The effects of cold stimulation and exercise on human health

There are several regions and countries worldwide, such as Kazakhstan, Russia, the United States, Greenland, Canada, Iceland, Finland and the northeastern region of China, which experience prolonged periods of severe cold^[1]. In these areas, the diurnal temperature difference is substantial, and the autumn and winter seasons maintain temperatures permanently at -10 to 20 degrees Celsius or even lower. Such extreme external temperature significantly impacts the thermoregulatory system, the central nervous system, respiratory system, and immune system. With the arrival of autumn and winter, a sudden drop in temperature occurs annually, leading to a notable increase in the incidence of cardiovascular diseases, including hypertension, heart disease, angina, arrhythmias, strokes, and even fatalities^[2]. In addition, severe cold weather and rapid temperature drops can pose lethal and damaging effects on the respiratory system, immune system and other bodily systems^[3].

Exercise is widely acknowledged as a key strategy for maintaining good health. Regular physical activity not only improves physical fitness and reduces the risk of illnesses, but also fosters a closer connection to nature, enriches our social and living environments, alleviates stress, and boosts overall well-being. Various studies have substantiated exercise's positive impact on health; however, caution must be exercised when engaging in vigorous physical activity in cold conditions, as it can also have detrimental effects on the body. For instance, inappropriate exercise in cold weather may cause bronchoconstriction and exacerbate bronchial asthma symptoms. Therefore, understanding how to uphold and promote good health in cold environments is of paramount importance. Regrettably, comprehensive reviews focusing on the effects of cold exposure and physical activity on health have been scarce in the past. Consequently, this review aims to extensively explore the ramifications of frigid weather, exercise, and their combined effects on health, providing valuable guidance to the public, especially in cold areas. By shedding light on these aspects, the review seeks to equip individuals with the knowledge needed to safeguard their well-being while staying physically active in colder climates.

1. Cold and health

Frigid weather has long been recognized as one of the earliest recorded detrimental factors to health^[4]. Cold air exposure significantly elevate the risk of morbidity and mortality, especially among vulnerable groups such as the elderly and people with heart and lung conditions^[5]. As autumn and winter approach, and temperatures plummet, the incidence of influenza and cold urticaria sharply rises. Moreover, a multitude of studies have substantiated that cold temperatures can inflict on human health^[6]. In this review, we provide a concise overview of the damage caused by cold temperatures and delve into the underlying mechanisms, we provide a concise overview of the damage caused by cold temperatures and delve into the underlying mechanisms, focusing on cold-induced hypertension, cardiovascular disease, respiratory disease, and immune system disorders (Fig. 1).

Figure  1.  Effect of cold stimulus on body health

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1.1 Cold and cardiovascular system

Cardiovascular responses can be affected by both acute and prolonged cold exposure^[7]. The World Health Organization (WHO) has identified exposure to cold room temperatures (< 18℃) as a risk factor for housing, which could increase the risk of disease^[8]. Hypertension is a significant risk factor for numerous diseases, including cardiovascular conditions^[9]. Research by Moore et al. has shown an independent and direct association between diastolic blood pressure (DBP) or systolic blood pressure (SBP) and the risk of stroke, coronary events, and death from cardiovascular disease (CVD)^[10]. During the cold season, cold stimulation triggers vasomotor adjustments through increased sympathetic activity, leading to vasoconstriction of peripheral and visceral arteries, and consequently elevating vascular tone. As a result, both acute cold exposure-induced elevation in blood pressure and sustained higher blood pressure can further exacerbate cardiovascular dysregulation and increase the risk of cold-related illnesses. This heightened risk encompasses subtle internal damage as well as severe events such as stroke, myocardial infarction, dementia, and renal failure^[3]. Notably, in China, the number of individuals with hypertension has reached 245 million, with 27.9% of patients aged over 18 or older, indicating that 3 out of every 10 adults have hypertension. Therefore, it is crucial to comprehend the underlying mechanisms and devise new approaches to control hypertension. In addition to genetic and dietary factors, environmental factors also play a significant role in the development of hypertension^[11]. Furthermore, hypothermia stimulation is recognized as a prominent risk factor for cardiovascular disease^[12]. Epidemiological data indicate that the incidence of CVD is higher in winter, with the highest blood pressure observed during this season among individuals with normal blood pressure and increased variability in those with hypertension. A study by Chen et al. showed that prolonged exposure to low temperature weather, lasting for five days or more, leads to a continuous increment in cardiovascular disease mortality. For example, at a temperature of 13 degrees Celsius, the mortality increased by 24% after 6-days exposure and further increased to 33% following exposure for 10 days. Mortality increases with longer exposure times, revealing the cumulative effect of consecutive moderately cold exposure on CVD mortality^[13].

The main pathophysiological mechanisms underlying hypertension due to cold stimulation include the activation of the renin-angiotensin system (RAS), the sympathetic nervous system (SNS), and the endothelium system, as well as the effects associated with inflammatory factors (interleukin(IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ). Additionally, cold exposure increases the expression of calcium channels and intracellular calcium ion concentration while reducing the production of vasodilatory substances like nitric oxide (NO). Animal studies have further demonstrated that exposure to low temperatures can impact blood pressure by reducing the diversity of the gut microbiota. A reduction in beneficial bacteria, such as the Lactobacillus genus and Ruminococcaceaegenus, and an increase in potentially pathogenic bacteria like genera Quinella, Rothia, and Senegalimassilia have been observed. Notably, regulating blood pressure levels through fecal bacteria cross-transplantation has been shown promising results^[14]. The frigid environment can also alter hemostatic factors, increasing the coagulation potential by affecting t-PA, v-WF, D-dimer, and fibronectin levels^[15]. This alteration may partially explain the high mortality rate of coronary artery disease. In summary, understanding the intricate relationship between cold exposure, cardiovascular responses, and hypertension is essential for devising effective strategies to mitigate the adverse health effects of cold weather and protect vulnerable populations.

1.2 Cold and respiratory system

In addition to its cardiovascular effects, cold weather significantly impacts various diseases, especially respiratory conditions. Both acute and chronic cold exposure can have a detrimental effect on the respiratory system. Research has demonstrated that cold stimulation can lead to a rapid decline in respiratory immunity and is associated with reduced lung function. A large-scale epidemiological study conducted in Finland reported that wheezing, breath tightness, coughing, and phlegm are more prevalent in colder climates, as the cold air renders individuals more susceptible to upper respiratory diseases, especially in the elderly. Chronic respiratory diseases, such as chronic bronchitis, emphysema, asthma, and chronic obstructive pulmonary disease (COPD), tend to exacerbate during cold weather, as resistance is diminished, particularly with prolonged exposure to cold air. Charlotte et al. found that cold stimulation predisposes people with COPD to exacerbations, increasing the risk of death in these individuals^[16].

Additionally, bronchial asthma, a chronic inflammatory airway illness, can be exacerbated by cold air. Prolonged and repeated exposure to sub-zero temperatures may induce symptoms like bronchoconstriction, airway inflammation, and bronchial hyperreactivity. Athletes engaged in winter endurance sports, such as cross-country skiers and outdoor mountain climbers, who are repeatedly exposed to dry, cold air, may experience severe respiratory symptoms, bronchial reactions, and asthma^[17]. As exercise intensity rises, inhaling increasingly cold air can result in heat and water loss from the airway mucosa, leading to airway dehydration. These cooling and osmotic stresses are believed to trigger the release of exercise-induced bronchoconstriction and inflammatory mediators. The precise mechanisms concerning the effects of cold stimuli on the airway are not fully understood. However, Haipei et al. found that freezing air could enhance inflammatory responses through the PKC/NF-κ B signal pathway mediated by TRPM8, a thermo-sensing cation channel, in primary airway epithelial cells of asthmatic mice^[18]. Understanding these mechanisms is crucial for developing targeted interventions to mitigate the adverse respiratory effects of cold exposure and protect vulnerable populations.

1.3 Cold and immune system

The immune system serves as the body's protective shield, safeguarding its health by fending off pathogenic microorganisms and preventing the onset of disease. An appropriate stress response enables the body to adapt to external stimuli and maintains homeostasis and stability. However, excessive or prolonged stress can inflict serious damage to the body. As a stressor, cold temperatures can disrupt the body's internal environment, leading to non-specific changes. Excessive cold stress triggers abnormal reactions, including the overproduction of glucocorticoids, which severely suppress the immune function, leading to decreased immunity and heightened susceptibility to diseases. Research on Nibea albiflora demonstrated that cold exposure inhibited the growth, liver function, and the immune system, leading to physiological failure and increased susceptibility to infections through the inhibition of immunomodulatory enzymes (alkaline phosphatase and acid phosphatase)^[19]. Similarly, a study on Oreochromis niloticus by Campos et al. revealed that external temperatures below 16 degrees Celsius affect physiological functions such as body immunity and food metabolism. Temperatures below 10℃ can pose life-threatening risks^[20]. Contradictory findings emerge from research on human populations. Straat's study indicated that mild cold exposure acutely increases mRNA levels of genes related to immune cell cytotoxicity in the blood^[21]. However, Castellani et al. pointed out that cold stimuli have no direct effect on the immune system. Furthermore, a recent population study in Bangladesh reported 1, 249 cold-related deaths during winters from 2009 to 2021, with the highest mortality in children aged 6 and under and seniors aged 65 and over^[22]. Similar patterns were observed in the USA, where these age groups also displayed the highest cold-related mortalityrates^[23]. The vulnerability of these age groups to cold-related mortality is attributed to their limited natural immunity against various diseases. In contrast, another study revealed that cold waves-related mortalities in India affected more males than females and children^[24]. Thus, the relationship between cold stimulation and organismal immunity remains unclear and necessitates further in-depth exploration through extensive research.

2. Exercise and health

The benefits of exercise to the organism are vast and profound. Physical activity serves as a cornerstone of nonpharmacological therapies and lifestyle modifications for treating various chronic diseases, notably cardiovascular disease^[25]. Engaging in regular physical activity has a positive impact on numerous cardiovascular risk factors, including body weight, lipid levels, blood pressure, insulin sensitivity, cardiac function, body fat composition, glucose metabolism, and endothelial function^[26]. Extensive research conducted by experts has confirmed the favorable health effects of regular physical activity, while also shedding light on the potential negative consequences of strenuous and excessive training. Moderate physical activity has been found to reduce the incidence of cardiovascular diseases, neurological disorders, and also exhibits a beneficial effect on patients with depression and certain types of cancer^[27]. Furthermore, moderate to vigorous exercise stimulates the activation of the sympathetic nervous system (SNS), leading to the release of catecholamines (CAT) such as epinephrine, norepinephrine, and dopamine. These neurotransmitters play pivotal regulatory and modulatory roles, affecting the immunity and metabolic processes. Currently, cardiovascular health, immune, and the potential anti-anxiety and anti-depressant effects of exercise are the major focus areas of research (Fig. 2).

Figure  2.  Effect of exercise on body Health

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2.1 Exercise and cardiovascular system

With the alarming rise in sedentary lifestyles and unhealthy eating habits, obesity and various metabolic diseases are escalating rapidly each year. Regular moderate-intensity exercise has emerged as a potent strategy to benefit cardiovascular health and reduce overall disease-related deaths^[28]. Exercise's positive impact on cardiovascular system dynamics includes reducing the incidence of coronary heart disease and cardiomyopathy, enhancing cardiac reserve capacity, and improving autonomic regulation. A substantial body of clinical and experimental evidence supports the notion that regular exercise improves cardiovascular health by lowering resting blood pressure, curbing the development of atherosclerotic disease, and augmenting the blood's oxygen-carrying capacity, thereby reducing mortality and the risk of cardiovascular diseases^[29]. For hypertensive individuals, physical exercise has proven to be particularly beneficial, as it can improve blood pressure and insulin sensitivity and mitigate pathological and plasma lipoprotein-lipid profile changes, as well as left ventricular hypertrophy. The underlying mechanisms behind these cardiovascular benefits are diverse and complex. Autophagy has been suggested to play a novel role in the cardiovascular adaptations resulting from exercise training. Regular physical activity, as a means to relieve physiological pressure, can trigger autophagy, particularly selective autophagy, which appears to contribute significantly to these cardiovascular adaptations^[30]. In addition, exercise has demonstrated the ability to improve the heart's antioxidant capacity and decrease the extent of damage from ischemia/reperfusion injury. This protection is attributed to the activation of the endothelial nitric oxidase (eNOS)/nitric oxide (NO) pathway and protein S-nitrosylation in the mitochondria, leading to a decrease in the production of reactive oxygen species (ROS) and inhibition of mitochondrial permeability transition pore (mPTP) activation^[31]. Furthermore, during exercise, the activation of β3-adrenoceptor (β3-AR) and vascular endothelial growth factor receptor (VEGFR) triggers the production of NO from endothelial cells in the vasculature and heart. This process promotes relaxation and vasodilation through the cGMP-dependent pathway, leading to improved coronary relaxation mediated by eNOS phosphorylation in the coronary endothelium^[32]. Furthermore, emerging research has highlighted the potential role of gut microbiota in mediating the health effects of exercise on cardiovascular system^[33]. In summary, regular moderate-intensity exercise stands as a powerful ally in promoting cardiovascular health and reducing the burden of cardiovascular diseases, and its positive effects are mediated through a plethora of intricate mechanisms.

2.2 Anti-depressant and anti-anxiety

In recent years, exercise has garnered widespread interest as a potent means of combating depression. Physical activity has been associated with a reduction in symptoms of depression and anxiety disorders, while also contributing to improvements in physical health, cognitive functioning, life satisfaction, and mental health^[34]. Conversely, physical inactivity appears to be linked to the exacerbation of psychological disorders^[35]. Exercise, in various forms, intensities, and programs, has proven to be highly effective in intervening with depressive symptoms, offering significant benefits without the side effects often associated with medication modalities. Oxygen exercise, in particular, demonstrates selective positive effects on different cognitive functions in individuals with depression, with notable improvements in visual learning, memory, and executive functions.

Research has shown that the development of depression is associated with disturbances in the brain's energy metabolism, and mitochondria, the primary site of energy metabolism in eukaryotic cells, may play a pivotal role in this the pathological mechanism leading to depression^[36-37]. This discovery has prompted exercise to be considered a promising primary treatment and a prominent research focus in the field of depression management. Furthermore, physical exercise exerts modulatory effects on neurotransmitters, such as serotonin, noradrenaline, and dopamine, while also promoting increased levels of brain-derived neurotrophic factor (BDNF) in individuals with major depressive disorder. This may be attributed to the upregulation of expression of markers such as CaMKII, p-IGF-1, Akt, and Bcl-2 in hippocampus^[38]. In addition, physical exercise induces changes in molecular pathways, including increased expression of the PGC1α gene, modulation of cytokines, metabolic shifts in kynurenine, and alterations in monoaminergic neurotransmission. These jointly contribute to an anti-inflammatory state in both the body and central nervous system, explaining how exercise exerts itsanti-depression and anti-anxiety effects^[39]. In conclusion, exercise has emerged as a powerful and multifaceted tool in the fight against depression, enhancing both physical and mental well-being through a variety of complex and interconnected mechanisms.

2.3 Exercise and immune function

The profound impact of exercise on the normal function of the immune system is widely recognized. Exercise and immune regulation are intricately interconnected, with exercise influencing white blood cells, red blood cells, and cytokines^[40]. Regular exercise has been found to reduce or deplete the number of senescent T cells, enhance the proliferative capacity of T cells, lower circulating levels of inflammatory cytokines, increase the phagocytic activity of neutrophils, and mitigate the inflammatory response to bacterial attack. These findings collectively suggest that habitual exercise can effectively modulate the immune system and decelerate immune aging. Furthermore, research indicates that short-term, high-intensity physical exercise may temporarily suppress immune function, while moderate-intensity exercise has a beneficial effect on improving immune function^[41]. For older individuals, it is recommended to engage in sports with a certain intensity to enhance their immunity and overall health^[42]. By carefully selecting the appropriate exercise intensity, older individuals can proactively improve their immune responses and promote better overall well-being.

3. Effects of combined cold exposure and exercise on health

In real life, cold stimuli and physical activity often coexist as external factors that exert a common influence on physical health. For example, workers may find themselves laboring in cold temperatures, and athletes may need to train in cold conditions, making these scenarios seemingly inevitable. Consequently, joint research on the effects of cold stimuli and physical activity becomes imperative. Here, we provide a concise overview of their impact on physical health, delving into several main areas of research (Fig. 3).

Figure  3.  The combined effect of cold stimulus and exercise on body health

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3.1 Cardiovascular implications

Winter swimming serves as the most typical example of the combined exposure of cold and exercise. Its effects on health have garnered significant academic interest. Some studies have shown an increased long-term risk of cardiovascular disease after swimming in cold seawater during winter^[43]. Acute exposure to cool water immersion in non-adapted individuals has been shown to present a severe cardiovascular stress stimulus and carries a notable risk of death, particularly for those with latent or underlying structural heart disease. On the other hand, winter swimmers who have attained a sufficient level of adaptation to cold water exposure and have developed effective protection mechanisms may benefit from this exercise activity, as it can promote and enhance cardiovascular health through various adaptive mechanisms^[44].

Despite the attention winter swimming has received, there remains a dearth of comprehensive studies on the health aspects of cold stimulation combined with exercise, and the underlying mechanisms are not yet fully understood. Given the limited information available, there is a need for further research on the type, intensity, and duration of exercise in low temperature environments that individuals may encounter in their daily lives. Specifically, investigating the effects of such exercise on individuals at increased cardiovascular risk warrants in-depth exploration through more animal experiments or population research^[45]. A thorough understanding of the interplay between cold exposure and exercise could offer valuable insights into cardiovascular health and risk management for individuals engaging in such activities.

3.2 Immune function

The immune and endocrine systems, now recognized as an interconnected entity, can be modulated by both exercise and environmental temperature, thereby impacting susceptibility to infection, disease, and pathological conditions. Acute exercise effectively modulates immune function by increasing the number and subpopulation of leukocytes, while also triggering the release of various immune mediators including pro- and anti-inflammatory cytokines (IL-6, IL-8, IL-10, and IL-12), growth factors, and other signaling proteins. Furthermore, exercising in a low-temperature environment has been found to reduce the exercise-induced systemic inflammatory response observed in a temperature-neutral circumstances. Research by Feng et al. showed that engaging in outdoor physical activities in winter, as a holistic intervention, could improve children's immunity and reduce the risk of catching colds.

For athletes involved in snow and ice sports, cold temperatures pose detrimental effects during training and competition, as prolonged exposure to cold temperatures can decrease the function of the body's immune system. It is suggested that moderate levels of exercise in cold surroundings can effectively boost the body's immune capacity, improving and enhancing the overall immunity. However, excessive exercise intensity may lead to a tendency for the body's immune capacity to decrease or even become immunocompromised. In addition, Kim et al. pointed out that exercise did not appear to affect immune changes in cold conditions when individuals had adapted to the cold environment^[46]. In summary, engaging in proper physical exercise in a low temperature environment can be highly beneficial for the body's immune system. It is advisable to avoid strenuous and short-term high-intensity activities, as maintaining a moderate exercise level can contribute to a bolstered immune response and improved overall well-being.

3.3 Fat metabolism and glycometabolism

Obesity serves as the underlying factor for numerous chronic diseases, and it can exacerbate conditions such as type 2 diabetes, insulin resistance, sarcopenia, hypertension, and certain types of cancer^[47]. For combating the progression of these chronic diseases, diet and physical activity are commonly regarded as effective treatments for weight loss. Nevertheless, high intensity physical activity may be limited for specific groups, such as the elderly and individuals with certain medical conditions. Consequently, experts need to explore additional interventions in order to enhance energy metabolism and energy expenditure to effectively reduce in these obese patients.

Recently, there has been a growing interest in the potential health benefits of cold exposure^[48]. Emerging studies have shown that physical training and exposure to chilly environments can be effective ways to regulate adipose tissue metabolism and boost metabolism in obese individuals. Exercise and hypothermia stimulation can induce the secretion of various circulating factors that play roles in altering metabolic homeostasis and improving insulin resistance. Moreover, repeated exposure to cold temperatures can increase energy expenditure and the utilisation of glucose and fatty acids throughout the body, resulting in reduced fasting blood glucose and insulin levels, even in healthy individuals.

The duration and intensity of exercise are key factors that significantly influence metabolism. Previous research has identified several myokines involved in the crosstalk between skeletal muscle and adipose, including irisin, IL-6, fibroblast growth factor 21 (FGF21), which can alter fat metabolism and insulin sensitivity. Although there is a strong additive effect when combining exercise and cold exposure, it is important to recognize that other interactive effects also come into play. Prolonged hypothermia prompts the body to compensate for heat loss, while exercise increases heat production^[47].

Published studies have provided inconsistent results regarding the effect of cold exposure on metabolism during exercise. It is widely recognized that the intensity of exercise and training status of individuals can significantly impact metabolism, regardless of environmental conditions^[49]. Additionally, the duration and intensity of cold exposure during exercise may also exert an influence^[50]. Consequently, when the two stimuli are combined, the physiological response becomes more complex. It remains to be determined whether there is an antagonistic effect between the two stimuli and which organ primarily influences the release of secretory elements. Given the complexity of their interaction, a more rigorous experimental design is required to explore the relationship between cold exposure and exercise with respect to their metabolic mechanisms. Further investigation is essential to gain a deeper understanding of how these factors interplay and influence metabolism, shedding light on potential synergistic or conflicting effects that may arise in different contexts.

In conclusion, the potential benefits of cold exposure and physical activity in enhancing metabolism and combating obesity have drawn considerable attention. Both modalities show promise in improving metabolic health and may serve as valuable tools in the battle against obesity and its associated chronic diseases.

4. Summary

As the seasons change, with summer flowers, autumn leaves, cold branches, and spring snow, the cold weather invariably arrives on schedule, always potentially impacting physical health. In essence, severe cold conditions can lead to elevated blood pressure, induce a range of cardiovascular diseases, exacerbate respiratory disorders, and worsen existing illnesses, while also suppressing immune function. On the other hand, exercise has demonstrated positive effects on physical health. Regular physical activity proves beneficial in improving cardiovascular health and enhancing the body's immune function, but short-term, strenuous exercise can temporarily reduce immune function. Although cold stimulation and physical activity are distinct influences, they often coincide. In recent years, a major research trend on the combined aspects of cold stimulation and exercise has been the exploration of the mechanisms by which cold exposure and exercise induce adipocyte browning. This process involves the conversion of white adipose tissue to brown adipose tissue, facilitating fat metabolism and energy expenditure, which holds promise for obese patients and individuals with type 2 diabetes. In general, the effects of cold stimulation and physical exercise on the body's health fall within a moderate range. Going beyond or falling below this range may become detrimental. The mechanisms underlying the effects of cold exposure and exercise on the body are highly complex, and many aspects are not yet fully understood. To advance our understanding, it is crucial to limit confounding factors and employ more rigorous experimental designs to explore their relationships and long-term or short-term benefits. Consequently, further research is essential to delve deeply into these aspects and unveil their intricacies.