Therefore, there is an argument that depression should be considered as a systemic disease rather than a threat factor of simple depression symptoms [11]. Fatigue is a common symptom of depression [12]. Fatigue includes mental and physical fatigue and is closely related to reactive oxygen species (ROS) generated in the body [13]. ROS are molecules that exist in the body, and their excessive generation damages cells [14]. Particularly, increased oxidative stress due to the failure to remove excess ROS can be the cause of the pathophysiological mechanisms of various neurological diseases, including major depressive disorders [15].

Fatigue is a significant factor that affects the health and quality of life of people with various illnesses [16]. This can be easily observed in daily life and is characterized by gradual weakening. One major cause of fatigue is ROS. Increased ROS production disrupts lipids and mitochondria, resulting in reduced activity. Oxidative stress caused by excessive ROS production can decrease mitochondrial activity, which is the primary source of cell energy production [17]. Reduced mitochondrial activity can cause fatigue. Many studies are being conducted on antioxidants, known as anti-fatigue nutrients, to address fatigue caused by excessive ROS [18]. Studies have indicated that lipid replacement supplements containing antioxidants can increase mitochondrial activity by mitigating membrane damage caused by oxidative stress [19]. Moreover, one research study demonstrates that antioxidants can improve muscle fatigue by addressing oxidative stress [20].

Moreover, the brain tissue uses 20% of the body’s oxygen and is more exposed to oxidative stress than other tissues [21]. Studies on major depressive disorders have shown that increased inflammatory cytokines increase lipid peroxidation of significant lipid components in the brain [22]. Research on the relationship between depression and oxidative stress is ongoing, and an increase in antioxidant enzyme levels has been observed after drug treatment [23]. Moreover, various studies have shown an apparent anti-fatigue effect of consuming nutrients containing antioxidants (ginseng, vitamin C, and coenzyme Q) [24-26]. This review discusses whether anti-fatigue nutrients are effective in improving depression.

In this comprehensive review, we examine how combining exercise with anti-fatigue nutrition can regulate ROS levels and mitigate depression and suicide risk. By exploring the potential synergistic effects of physical activity and specific nutritional interventions inferred from a literature review, this study aimed to provide a holistic approach to improving mental health and reducing suicide risk.

MECHANISM OF SUICIDE RISK AND DEPRESSION THROUGH ROS AND OXIDATIVE STRESS

Wisłowska-Stanek et al. suggested that controlling neurobiological risk factors is essential for preventing and treating suicide and depression [27]. The etiological factors of depression that lead to suicide risk include changes in neurotransmitters, influence of glucocorticoids and corticotropin-releasing factor (CRF), action of cyclic adenosine monophosphate response element-binding protein (CREB), and inflammatory responses through cytokines [28]. First, changes in neurotransmitter levels contribute to depression development through ROS. Decreases in monoamine neurotransmitters (serotonin [5-HT] and norepinephrine [NE]) and excessive ROS production in synapses cause neurotransmitter imbalance [29,30]. ROS-induced cytokines accelerate depression via NE and 5-HT reuptake [31]. Patients with depression who had attempted suicide had lower levels of 5-HT metabolites than those who had not attempted suicide [32]. Second, acute or chronic stress can lead to excessive ROS production and CRF. Excessive ROS generation activates the hypothalamic-pituitary-adrenal (HPA) axis [33,34]. This effect on brain function increases glucocorticoid secretion and reduces hippocampal volume, thereby causing depression [35]. Third, ROS disrupts brain signaling pathways by reducing the expression of CREB and brain-derived neurotrophic factor (BDNF), causing depression.

In summary, the main mechanisms of suicide risk and depression through ROS are closely related to the fact that these risk factors act as stressors, causing the loss of brain function and accelerating depression, thereby increasing suicide risk. Stress can lead to changes in brain function and neurochemical balance, increasing ROS levels, and the risk of developing mental health disorders, such as depression and anxiety, which are important risk factors for suicidal behavior [36]. Oshnohkhah et al. identified an association be-tween ROS and suicidal behavior in attempters aged 18–35 years old [37]. The study population had low blood malondial-dehyde, superoxide dismutase, and total antioxidant capacities.

Figure 1 illustrates possible mechanisms underlying suicide risk and depression. The evidence supporting Figure 1 is the excessive production of endogenous or exogenous ROS and reactive nitrogen species due to stress, along with an imbalance in the body’s scavenging function, which results in cell damage due to oxidative stress [38]. In particular, damaged cells undergo lipid peroxidation, protein oxidation, and mitochondrial dysfunction, ultimately increasing the risk of developing systemic diseases [39,40]. Recent findings suggest that mitochondrial dysfunction due to oxidative stress in various brain regions is associated with depression [41].

Figure 1.

Suicide and depression risk factors. Corticotropin releasing factor (CRF), cyclic adenosine monophosphate response element binding protein (CREB), hypothalamic-pituitary-adrenal (HPA), norepinephrine (NE) and serotonin (5-HT), anterior cingulate cortex (ACC) and prefrontal cortical (PFC).

EFFECT OF EXERCISE ON SUICIDE AND DEPRESSION

Exercise can prevent metabolic syndrome, hypertension, heart disease, arthritis, anxiety, arthritis falls, and diabetes [42]. Exercise has been shown to have an excellent effect on mental illness. Regular exercise can improve depression [43]. Therefore, we conducted a clinical trial to determine the effects of exercise on depression. The anatomical changes in the brain regions of attempters and patients with depression are closely related. Suicide decedents have been shown to have lower gray matter volumes in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) and to have lower volume [44]. Similarly, the hippocampi of suicide attempters with depression were reported to have a smaller volume than those of patients who did not attempt suicide [45]. The hippocampal volume in patients with depression is approximately 5% smaller than that in healthy individuals [46]. A decrease in the volume of the PFC and ACC regions of the brain was evident in patients with depression [47]. A previous study showed that when moderate-intensity aerobic exercise (brisk walking) was performed three times a week for 2–12 months, the hippocampal volume of patients with degenerative diseases increased by approximately 2%. In another clinical study, walking exercise was applied to patients with depression for six months before showing an increase in the PFC and ACC regions of the brain [48].

ANTI-FATIGUE EFFECT OF NUTRIENTS IN DEPRESSION-INDUCED FATIGUE

Various psychological studies have reported the importance of unresolved fatigue in depression, as it worsens the disease [49]. In addition, chronic fatigue symptoms such as loss of appetite and weight loss due to the side effects of depression treatments increase the risk of further promoting suicidal impulses [50]. Ahn et al. analyzed the relationship between chronic fatigue and suicidal ideation in Middle East respiratory syndrome survivors [51]. Most patients who experienced or attempted suicide were unaware of the chronic fatigue syndrome; however, epidemiological data later showed that severe fatigue syndrome caused the disease. Therefore, addressing unresolved fatigue in depression reduces the side effects of medications and contributes to reduced suicide rates due to the severity of depression.

Table 1 shows the substances that can improve fatigue according to clinical trial results. Amino acid complexes (valine, arginine, and serine) can reduce physical fatigue, as indicated by the visual analog scale and perceived exertion rating [52]. Phenylcapsaicin, a capsaicin family member, directly reduces neuromuscular fatigue, improves exercise capacity, and reduces aspartate aminotransferase levels in the body [53,54]. Hydrogen-rich water is a product in which hydrogen gas is added to water. When consumed 30 min before exercise, it is effective in reducing fatigue by reducing lactic acid in the blood [55]. Egg white hydrolysate improved antioxidant capacity and reduced mental fatigue with just one intake over 2 weeks [56]. Daily chicken extract consumption for 4 weeks was shown to reduce mental fatigue [57]. Additionally, daily Korean Red ginseng consumption in patients with chronic fatigue has been shown to reduce fatigue in middle-aged individuals aged over 50 years [58].

Table 1.

Types of nutrients that have the potential to improve fatigue.

DISCUSSION

This review focused on integrated thinking about exercise and nutrition in suicide prevention (Figure 2). We confirmed that depression is closely related to suicide, and investigated the main parameters associated with neuronal damage at disease onset and progression. Prescriptions for treating depression include monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors. Among them, SSRI treatment is the most widely used but can cause suicidal thoughts as a side effect and serious problems if used continuously [59]. Complementary or alternative treatments are required even when medication compliance is high. However, according to clinical studies, antidepressants have been reported to cause suicidal behavior despite the use of antidepressants [60]. Therefore, the treatment of depression by relying on neurological drugs has a moderately lower potency, and alternative and symptomatic treatment strategies are needed. The pathogenic factors of depression are 5-HT and NE depletion, and BDNF reduction, which lead to excessive ROS generation. Consequently, it leads to neuronal degeneration and reduced brain PFA, ACC, and hippocampal volume. Strategies to reduce the risk of suicide and depression include the suppression of excessive ROS levels and brain function restoration in response to oxidative stress.

Figure 2.

Effect of nutrition and exercise on regulating suicide risk factors. Abbreviation: anterior cingulate cortex (ACC), prefrontal cortical (PFC).

First, we confirmed the clinical results of the improved brain volume after exercise. However, this study has many limitations because it was conducted on older adult people with degenerative diseases and not on patients with depression or suicide attempts. Nevertheless, exercise has been shown to improve the brain structure in patients with degenerative diseases by significantly increasing the PFA, ACC, and hippocampal volume [61]. These clinical results suggest the need for a long-term exercise period of at least 12 weeks [52-55]. The appropriate exercise for these patients is low- to medium-intensity aerobic exercises. The need for long-term exercise suggests that recovery of brain function takes a long time. Clinical trials and research on overcoming depression have shown limited results regarding the complete treatment of depression through exercise alone. Brain volume changes that overcome depression require long-term exercise, and there are limitations owing to differences in exercise abilities between individuals [62]. Based on recent results, exercises for older adults are simple exercises suitable for their physical condition and require continuous exercise. Therefore, we speculate that the supply of nutrients is fundamental for improving exercise ability and activating brain function.

Next, we aimed to identify ways of overcoming suicidal impulses, risk factors, and depression using nutrition. Most patients with depression complain of fatigue, which increases depression and causes them to feel suicidal [63]. Therefore, we investigated various anti-fatigue nutritional substances currently undergoing clinical trials and reviewed their functions. Amino acids have antioxidant functions and are intermediate products of protein production, neurotransmitter metabolism, and GABA biosynthesis [64]. Xu et al. performed a comparative analysis of the antioxidant abilities of essential amino acids and reported that seven types of amino acids (tryptophan, lysine, cysteine, methionine, tyrosine, and histidine), including arginine, exhibited strong antioxidant abilities [65]. Therefore, depression is a characteristic disease that is accompanied by fatigue, and it has been suggested that nutritional intake, which helps relieve fatigue that cannot be resolved with medication, helps treat depression.

Based on these results, we confirm the importance of exercise in improving brain function by suppressing suicidal impulses and preventing depression. We confirmed that the mechanism of nerve damage at the molecular level involves excessive ROS and oxidative stress and that long-term aerobic exercise can reduce this. However, if the fatigue that inevitably occurs during exercise is not resolved, it may have adverse effects on depression. Therefore, further clinical research is needed to determine the synergistic effects of anti-fatigue nutritional intake and long-term aerobic exercise on free radical levels.

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