Background: The progressive dysfunction of the immune system during aging appears to be involved in the pathogenesis of several age-related disorders. However, regular physical exercise can present “antiaging” effects on several physiological systems. Methods: A narrative review of studies investigating the chronic effects of exercise and physical activity on the immune system and its association with age-related chronic diseases was carried out according to the guidelines for writing a narrative review. Results: There is compelling evidence suggesting that age-related immune system alterations play a key role on the pathophysiology of atherosclerosis, hypertension, chronic heart failure, type 2 diabetes, obesity, arthritis, and chronic obstructive pulmonary disease. On the other hand, the regular practice of physical activity appears to improve most of the inflammatory/immunological processes involved in these diseases. Conclusion: Epidemiological, experimental, and clinical studies permit us to affirm that regular physical activity improves immunomodulation and may play a key role in the prevention and treatment of several age-related chronic diseases. However, further studies are needed to better describe the prophylactic and therapeutic effects of physical exercise in specific organs of older individuals, as well as the mechanisms involved in such response.

Population aging is an unprecedented worldwide phenomenon that affects both developed and developing countries.1 This aging process is changing the demographic profile of society, resulting in a need for adapting the sociopolitical system to the new reality of increasing demand for geriatric services, which brings serious concern to both governments and populations.1 The functional and structural deterioration of almost all physiological systems that occur during aging, even in the absence of a discernible disease, results in an increased incidence/progression of chronic diseases and reduced independence.1,2

Among the age-related physiological deteriorations, there is a progressive dysfunction of the immune system, in both innate and adaptive immune functions.3,4 Impaired phagocytosis and chemotaxis of neutrophils and monocytes/macrophages, lower number and altered tissue distribution of dendritic cells, as well as aging of hematopoietic stem cell niche and reduction of its circulating levels, are some of the immune system alterations during aging.36 Some of these alterations appear to play a major role in the age-related low-grade chronic systemic inflammatory profile, characterized by modest increases in cytokine levels, the so-called “inflammaging.”3,7 This chronic inflammation is involved in the pathogenesis of several age-related disorders, including cardiovascular disease (CVD), diabetes, neurodegenerative diseases, cancer, chronic obstructive pulmonary disease (COPD), and rheumatic diseases.810 Consequently, inflammaging has been associated with frailty, cognitive decline, and mortality.4

On the other hand, there is strong evidence that physical exercise can prevent or reduce age-related alterations in immune system, contributing to health improvement and the management of several chronic diseases.3,4,8 The exercise benefits to the immune system may occur both after an acute exercise bout (improvements on the trafficking and functional capabilities of hematopoietic stem cells, myeloid lineage, and lymphoid lineage cells) and after an exercise training program (suppression of chronic inflammation and improvement on immune response to influenza vaccination and antigenic challenge).3,4 Physical exercise has an important role regarding the prevention and management of innumerous age-related chronic diseases,1,1113 and it is likely mediated, in part, by its effects on the immune system (Figure 1).3,4,8

Figure 1
Figure 1

—The cycle of aging, sedentary lifestyle, immunomodulation, and age-related disease, and the potential role of exercise training counteracting this cycle.

Citation: Journal of Physical Activity and Health 17, 6; 10.1123/jpah.2019-0237

The present review summarizes the clinical and experimental studies performed in the field of physical exercise and immunomodulation, discussing the responses and adaptations of the immune system to different types of physical exercises, particularly the innate and adaptive immune response of age-related diseases, such as CVD, metabolic diseases, rheumatic diseases, and COPD.

Literature Search Strategy

A narrative review of studies investigating the chronic effects of exercise and physical activity on the immune system was carried out according to a published guideline for writing a narrative review.14 We searched PubMed, Web of Science, and Embase databases for articles published until May 2019; however, studies could be excluded if similar information was obtained from more recent studies or systematic reviews. The search was made by crossing the terms “physical activity,” “exercise,” “exercise training,” “exercise program,” “physical fitness,” or “physical capacity” with “immune system,” “innate immune function,” “adaptive immune function,” “innate immune response,” “adaptive immune response,” “immunosenescence,” “immune system aging,” “immune modulation,” “inflammaging,” “chronic inflammation,” or “inflammatory response.” Additional studies were found by reviewing the reference lists from the most relevant published papers located for this review.

The inclusion criteria included the following: (1) studies published in English, Portuguese, or Spanish; (2) some form of exercise- or physical-activity–related intervention or outcome, such as exercise programs, physical activity promotion programs, or physical fitness; (3) assessment of an immune system outcome; (4) assessment of an age-related immune system impairment; and (5) original investigations (cross-sectional or randomized and nonrandomized controlled trials) or systematic reviews. Studies were not included if adjustments for potential confounders were not made or if they had mixed interventions with no attempt to assess the independent effects of exercise or physical activity.

Exercise as an Immunomodulator in CVDs

Cardiovascular disease is the leading cause of death worldwide, accounting for nearly 17.3 million deaths in 2013 (31.5% of all deaths), whereas both its prevalence and its mortality rates increase by several folds during aging.15 Although it is not clear whether inflammatory and immunological alterations are the cause or consequence of CVD, there is compelling evidence that age-related immune system alterations play a key role on CVD pathophysiology. Atherosclerosis, the pathological basis of most CVD (eg, coronary heart disease, stroke, hypertension), is a typical inflammatory disease that develops as a lifelong process, with its clinical manifestations generally occurring at more advanced ages.16 Typical inflammatory stages of atherosclerosis are characterized by an upregulation of cell adhesion molecules (ICAM-1 and VCAM-1) and E-selectin expression by the vascular endothelium in response to inflammatory mediators, such as tumor necrosis factor-α (TNF-α), predisposing the vascular wall intima to adhesion and infiltration of inflammatory cells.16,17 T cells have a key role in the immune system response during atherogenesis.17 For example, CD4+ T cells are abundant infiltrating cells17 that are associated with atherosclerosis and coronary heart disease progression.18 In addition, the T cells subset changes during aging and are associated with an overexpression of TNF-α and INF-γ,19,20 which may contribute to a vicious cycle of inflammaging and increased cell adhesion/infiltration,20 culminating in clinical events, such as acute coronary syndrome2022 and its poor outcome.23

It has been suggested that T cell alterations during aging are also involved in the pathophysiology of hypertension.19 For example, increased circulating levels of the T cells subset (ie, CD8+CD28null and CD8+CD57+) and C-X-C chemokine (CXC) receptor type 3 (ie, CXCL9, CXCL10, and CXCL11), as well as increased levels of CD8 T cells-derived TNF-α, IFN-γ, perforin, and granzyme B, have been found in hypertensive patients.24 In addition, hemodynamic (ie, endothelial function and arterial stiffness), neurohormonal (ie, sympathetic and renin-angiotensin system), and metabolic (ie, glucose and lipoprotein metabolism) abnormalities involved in the pathophysiology of hypertension,2527 which are altered before any blood pressure increase in individuals with a high familial risk of hypertension,28 are also involved in immune response during aging.2931 In this context, substantial experimental and clinical evidence indicate that peripheral alterations and neuroinflammation play a key role in the pathophysiology of hypertension,30,3133 with an experimental study showing that increased sympathetic drive can mediate hypertension onset by the activation of the norepinephrine-mediated T cell.34 In addition, endothelial dysfunction and/or senescence might be an important contributor to age-related changes in the immune system and inflammaging.29 Indeed, increased levels of several cytokines (ie, TNF-α, interleukin (IL)-6, IL-17, and IFN-γ), which are markers of inflammaging, are involved in the hypertension pathogenesis, probably by promoting vasoconstriction, sodium reabsorption, and vascular and renal dysfunction.30,31 Accordingly, a longitudinal study showed that blood pressure and TNF-α acted synergistically to increase the potential stickiness of intravascular cells (measured by leukocyte CD11b adhesion molecule expression) in older adults.35 Although future studies are needed to clearly determine whether the immune system alterations during aging may be a cause and/or consequence of hypertension, a hypothesis has been suggested.23,31 Increased sympathetic outflow by central hypertensive stimuli (eg, angiotensin II, salt, stress, etc) lead to blood pressure elevation that may result in protein modifications. These repeated antigenic stimulations ultimately lead to T cell stimulation, which results in increased frequency of CD8+CD28null and/or CD8+CD57+ and senescent T cell accumulation. These cells then release proinflammatory cytokines (TNF-α, IL-17, and IFN-γ) and cytotoxic mediators (perforin and granzymes) that promote renal sodium/water retention and vascular constriction and remodeling, which then amplify and sustain the hypertensive response.

It is important to note that inflammaging appears to be a result of several immune system alterations that occur during the aging process.36 Anti- and proinflammatory cytokines are biomarkers of inflammaging involved in the pathophysiology of CVD, and have received increased attention. For example, TNF-α appears to play a key role in atherosclerosis by stimulating the upregulation of ICAM-1, VCAM-1, and E-selectin expression by the vascular endothelium, which predisposes the vascular wall intima to mononuclear cell adhesion and infiltration.16,17 Evidence also suggests that increased TNF-α levels may predispose to atherosclerosis by promoting impaired lipid profile and endothelial dysfunction.8 Because endothelial dysfunction has a key role in the development of hypertension,28 increased TNF-α levels may also predispose to hypertension. In agreement, TNF-α blocker therapy reduced the progression of arterial stiffness and intima-media stiffness in patients with rheumatoid arthritis (RA).37,38 Increased levels of TNF-α have also been associated with the development of chronic heart failure (CHF) in animal models39,40 and with a poor prognosis in patients with CHF.41 Increased levels of IL-6 and IL-1β have also been shown to play a key role in the pathogenesis and progression of CHF.20,41,42 In this context, a recent study showed that, besides an increased level of innumerous markers of immune system dysfunction, patients with CHF have increased proinflammatory status, and that both immune system alterations and proinflammatory status are directly associated with disease severity.42 In addition, increased IL-6 levels were closely related to an increased aging process of the immune system in these patients. In this context, a model was proposed in which CHF, immunomodulation aging, and inflammation increase following a feedback mechanism.42 However, multicenter longitudinal studies are necessary to confirm this hypothesis.

On the other hand, physical exercise is a fundamental tool for preventing, treating, and managing CVD.12,13,27 Its benefits include reduced CVD incidence1,2,43 and mortality,44,45 even in the presence of coronary heart disease.45 In addition, physical exercise improves innumerous mechanisms involved in the pathophysiology of CVD,26,27,46 including CVD-related immune system alterations.3,4,8 For example, physical exercise is a well-known anti-inflammatory strategy to counteract CVD-related chronic inflammation. A recent literature review brings evidence from experimental and human studies that an acute bout of moderate exercise promotes substantial improvements on the release of anti-inflammatory and proinflammatory substances (ie, IL-6, cortisol, and TNF-α), which may result in neutrocytosis and lymphopenia.8 The anti-inflammatory effect of exercise has also been shown after an exercise training period,8 including in individuals with CVD.47 In patients recovering from an acute myocardial infarction, a thrice-weekly aerobic exercise program performed for 8 weeks resulted in increased levels of IL-10 and in the downregulation of ICAM-1 and CVCAM-1, which could potentially reduce the atherosclerosis evolution.47,48 A 3-week moderate-intensity exercise program, performed in the early period after myocardial infarction, also resulted in an improved inflammatory profile, characterized by decreased levels of acute phase reactant and soluble TNF-α receptor-1.48

A recent systematic review has suggested that acute and chronic exercises have considerable positive effects on markers of immunomodulation associated with inflammaging, which may be involved in the pathophysiology of CVD.3 In addition, it is well known that exercise training improves the above-mentioned hemodynamic (ie, endothelial function and arterial stiffness), neurohormonal (ie, sympathetic and renin-angiotensin system), and metabolic (ie, glucose and lipoprotein metabolism) abnormalities involved in both CVD pathophysiology2528 and in the immune system response during aging,2931 and that these improvements occur in individuals with and without CVD.1,2527,49 Given the benefits of exercise on the inflammatory status, pathogenesis of CVD, and immunomodulation markers, it is reasonable to speculate that exercise training may counteract the above-described feedback mechanism (vicious cycle) involving CVD pathophysiology, age-related immunomodulation alterations, and inflammation that has been hypothesized in coronary heart disease.1923,31,42 However, future multicenter longitudinal studies are necessary to confirm (1) whether exercise may really counteract age-related immunomodulation alterations; (2) the hypothesized feedback mechanism between CVD pathogenesis, age-related immunomodulation alterations, and inflammation; and (3) whether exercise may really counteract the hypothesized feedback mechanism.

Exercise as an Immunomodulator in Metabolic Diseases

Metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM), are increasingly prevalent health problems in developed and developing countries that pose significant challenges to both individual and public health.50,51 Obesity and T2DM increase their prevalence during the aging process and are associated with chronic inflammation.8,20 Indeed, evidence suggests that inflammation, a common characteristic of the aging of the immune system (the so-called inflammaging), is involved in the development and/or progression of T2DM.8 Increased levels of inflammatory markers (ie, cytokines, chemokines, and C-reactive protein [CRP]) are found in individuals with obesity and/or T2DM,8,20 whereas some of these markers (ie, CRP, TNF-α, IL-1β, IL-6, and IL-1ra) are predictive of T2DM.8 For example, evidence exists that IL-1β has a key role in β-cell damage, whereas TNF-α is involved in peripheral insulin resistance.8

Sarcopenia and body fat accumulation, common features of the aging process,1 may potentiate inflammaging and a predisposal to the development and/or progression of T2DM.8,52,53 Some inflammatory markers, such as IL-6, TNF-α, and CRP, are also released by other body cells, such as adipocytes.52 Adipocytes may also exhibit properties similar to those of the neuroendocrine and immune system,52 synthesizing and secreting more than 50 types of hormones, and signaling molecules, called adipokines.53,54 These adipokines perform autocrine, paracrine, and/or endocrine functions concerning metabolism and the immune process, including the inflammatory processes.52,54,55 Evidence exists that adipocytes of lean individuals primarily secret anti-inflammatory adipokines (ie, transforming growth factor-β, IL-1ra, IL-3, IL-4, IL-10, and apelin), whereas adipocytes of obese individuals primarily secret proinflammatory adipokines (ie, chemoattractant rotein to monocytes-1 [MCP-1], TNF-α, lepitin, resistin, vistafin, IL-6, angiotensin II, and plasminogen activator inhibitor-1).54 This obesity-related proinflammatory status may negatively affect phagocytosis and machrophages phenotype55 and is considered to be a focal point in the pathogenesis of insulin resistance and T2DM, as well as metabolic syndrome and CVD.54,55

For example, leptin is a proinflammatory adipokine that has its secretion proportional to fat cell mass.54,56 Leptin’s proinflammatory functions include the stimulation of T-cell proliferative responses, polarized naïve CD4+ T-cell proliferation toward the Th1 phenotype, an increase in Th1-type cytokine production, and the induction of proinflammatory cytokines expression by macrophages and monocytes.54,56 Leptin directly stimulates CRP production from hepatocytes, and may induce chemotaxis of neutrophils and activate human B lymphocytes to secrete TNF-α, IL-6, and IL-10.54,56 Leptin is also involved in the development and maintenance of a functional natural killer (NK) pool and induces the production of IL-6 and TNF-α from macrophages.54,56 Indeed, the above-mentioned obesity/T2DM-related proinflammatory status is associated with increased oxidative stress and hemodynamic alterations.20,23,31 Thus, although future research is needed to better understand the link between obesity/T2DM and age-related changes in immunomodulation, there is compelling evidence that obesity and T2DM are inflammatory diseases and, combined with other age-related alterations (including the alterations in the immunological process), may further alter the immune response in a feedback mechanism.

Regular practice of physical exercise is an important tool for preventing and managing obesity and T2DM, as well as its complications, which includes glycaemic control, cardiometabolic risk, and psychological well-being.1,5759 For example, a recent study by our group showed that a thrice-weekly aerobic exercise program performed for 16 weeks promoted several benefits in overweight/obese T2DM women, which included reductions in fasting glucose (∼14.3%), HbA1c (∼12.8%), triglycerides (∼17.7%), systolic blood pressure (∼3.7 mm Hg), body weight (∼2.2%), body mass index (∼2.1%), waist circumference (∼4.0%), and subcutaneous fat (∼18.6%), as well as increases in high-density lipoprotein cholesterol (∼21.1%) and endurance performance (∼9.8%).58 Indeed, these improvements occurred even with a reduction in the daily dosage of antihyperglycemic and antihypertensive medication by some patients. Given the above-mentioned association between the metabolic alterations and the inflammation in this population, it is reasonable to speculate that exercise-induced improvements in metabolic variables of obese/T2DM individuals may be associated with immune system improvements. Accordingly, in experimental models of obesity and/or insulin resistance, exercise training has reduced muscle inflammation,60 macrophage infiltration,60 adipocyte macrophages type 1,61 CD8+ lymphocytes,61 and adipocyte cytokines expression.62

Although studies in obese and/or T2DM are less frequent, exercise training has reduced circulating levels of proinflammatory markers in obese individuals.63 In addition, because of the above-mentioned key role of TNF-α in insulin resistance,8 the training-induced improvements on TNF-α and soluble TNF-α receptor-18,48 may have a key role on T2DM development and/or progression.8 The exercise-induced increase in circulating levels of cortisol and IL-6 provokes a further increase in anti-inflammatory IL-1ra and IL-10,8,47,48,64 which may protect against IL-1-mediated β-cell destruction.8 Indeed, the above-mentioned exercise-induced anti-inflammatory cytokines elevation may inhibit others proinflammatory cytokines8 and counteract the development and/or progression of insulin resistance and T2DM, as well as metabolic syndrome and CVD.8,54,55 However, future multicenter longitudinal studies are necessary to confirm this hypothesis.

Exercise as an Immunomodulator in Rheumatic Diseases

Rheumatoid arthritis and osteoarthritis (OA) are highly prevalent age-related disorders that negatively impact individuals’ quality of life and vitality.11,6567 These degenerative chronic diseases present common symptoms caused by the structural and functional changes in the joints, whereas the main one is the inflammation in the synovial membrane, which is clinically characterized by heat, swelling, and pain.65,67 This inflammatory process persists for many years and typically affects multiple joints throughout the body (hands and body support joints are commonly affected by OA, whereas any joint may be affected by RA) and can cause damage to cartilage, bones, tendons, and ligaments.65,66

The association between OA and the immune system alterations started with the intriguing correlation between hand OA and obesity,68 which cannot be explained by mechanical stress. Further studies have raised the hypothesis that osteoblasts, chondrocytes, and adipocytes share a common mesenchymal stem cell precursor, suggesting a link between connective tissues and lipid metabolism.69 In addition, several adipocyte-derived chemokines, such as adiponectin, resistin, and leptin, are presented in the synovial fluid of patients with OA and RA.70,71 Although little is known about their contribution to the progression of joint damage, evidence exists that these adipocyte-derived chemokines may play a key role in the pathogenesis of OA and RA69,70 by affecting tissues and cells such as the synovial fluid and membrane, cartilage, bone, and immune cells.7174 For example, leptin is found in both osteophytes and cartilage from OA patients and exhibits biological activity on chondrocytes, including the induction of the growth factors expression, as well as the stimulation of proteoglycan, collagen synthesis, and the proinflammatory cytokine stimulatory effects on nitric oxide production.70,71,73,74 Leptin also exerts regulatory effects on bone tissue.75 Resistin, also called FIZZ 3, is a 12.5 kDa protein, belonging to a family of resistin-like molecules, that is secreted by adipocytes, monocytes, macrophages, and the spleen in humans.52,76 The involvement of resistin in RA pathogenesis has been supported by its increased levels in plasma and its presence in the synovial fluid of patients with RA. Indeed, an arthritislike condition with leukocyte hypertrophy of the synovial layer, infiltration in the synovial tissues, and pannus formation was induced by the injection of resistin into the joints of mice.77 Vistafin, a pre-B cell colony-enhancing factor expressed by fat cells that play a key role in the persistence of inflammation, is also expressed in OA cartilage, stimulating the terminal enzyme of PGE2 synthesis, mPGES-1, and inhibiting the degradative enzymes PGE2 and 15-PGDH, playing a proinflammatory role in OA.78 More recently, adipokines has been shown to induce an altered proinflammatory response in activated CD4+ T cells from OA patients chondrocytes.72

Because TNF-α plays a key role on systemic inflammation, being able to generate a cascade of inflammatory response by stimulating the production and secretion of other cytokines, its elevated levels may also be involved in OA and RA pathogenesis.79 In addition, TNF-α downregulates the Klotho expression.80 Klotho is a protein expressed by renal cells that have been suggested to delay age-related declines in physiological functioning.81 There is a strong association between the Klotho expression and hand81 and knee OA,82 and is hypothesized that variations in the Klotho gene may affect cartilage metabolism.82 Although future studies are necessary to better understand the role of the immune system and its aging on OA and RA pathogenesis, there is compelling evidence that proinflammatory immune system alterations, an important remark of age-related changes in immune system, play a key role on the pathogenesis of these diseases.

The hope for good outcomes with drugs that could decrease pain and/or improve the progression of OA and RA has greatly decreased, and many researchers are increasingly considering the advantages of nonpharmacological treatment.65,83 Physical exercises and educational programs for self-control are the cornerstones of nonpharmacological treatment of OA and RA.11,65,84 The physical exercise-related benefits for patients with OA or RA include pain relief, body weight reduction, muscular strength increase, and cardiorespiratory fitness and flexibility improvements, which may be acquired with a great variety of exercises.11,65,84 In addition, the already cited anti-inflammatory effects of exercise (see previous sections) may play an important role on OA and RA management, as well as on the development and/or progression of other chronic disorders that accompany these diseases.9 For example, OA and RA patients present an increased evolution of atherosclerosis.85 As previously discussed, physical exercise may manage atherosclerosis progression by several mechanisms, including by its anti-inflammatory effects (ie, reduction of proinflammatory and increase of anti-inflammatory cytokines). In accordance, TNF-α blockers may prevent the progression of pulse wave velocity and intima-media thickness in patients with inflammatory arthritis.37,38

Because of the negative impact that musculoskeletal impairments pose on individuals with OA or RA, resistance training has been primarily recommended for the management of these diseases.11,85 Coincidentally, resistant training has been identified as an efficient tool for stimulating the secretion of anti-inflammatory cytokines.85,86 Besides the benefits associated with OA and RA pathophysiology, resistance training may also reduce body fat and increase muscle mass,1,11 which may prevent OA development, as well as indirectly reduce joint inflammation by reducing its impact/attrition during daily activities.85,86 Aerobic exercise training may also impact OA and RA management by immune activation. For example, low- to moderate-intensity aerobic training increased the plasma levels of Klotho,87 whereas a single maximal aerobic exercise session (20 min of duration) increased the serum levels of Klotho, particularly in women.88 Because of the association between cartilage metabolism and variations in the Klotho gene in patients with OA,82 aerobic-exercise-training–induced changes in Klotho may have a role in the development and/or progression of OA. Besides all of the mentioned evidence suggesting the positive role of an immune-system–derived effect of exercise on OA and RA management, future studies assessing the effects of resistance and/or aerobic exercise training are required to better understand the role of exercise on immunomodulation and its effect on OA and RA pathogenesis.

Exercise as an Immunomodulator in COPD

Chronic obstructive pulmonary disease is a preventable, treatable, and highly prevalent disease, characterized by persistent respiratory symptoms, such as dyspnea, cough, and sputum production.89,90 These symptoms are attributed to airway inflammation, characterizing chronic bronchitis, and also by parenchymal destruction, characterizing lung emphysema.89,90 The main risk factor for COPD development is tobacco smoking, although exposure to different sources of biomass and to air pollution can also contribute.89,90 Aging is also considered a risk factor for COPD, although it is not clear if healthy aging is a real risk for COPD or if aging only reflects a whole-life exposure for several agents that can induce COPD.89,90

Of note, the manifestations of COPD occur in individuals older than 40 years old, although the highest prevalence is among those older than 60 years old.89,90 In any case, a plethora of molecules involved in the senescence, such as reactive oxygen and nitrogen species, cytokines, transcription factors, and sirtuins, are believed to have a central role in the pathophysiology of COPD.9094 Of particular interest, it has been demonstrated that airway epithelial cells exert an important role in the pathogenesis of COPD.92,95,96 Airway epithelial cells may be disrupted through the inhalation of noxious gases, increasing the rate of exposure of the subepithelial layers.95 This leads to the hyperactivation of reminiscent epithelial cells, which is characterized by an increased activation of proinflammatory transcription factors with consequent increases in the synthesis and release of proinflammatory cytokines, growth factors, reactive oxygen and nitrogen species, and matrix metalloproteases, contributing to the establishment of a whole COPD phenotype.92,95,96 In this context, the airway epithelial cell hyperactivation by hydrogen peroxide was closely related with the aging of epithelial cells, and a reduction in the expression in sirtuin 1 and 6 was observed as a possible mechanism.92 However, not only hyperactivation of lung structural cells, such as airway epithelial cells, but also pulmonary and peripheral leukocytes contribute to the pathogenesis and severity of COPD in similar pathways, as described above.97,98

Besides the above-mentioned plethora of common molecules and cells that occurs during both lung aging and COPD, aging lungs present several similarities to COPD lungs, both functionally and from the immune response point of view.99,100 Functionally, a reduction in the forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), in the relation of FEV1/FVC, and in the functional residual capacity have been demonstrated.100 In addition, COPD has been viewed as a disease of premature accelerated aging of the lungs.99,100 A growing number of studies have demonstrated that COPD presents all the hallmarks of aging, including telomere shortening, cellular senescence, the activation of PI3 kinase-mTOR signaling, impaired autophagy, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, abnormal microRNA profiles, immunomodulation alterations, and a low-grade chronic inflammation due to senescence-associated secretory phenotype or simply “inflammaging.”99,100 Thus, inflammaging has been considered directly linked to the pathogenesis of COPD, resulting in pulmonary and extrapulmonary consequences. In addition, besides increased proaging molecules, antiaging molecules, such as sirtuins and Klotho, have been found to be decreased in COPD patients.100 For instance, reduced Klotho expression has been found in the epithelial cells of COPD patients, as well as in the serum of these patients.101

So, considering the importance of aging on lung structural cells and also on pulmonary and peripheral leukocytes for COPD, it is important to note that regular physical exercise can positively modulate these molecules involved in both aging and COPD.102106 In addition, physical exercise has been demonstrated to be effective to inhibit the deleterious effects of air pollution, which is a risk factor for COPD.107,108 In fact, the beneficial effects of physical exercise for COPD, both in experimental and in clinical settings, have shown that physical exercise is able to positively modulate both pulmonary and systemic inflammation.102104,106,109 For instance, it has been demonstrated that exercise performed at home, as part of a home-based pulmonary rehabilitation program, can inhibit systemic inflammation in COPD patients, as demonstrated by a reduction in IL-8 and a tendency toward reduction in IL-6 serum levels,109 which are molecules that are elevated in older adults due to inflammaging. Another study has compared the potential anti-inflammatory effects of aerobic versus resistance training in COPD, and showed that both training modalities induced a reduction in the plasma levels of TNF-α, IL-2, IL-4, IL-6, and CRP, which are also molecules increased in older adults due to inflammaging.110 Of note, a single bout of exercise88 or chronic exercise training87 can increase the circulating levels of Klotho, perhaps counterpointing the proaging effects in the context of COPD. However, such a hypothesis, as well as other possible cellular and molecular mechanisms involved in the inflammaging response in COPD, remains to be further investigated.

In this way, experimental studies investigating the beneficial effects of aerobic exercise for COPD has been performed.102104 More specifically, in an experimental model of smoke-induced COPD in mice, it was demonstrated that chronic regular moderate-intensity treadmill aerobic training reduced the number and activation (reactive oxygen and nitrogen species production) of pulmonary macrophages, reduced the pulmonary accumulation of 8-isoprostane, increased the expression of antioxidant enzyme glutathione peroxidase, and reduced the expression of CCL2/MCP-1, resulting in a reduced level of lung emphysema and improved lung elastance.102 In a similar study, it was shown that a preeminent antioxidant effect, induced by exercise in a model of smoke-induced COPD in mice, resulted in reduced collagen fiber accumulation and in reduced levels of lung emphysema.103 It is important to note that the 2 above-cited studies have been performed in a prophylactic fashion, because of beginning of aerobic exercise concomitantly with cigarette smoke exposure.102,103 However, a recent study tested, for the first time, the therapeutic effects of aerobic exercise in a model of smoke-induced COPD.104 This study showed, for the first time, that even when exercise began after the establishment of COPD, it was still capable of reducing several features of COPD, such as systemic and airway inflammation, airway remodeling, and lung emphysema.104 In addition, this study showed, for the first time, that such beneficial effects of aerobic exercise were followed by the downregulation of STAT-3 expression by airway epithelial cells, and peribronchial and parenchymal leukocytes, which presents a pivotal role in the pathogenesis of COPD.104 So, although further studies are needed to confirm the beneficial effects of physical exercise for COPD and especially the cellular, molecular, and immunological mechanisms involved, this initial evidence points out that physical exercise can inhibit and positively modulate the immune response in the age-related disease COPD.

Perspective

Performing vigorous exercise is associated with a greater reduction of risk for CVD and mortality than low to moderate physical activity, independently of exercise frequency, duration, and energy expenditure.44,45,111114 In addition, high-intensity interval training (HIIT) appears to be superior to continuous moderate exercise for improving endothelial function,26,115,116 arterial stiffness,26,49 markers of sympathetic activity,25,26 insulin sensitivity and fasting insulin,115,117 as well as for reversing left ventricular remodeling116 and for reducing central body fat and inducing fat loss.117 Indeed, HIIT is a time-effective tool for managing T2DM58 and dyslipidemia.118,119 Thus, 1 minute of vigorous-intensity exercise is suggested to be equivalent to 2 to 4 minutes of moderate-intensity exercise.120 Coincidentally, a recent systematic review suggested the superior effect of high-intensity exercise on markers of cellular immunological alterations during aging.3 Thus, future research should focus on the effects of vigorous-intensity exercise on immunomodulation and its role on the development and/or progression of age-related chronic disease. Finally, because of the different impact of aerobic and resistance training on the immune system, future research assessing the combined effect of these exercises is welcome.

Conclusion

In summary, although few studies exist in the field of immunomodulation during aging and physical exercise, particularly about its effects on the prevention and/or management of age-related chronic disease, there is compelling evidence from epidemiological, experimental, and clinical studies that permits us to affirm that, in general, regular physical exercise improves immunomodulation and may play a key role in the prevention and treatment of several of these diseases. However, further studies are needed to better describe the prophylactic and therapeutic effects of physical exercise in specific organs of older individuals, as well as the mechanisms involved in such a response.

Acknowledgments

The authors thank the Brazilian Council of Research and Development (CNPq—grants 303399/2018-0, 402468/2016-3, 427889/2016-2, 313239/2018-8, and 311335/2015-2), Sao Paulo Research Support Foundation (FAPESP—grants 2017/25648-4, 2012/15165-2, 2012/02409-0, and 2004/568-8) and Comissão de Aperfeiçoamento de Pessoal de Nível Superior (CAPES—Finance Code 001) for their constant support to our research groups in Brazil. The authors have no conflicts to declare.

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If the inline PDF is not rendering correctly, you can download the PDF file here.

Ciolac and Rodrigues da Silva are with the Exercise and Chronic Disease Research Laboratory (ECDR) and Post-Graduate Program in Movement Sciences, Department of Physical Education, School of Sciences, São Paulo State University (UNESP), Bauru, Sao Paulo, Brazil. Vieira is with the Post-Graduation Program in Sciences of Human Movement and Reghabilitation, Federal University of São Paulo, Santos, Sao Paulo, Brazil; Post-Graduate Program in Bioengineering and in Biomedical Engineering, Universidade Brasil, Sao Paulo, Brazil; School of Medicine, Anhembi Morumbi University, São José dos Campos, Sao Paulo, Brazil; and Brazilian Institute of Teaching and Research in Pulmonary and Exercise Immunology, São José dos Campos, Sao Paulo, Brazil.

Ciolac (emmanuel.ciolac@unesp.br) is corresponding author.
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    —The cycle of aging, sedentary lifestyle, immunomodulation, and age-related disease, and the potential role of exercise training counteracting this cycle.

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