A RECENT HISTORY OF EXERCISE AND IMMUNITY
Exercise immunology is a relatively new discipline that came of age in the late 1980s (1). Early work in the field showed that individuals who engaged in regular exercise of moderate intensity were less likely to report incidences and symptoms associated with upper respiratory tract infections (URTIs) compared with sedentary individuals (2). This work triggered a surge in studies focused on examining how the immune system responds to both acute (single bout) and chronic (training) exercise in different groups, including athletes, older adults, people with obesity, and individuals living with HIV (3). Questions related to intensity and duration, mode (e.g., endurance versus resistance), single versus multiple bouts, and the aspects of immunity that are affected by exercise were quickly investigated and followed up with mechanistic studies in animals (3). From this work, there is now a general consensus that regular bouts of short-lasting (<45 minutes) moderate- to vigorous-intensity exercise are beneficial for host immune defense, particularly in older adults and individuals with chronic diseases (1,2). This intensity and duration of exercise also has been shown to lower the risk of respiratory infection/illness and some cancers. Unaccustomed prolonged arduous exercise that far exceeds the physical activity (PA) levels recommended for health (i.e., those typically practiced by high-performance athletes and the military) is considered by some to have detrimental effects on the immune system. However, this remains a contentious issue (1) and should not be used to discourage the vast majority of the population from engaging in daily exercise.
IMMUNE SYSTEM BASICS
The immune system is an intricate network of organs, cells, and proteins that work in an orchestrated manner to protect us from infection, prevent disease, and promote wound healing. There are two main arms of the immune system that are broadly defined as innate immunity and adaptive immunity. Innate or “nonspecific” immunity is our critical line of defense against bacteria or pathogens when protective barriers such as the skin and mucous membranes are breached. Innate immunity involves a coordinated response between enzymes and certain immune cells known as phagocytes (e.g., neutrophils and macrophages), which scavenge and digest the foreign pathogens. Plasma proteins complement the innate response by enhancing the ability of antibodies and phagocytic cells to recognize and destroy microbes and damaged cells. Mucous membranes in the oral and nasal cavity contain many different types of antimicrobial proteins that function to destroy microbes before they can enter the airways and cause infections. Cytokines (interleukin [IL]) such as interferon, are capable of destroying viral envelopes or virus-infected cells. Natural killer (NK) cells are a type of lymphocyte capable of immediately recognizing and destroying a cell that has become cancerous or infected with a virus. They do this by perforating holes in the membrane of the target cell and pumping it with cytolytic granules that lead to its destruction. Advantages of the innate immune response include the speed by which it can eliminate a potential disease-causing pathogen (within a few hours) and its ability to recognize and respond to a broad range of microbes. Disadvantages include its lack of “memory” and inability to initiate a “targeted” immune response that leads to long-term protection (3).
Many pathogens can evade the innate immune response, at which point the adaptive immune system is activated. This response is more specific, as it “targets” the type of microbe causing the infection and involves the actions of T cells and B cells. Although the adaptive response is much slower than the innate response, when it responds, it does so with more accuracy and is therefore more effective at resolving the infection. The adaptive response is the reason why there are many illnesses that we only get once in our lifetime. This is because our T and B cells “remember” the pathogens they encounter and can endure indefinitely. In addition, they can elicit a more rapid and specific immune response should the pathogen be encountered again. Vaccination works in a similar manner to prevent disease by “educating” the adaptive arm of the immune system so it can mount a swift response should we be exposed to the actual infectious agent in the future. Although the immune system is generally divided into these two broad categories, innate and adaptive, both arms of the immune system can work synergistically in the overall immune response. For instance, innate immune cells help facilitate specific memory immune responses through antigen presentation, whereas adaptive immune cells can release cytokines and other messenger molecules that regulate innate immune cell function. Both arms of the immune system also are involved in the inflammatory response to infection or injury (3).
A normal functioning immune system can protect against multiple pathogens, but weakens with age (“immunosenescence”) and adiposity. Because the Western population is steadily getting older and more obese, maintaining optimal immune function is critical to maintain our quality of life and improve the proportion of life spent in good health, or “health span” (4). In fact, data show that obesity was one of the major risk factors for fatality related to COVID-19 (5). In addition, a failing immune system is implicated in multiple diseases by increasing susceptibility to cancer, infection, inflammatory disease, neurodegeneration, cognitive impairment, cardiovascular disease, and autoimmunity.
A normal functioning immune system can protect against multiple pathogens, but weakens with age (“immunosenescence”) and adiposity. Because the Western population is steadily getting older and more obese, maintaining optimal immune function is critical to maintain our quality of life and improve the proportion of life spent in good health, or “health span” (4).
||This is our critical line of defense against bacteria or pathogens when protective barriers such as the skin and the mucous membranes are breached.
||A type of cell within the body, and part of innate immunity, capable of scavenging and digesting foreign pathogens, bacteria, and other small cells and particles.
||Complement the innate response by enhancing the ability of antibodies and phagocytic cells to recognize and destroy microbes and damaged cells.
||Capable of destroying virus-infected cells, and does so in the form of interferon, IL, growth factors, etc., which are secreted by certain cells of the immune system.
||A type of immune cell capable of immediately recognizing and destroying a cell that has become cancerous or infected with a virus.
|T cells and B cells
||A type of leukocyte (white blood cell) that is an essential part of the immune system. T cells and B cells remember the pathogens they encounter and can endure indefinitely.
|Adaptive immune system
||The adaptive immune system, also called the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens by preventing their growth.
EXERCISE AND THE IMMUNE RESPONSE
A single bout of exercise causes a massive and almost instantaneous mobilization of immune cells to the bloodstream (3). The total leukocyte count can increase two- to threefold after even brief (order of minutes) dynamic exercise, whereas prolonged endurance exercise from one to several hours can cause an increase in leukocytes by up to fivefold (2). This translates to literally billions of immune cells being redeployed between the blood and the tissues in response to every single bout of exercise we perform. Among the most responsive cells are the lymphocytes, which consist of T cells (CD4+ and CD8+) and NK cells. Interestingly, the cells that are mobilized the most have the greatest ability to “traffic” and migrate to the tissues or lymphoid organs where they can recognize infected or cancerous cells. Several types of T cells mobilized with exercise have an increased ability to recognize and respond to viruses. These mobilized cells do not stay in the blood very long and quickly egress within just a few short minutes after exercise cessation (6). This rapid mobilization of immune cells is considered an archetypal feature of the “fight or flight” stress response and is driven by increases in hemodynamic activity within the vasculature and stress hormones such as epinephrine (7,8). The mobilized cells display an activated phenotype and are said to be “looking for a fight,” allowing them to fend off any potential pathogen or aid in the repair and regeneration of damaged tissue (7). Our exercising muscles also play an important role in maintaining immune function. Contracting skeletal muscle secretes cytokines (i.e., “myokines”) such as IL-6, IL-7, and IL-15. These hormone-like proteins are responsible for the production of new immune cells and the maintenance of existing immune cells, and they help certain immune cells traffic toward sites of infection, injury, or malignant cell growth (4). Although immune responses to single exercise bouts are transient, it is likely that these effects cumulate over time and form the immunological adaptations seen with chronic exercise training (9). Indeed, exercise studies in tumor-bearing mice have shown that the immediate mobilization and redistribution of NK cells, coupled with the release of IL-6 from the muscle, is responsible for facilitating immune cell infiltration, mitigating tumor growth, and extending survival (10). As such, it is now generally accepted that the release of muscle-derived cytokines and the frequent exchange of immune cells between the blood and the tissues with each bout of moderate- to vigorous-intensity exercise likely contributes to enhanced immune surveillance, improved health, and a lower risk of illness (1).
Long-term exercise training, particularly cardiorespiratory-based exercise, has consistently been associated with markers of better immunity (2,4). Physically active older adults with higher levels of cardiorespiratory fitness typically present with “younger” looking immune systems, especially regarding T cells. This “young phenotype” is characterized by having fewer senescent cells, more naïve cells, and longer telomeres (11,12). Active older adults also are able to mount more effective immune responses to vaccination (13). Similarly, leaner and fitter individuals have lower levels of systemic inflammatory proteins released by inflammatory immune cells that infiltrate excess adipose tissue (14). This chronic low-grade inflammation is believed to underpin multiple inflammatory diseases but can be mitigated with regular endurance exercise. Several studies have demonstrated beneficial relationships between PA and/or physical fitness and the incidence and severity of infection (e.g., influenza and rhinovirus) and latent viral reactivation (4). Adults 18 to 65 years old who exercised more than 5 days a week for 12 weeks reported 43% fewer days with symptoms of URTI compared with sedentary (PA <1 day per week) age-matched controls (2). Randomized controlled trials also have shown that a period of exercise training can boost immune responses to vaccination and lower chronic low-grade inflammation. In fact, long-term regular cardiovascular exercise in older adults (age >65 years) extended seroprotection provided by the influenza vaccine for up to 24 weeks (13).
Exercise also can help preserve immunity because of its ability to mitigate stress. Individuals experiencing long-term stress and anxiety have sustained elevations in stress hormones, such as cortisol, which inhibit many critical functions of our immune system. Immune cells become less efficient at responding to infectious agents, trafficking to tissues, and mounting protective antibody responses to vaccination in conditions of stress or cortisol exposure. This stress-induced immune depression also can allow previously acquired infections that have become latent (e.g., herpesviruses) to reactivate and cause overt disease and symptoms such as cold sores and shingles. The interplay between the immune system, stress, and exercise came to the forefront during the COVID-19 pandemic. Billions of people have spent many months in isolation and confinement while living with fear and uncertainty during an economic downturn (chronic stress), amid a global pandemic (immunological challenge), coupled with limited access to gyms and parks (inactivity). Space travel is considered to be a highly stressful environment, and increased cardiorespiratory fitness and maintenance of fitness has been shown to protect astronauts from latent viral reactivation during a 6-month space flight mission (15). This indicates that exercise may protect host immunity because of its ability to curtail negative effects associated with long-term activation of the biological stress response. Because of this and the known antiviral effects of exercise, PA has been strongly supported during the COVID-19 pandemic (16).
Exercise also can help preserve immunity because of its ability to mitigate stress. Individuals experiencing long-term stress and anxiety have sustained elevations in stress hormones, such as cortisol, which inhibit many critical functions of our immune system. Immune cells become less efficient at responding to infectious agents, trafficking to tissues, and mounting protective antibody responses to vaccination in conditions of stress or cortisol exposure.
EXERCISE TO IMPROVE IMMUNITY
Although the beneficial effects of exercise and PA on immunity are not disputed, less is known about the optimal frequency, duration, intensity, and mode of exercise required to support optimal immune function in specific populations. Cardiorespiratory exercise seems to exert more discernible beneficial effects on immunity compared with resistance exercise. However, it should be noted that the literature is heavily tilted toward aerobic-based exercise, and there is a need to determine the effects of resistance exercise on reliable end points of global immunity such as vaccine responses, latent viral reactivation, and/or susceptibility to laboratory confirmed infections. Altering the lean-to-fat mass ratio with resistance exercise will likely exert multiple immunological benefits and reduce the inflammatory burden in the host. In terms of exercise prescription, the PA guidelines provided by many governing bodies throughout the world recommend 150 to 300 minutes of moderate- to vigorous-intensity cardiorespiratory PA per week and two sessions per week of muscle strength training (17). These recommendations are consistent with what has been shown to exert positive immune outcomes in a large number of studies. Notwithstanding, there is a critical need to determine the specific exercise doses and formulations that will be most effective in boosting immunity and lowering infection risk and other immune-related health issues in certain individuals and groups. For instance, there has been a surge in the popularity of high-intensity interval training due to its low time commitment and positive responses exerted in outcomes related to fitness and cardiovascular disease, but whether this type of exercise will facilitate optimal immune function remains to be seen. Until the most effective and personalized exercise prescriptions can be determined, we recommend that individuals looking to maintain optimal immune function should avoid prolonged periods of sitting time (>60 minutes) and follow the PA guidelines for Americans (2nd edition) that are currently supported by the American College of Sports Medicine and the Centers for Disease Control and Prevention (17). Even if these guidelines are not attainable, participating in just a few minutes of PA at regular intervals throughout the day will still likely confer some immune benefits over prolonged sedentary behavior. Exceeding these guidelines (e.g., training for a marathon or similar activity) is not discouraged, but there is no evidence that this will lead to greater enhancements in immunity than the recommended PA guidelines. Excessive unaccustomed exercise, coupled with nutritional deficiencies, muscle damage, and exposure to large groups of people (e.g., during an organized race), might even impair immunity and increase the risk of infection (1). Applying sound principles of training (e.g., progressive overload, recovery, and adaptation) when preparing for such events will help minimize any risks that might exist.
Exercise has a profound effect on the normal function of the immune system and has particular benefits for older adults and individuals with cancer, obesity, inflammatory disease, diabetes, and chronic viral infections (e.g., HIV). Maintaining adequate PA levels in healthy people helps sustain optimal immune function and prevent immune decrements that come with advancing age and increasing adiposity. Until individualized immune-enhancing exercise prescriptions can be determined, avoiding sedentary behavior and meeting the PA guidelines through regular exercise can help maintain immune health in most individuals.
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