Physical Exercise and Immune Response

#### **Chapter 11**

## Exercise Training in the Spectrum of Breast Cancer

*Ana Cristina Corrêa Figueira, Ana Pereira, Luis Leitão, Rita Ferreira and José Alberto Duarte*

#### **Abstract**

Exercise training and regular physical activity have been mentioned as one of the non-pharmacological approaches to enhance breast cancer outcomes. Such evidence encourages health professionals to recommend it as an adjuvant in treatment conditions to improve cardiorespiratory fitness that, can increase the rate of completion of pharmacologic therapies, reduce cancer-related fatigue, and improve muscle strength and quality of life. Research results have highlighted a positive relationship between exercise and breast tumor outcomes, that seem to be dose dependent (the more activity the more protection) and can be mediated through several biological mechanisms. In this chapter, we intend to summarize the current knowledge about the effects of exercise in the regulation of metabolic and steroid hormones, tumor-related inflammation, and the attenuation of cancer-induced muscle wasting, highlighting the exercise designs that can prompt the best results.

**Keywords:** exercise training, breast cancer, physical activity

#### **1. Introduction**

Cancer remains not only one of the most daunting diseases worldwide, but also a major public health concern. Although extensive research has been conducted on cancer prevention, diagnosis, and treatment, statistics of cancer's effects are disheartening [1].

Among cancer's various types, breast cancer is the second-most common and the most common among women, and it is assumed that one of every eight women will develop this type of cancer at some point in their lives [2].

The risk of developing breast cancer encompasses reproductive factors, hormonal factors, genetic alterations, age, race, sex, and factors related to lifestyle [3, 4].

Among the lifestyle factors that increase the risk of breast cancer, alcohol consumption [5], tobacco use [6], unhealthy diet [7], and reduced levels of daily physical activity or exercise are ranked among the most major [8].

Unlike determined genetic factors, regular physical activity and/or regular exercise training (RPA/REX) are modifiable ones [9].

In general, RPA/REX can contribute to overall health, with undeniable benefits for cardiorespiratory fitness (CRF), muscle strength insulin resistance, immune function, and body mass index (BMI) maintenance which can particularly be extended to the prevention of several diseases, including breast cancer [10, 11].

Nevertheless, the biological mechanisms underlying the protective effect of RPA/ REX on breast cancer remain poorly understood. Biomarkers proposed to support that association include the modulation of circulating levels of both metabolic hormones (e.g., insulin, and insulin-like growth factors, IGFs) and steroid hormones (e.g., estradiol and progesterone), the reduction of pro-inflammatory and anti-inflammatory factors (e.g., interleukins, IL-6 and IL-10; tumor necrosis factor-α TNF- α; C-reactive protein, CRP; adiponectin and IL-1), immune function (e.g., natural killers cells and leukocytes), and oxidative stress (i.e., reactive oxygen species) [8, 12, 13].

A considerable number of reviews have reported epidemiological evidence that establishes a connection between RPA/REX and cancer prevention by associating the amount of exercise performed with a decreased risk of developing cancer. Although the role of RPA/REX following the diagnosis of cancer has received less attention from researchers, its importance in controlling and reducing the side effects of cancer therapy is evident [14]. This evidence inspires health professionals to recommend RPA/REX as an adjuvant to improve cardiorespiratory fitness that, consecutively, can improve the rate of completion of pharmacologic therapies, reduce cancer-related fatigue, and improve the quality of life (QoL) [15].

To enhance the survival of patients with breast cancer early detection and improved treatments are fundamental [16]. Researchers in the exercise-oncology field have several concerns regarding therapies that best suit specific cases, minimize the number of deaths, and reduce recurrence. Thus, targeting the association between active behaviors and the cellular and molecular mechanisms underlying that association has been the main target in recent years [17].

Literature provides sufficient evidence to suggest that RPA/REX, when performed at moderate to vigorous intensity for at least 30 min/day, is safe and welltolerated by patients both during and after therapy [18]. The American College of Sports Medicine (ACSM) recommends that patients with breast cancer avoid inactivity. They should be as active as tolerable by their conditions and should follow the guidelines for healthy individuals when possible: 150 min/week of exercise training at moderate intensity or 70 min/week of exercise training at a vigorous intensity, combining endurance and resistance exercises [19]. Furthermore, these are also the recommendations supported by the American Cancer Society (ACS) [18]. Nevertheless, the patient's overall status should always be examined to ensure an individually adjusted amount of activity by defining personal thresholds of activity determined on a symptom-based approach [20].

A considerable number of studies have provided sufficient evidence that supports those recommendations. Almost a decade ago, a systematic review with meta-analysis, that considered 14 randomized controlled trials (RCT) involving 715 patients with breast cancer, concluded that resistance exercise training (RET) and aerobic exercise training (AET) increase self-esteem, body composition, physical fitness, and the rate of chemotherapy completion [21]. Two years later, a prospective study that involved more than 4000 patients, disclosed that being active during and after treatment for breast cancer can reduce mortality among women regardless of age, state of the disease, and the body mass index (BMI) [22], while a short after, another study, involving more than 14,000 women, showed that high levels of cardiorespiratory fitness were strongly associated with fewer deaths [23]. Similar results were found in another six prospective cohort studies involving more than 12,000 breast cancer survivors gathered in a meta-analysis; results showed that physical activity after the diagnosis of breast cancer reduced death by 34% and recurrence by 24%, regardless of BMI, while pre-diagnosis physical activity reduced the risk of mortality only in women with a BMI <25 kg/m<sup>2</sup> [24]. In more recent years, Lahart et al. [25] and Lipsett et al. [26] quantified the effects of

#### *Exercise Training in the Spectrum of Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.102427*

exercise training in breast cancer outcomes during therapy with two meta-analyses. Both revealed that patients with breast cancer benefited by engaging in exercise training activities. While Lahart et al. [25] determined that a combination of RET and AET affords significant benefits by reducing fatigue, Lipsett et al. [26] reported an inverse relationship between RPA levels and breast cancer-related deaths and recurrence.

The results observed, most of which have stemmed from epidemiological evidence, have highlighted a positive association between RPA/REX and breast tumorassociated deaths and recurrence which, apparently, seems to be dose-dependent, meaning more activity, more protection. Nevertheless, confusion remains about the specific amount of exercise that can induce the greatest outcomes.

In contrast, to the studies in clinical contexts that have provided extensive evidence showing that RPA/REX promotes patients' survival and reduced recurrence, such linearity in animal studies has not been found. Furthermore, although evidence showing a positive relationship between RPA/REX and the development of mammary tumors [27] exists, the opposite has also been reported by several researchers [28].

The up mentioned uncertainty has determined interest in understanding whether RPA/REX has a considerable role in tumorigenesis-related outcomes by modulating tumor behavior [24]. Researchers in this area have sought to confirm a relationship between RPA/REX and concurrent biological changes that can determine better outcomes. That association encompasses the intensity, type, and duration of exercise bouts, possible pathophysiological pathways, and breast cancer-associated mechanisms within the context of the advantageous effects of exercise [29]. The present chapter presents an attempt to summarize the insights that linked exercise training and cancer-associated mechanisms along the breast cancer continuum.

#### **2. Exercise training and glucose-related factors**

The modulation of metabolic hormones, including markers of glucose-insulin homeostasis are reported to relate to exercise. An altered cellular metabolism that favors aerobic glycolysis to support rapid cell proliferation and high-energy turnover, are features from which the tumors are recognized. The increased consumption of glucose by some tumors, such as those in the breast, that result in increased lactate production (i.e., the Warburg effect), is a well-described mechanism [30]. It seems that limiting glucose availability should restrict the capacity of growth factors to preserve cellular viability, thereby leading to cell death, is a process in which RPA/REX might be crucial. Further, RPA/REX has been hypothesized as an inducer of perturbations in the insulin–glucose axis, enhanced insulin sensitivity, and therefore, promoting a reduction in the circulating levels of insulin and glucose [31].

In the past few years, several studies, mostly RCT, have sought to elucidate whether RPA/REX acts in the modulation of glucose-related factors improving the outcomes in women with breast cancer. In an RCT conducted by Fairey et al. [32] that aimed to determine the effects of REX in glucose-related markers of 53 postmenopausal breast cancer survivors, the women that trained on cycle ergometers for 15 weeks (3 days/week for 35 min) at a moderate intensity have not shown significant changes in fasting insulin, glucose, insulin resistance, or Insulin-like growth factor binding protein-1 (IGFBP). However, the exercise training markedly improved the levels of Insulin-like growth factor (IGF) and Insulin-like growth factor binding protein-3 (IGFBP-3). Theoretically, increases in IGF-1 imply improvements in cell division and the inhibition of cell death [33]; however, also theoretically, because IGFBP-3 is responsible for binding the majority of IGF-1, increased levels of IGFBP-3 should be a good sign. In a different exercise paradigm, Schmitz et al. [34] also led an RCT with 85 postmenopausal breast cancer survivors who experienced a twice-weekly (60 min/session) weight training for one year. The training sessions were supervised for 6 months, and all the participants learned how to work alone and how to improve their workload. Thereafter, and for another 6 months, they continued the training unsupervised. Positive results were found regarding IGF-2 levels, but no evidence was detected concerning improvements in insulin sensitivity and glucose levels [34]. The above-mentioned results, which are both discouraging and challenging, do not indicate that REX can effectively improve glucose levels, insulin levels, or insulin resistance. Although a positive relationship regarding IGF-2 levels was found, this can be related to the different exercise designs presented in both studies, namely the different lengths of exercise exposure, the differences in the types of exercise, or the reductions in women's BMI, that was reported in the latter but not in the former study.

A few years later, 101 sedentary and overweight breast cancer survivors, were randomly assigned by Ligibel et al. [35] to either a 16-week program of unsupervised AET (90 min/week) combined with RET (2 days/week for 50 min with supervision) or to a control group. Aiming to analyze the influence of REX on insulin concentrations, positive changes were reported for fasting insulin with some evidence for improvement in insulin resistance but not for fasting glucose [35]. Likewise, Irwin et al. [31] studied 75 postmenopausal breast cancer survivors who were subjected to an exercise program involving three weekly supervised sessions and twice-weekly unsupervised sessions (30 min of moderate AET for 6 months). Women with higher exercise levels were reported to show a decrease in insulin, IGF-1, and IGFBP-3. Interestingly and despite other evidence [36], the authors assumed that the decrease in IGFBP-3 was probably related to a similar reduction of IGF-1 levels.

In the same line of research, an RCT conducted by Guinan et al. [37] with 26 breast cancer survivors, that combined supervised exercise with a home-based program, performed twice a week for 60 min during 8 weeks, did not find any evidences of positive changes in the circulating levels of glucose and insulin. Likewise, Thomas et al. [38] included 65 postmenopausal breast cancer survivors in an exercise program that combined supervised (3 days/week) and unsupervised (2 days/week) 30-min training sessions of moderate exercise, aimed to achieve 150 min/week during a period of 6-month. Significant results were found, translated into a reduction in fasting glucose among the more active women (>120 min/ week). Again, the different results are probably related to the different exercise designs used, which prevent us to reach a satisfactory conclusion about the type and amount of exercise to prescribe for breast cancer patients and that best contribute to positive outcomes. Two recently published meta-analyses did not highlight any clues to clarify this matter. Albeit demonstrating that exercise can reduce fasting insulin levels and IGFs [39] in breast cancer survivors, differences in the exercise training protocols prevent the attempt of a strength subgroup analysis in one of them [39]. On the other, the heterogeneity in exercise designs was mentioned as a limitation, and no subgroup analysis was performed [40]. Comparably, to trends in human studies, contrasting results also characterize preclinical data. Several reports have associated RPA/REX with increases in the levels of glucose-related factors [41], whereas others have related the opposite [42]. Additionally, and similarly to the research in human populations, the use of different exercise training programs prevents any clear understanding of the amount of exercise needed to enhance the glucose-related indicators.

#### **3. Exercise training and inflammation-related factors**

Another key factor in the improvement and progression of breast cancer is chronic inflammation. RPA/REX could neutralize the permanent state of inflammation by promoting a systemic anti-inflammatory environment. One of the mechanisms by which exercise can reduce cancer-related inflammation is through the increasing levels of anti-inflammatory myokines produced by the working skeletal muscles. Such decreases in cancer-related inflammation could be related to the frequency, intensity, type, and duration, of the exercise training sessions. In fact, it seems that the intensity may be the key. Higher levels of RPA/REX intensity (i.e., moderate or vigorous) can promote the reduction of the circulating levels of proinflammatory cytokines and improve immune function [43].

The collected data relating to cancer-induced inflammation and exercise training in human patients can illustrate the urgency for more studies.

In an RCT with 52 breast cancer survivors, Fairey et al. [44] exposed the participants to 15 weeks of moderate exercise in cycle ergometer and observed significant enhancements in immune function expressed by exercise-induced natural killer cell activity, but any association between REX and anti-inflammatory interleukins (i.e., IL-4 and IL-10), pro-inflammatory interleukins (i.e., IL-1 and IL-6), tumor necrosis factor-α (TNF-α) and cytokines, were not detected. With the same intervention group, the authors reported positive associations between REX and the C reactive protein (CRP) levels. Equally, Hutnick et al. [45] in a study involving 28 breast cancer survivors exposed to moderate treadmill exercise program combined with resistance training for 6 months, did not observe any association between REX and plasma IL-6 levels and interferon-gamma (IFN-γ). Nevertheless, the improved activation of lymphocytes in women who exercised showcased a positive relationship between immune function and exercise. In another RCT, conducted by Gómez et al. [46] with 16 breast cancer survivors exposed to an 8-week, a three-timesweekly program that combined resistance exercise training with aerobic training, did not detect significant changes in their inflammation-related systemic markers (e.g., IL-6, IL-10, and TNF-α). Rogers et al. [47] after a 3-month training program combining AET and RET in breast cancer survivors, found a positive relationship between leptin levels and REX, showing relevant evidence of the benefits induced by REX in proinflammatory cytokines (i.e., IL-6 and TNF-α).

Likewise, Campbell et al. [48] did not find significant associations between a 24-week home-based program of moderate exercise and inflammatory markers in 37 postmenopausal breast cancer survivors.

Although the amount of research performed in the last decade, the importance of RPA/REX to induced changes in the systemic repercussions of breast cancer, remains doubtful. Once again, differences among studies can confound the true benefits of exercise training in inflammation-related markers and enhancing immune response.

Trying to overtake this uncertainty, a recent meta-analysis highlighted the positive effects of chronic exercise training in low-grade inflammation in women with breast cancer. The benefits associated with the intervention program duration (>45 minutes/session) and length (>11 weeks) showed that a significant decrease in TNF-α levels were associated with decreased levels of adiposity [49]. Yet encouraging, such results should be interpreted with caution given the number of correlations performed, which in some cases were quite a few.

Similarly, the preclinical data about the advantages of RPA/REX to modulate inflammation are also diverse, including the improved expression of several inflammation biomarkers (e.g., CRP, TNF-α, IL-6, INF-γ, monocyte chemoattractant protein 1 [MCP1], serum amyloid P [SAP], leptin and spleen weight) [50], although other data has reported the opposite, primarily regarding in IL-6 regulation [51].

In that case, the considerable variety of exercise designs and breast tumor models might have significantly influenced the outcomes.

#### **4. Exercise training and estrogen levels along the breast cancer continuum**

RPA/REX has been associated with lower levels of circulating estrogen, which could describe its positive association with breast cancer. Cell proliferation and the inhibition of apoptosis via ER (estrogen receptor)-mediated mechanisms have been associated with the circulating levels of estrogen [52]. Apparently, physically active women with breast cancer, shows lower estrogen levels that can improve survival, particularly with tumors overexpressing positive estrogen receptors (ER+) and positive progesterone receptors (PR+), though the lack of data from human studies to support that hypothesis [24].

Using 1970 women from a previous cohort study to assess the levels of RPA/REX self-reported on a questionnaire, Sternfeld et al. [53] found no differences in levels of RPA/REX, tumors' hormonal status, or the number of breast cancer deaths. Curiously, the number of all-cause deaths was markedly lower among women who presented ER+ and PR+ tumors and had engaged in RPA/REX programs of moderate intensity. Irwin et al. [54] measured the self-reported data of 2910 women with breast cancer regarding their RPA/REX behaviors, to examine whether such behaviors influenced mortality, but did not find significant results between the RPA/REX levels and mortality in women with ER+ and negative Human Epithelial Growth Factor Receptor (HER−) tumors. The methodological approach of the study conducted by Chen et al. [55] was identical, but the results differed starkly. The authors observed significant effects between RPA/REX levels and the reduced number of total mortalities only among women with ER− or PR− tumors, but not with ER+ or PR+ ones. Human studies have divergent results and evidence even though most have used the same or similar methodological processes. Of note are the reduced number of studies concerning the relationship between RPA/REX condition and the circulating levels of estrogen in the progression and development of breast cancer, especially because those concentrations are associated with the growth of tumor cells [56].

The lack of data in preclinical research also restrains any understanding of the role of RPA/REX and the circulating levels of progesterone and estrogen. In this field, some studies have shown a positive association [41, 57], between RPA/REX and the circulating levels of sex hormone, while the contrary can be also found [58]. These findings suggest that methodological limitations, including heterogeneous cohorts, small sample sizes, and randomized characteristics, could translate the conflicting results regarding the effect of RPA/REX on breast cancer-associated markers.

A recent systematic review with meta-analysis in pre-clinical data reported considerable improvements in sex hormone concentrations, cancer-induced inflammation, and glucose-related factors among the animals exposed to exercise [59]. Performing vigorous exercise for 85 min per week improved sex hormone levels and reduced systemic inflammation.

#### **5. Exercise training and muscle mass in the breast cancer continuum**

The loss of skeletal muscle is a well-documented process in cancer that affects most patients, even though different degrees [60]. The musculoskeletal system

*Exercise Training in the Spectrum of Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.102427*

provides the basic functions of strength generation, locomotion, and respiration. The protection of muscle mass whether in disease or with health is crucial [61]. The preservation of muscle fiber size and muscle mass depends on protein turnover, in which the balance between protein synthesis and protein breakdown should be maintained. A complex system of signaling pathways regulates that stability, and under pathological conditions, such regulation can be compromised and result in muscle decrease and atrophy [62]. Muscle function in oncology relies on the study of cancer-associated cachexia. Systemic metabolic disorder and inflammation caused by tumors seem to affect protein turnover by promoting wasting in muscle mass involving diminished muscle fiber diameter, reduced protein content, decreased fatigue resistance, and force production [63].

In disease the loss of muscle mass reduces the patients' functional capacity, thus considerable efforts have been made in the past few years to find an effective anticachectic gent, and exercise has been suggested as a possible measure to mitigate or reverse muscle dysfunction and wasting or both [64]. Studies in humans with different types of cancer have reached different conclusions although, most of them, normally favor exercise. Unfortunately, in patients with breast cancer, results are insufficient due to the lower incidence of breast cancer patients who suffer from cachexia. As mentioned in a study conducted by Schmitz et al. [34], with 85 cancer survivors divided into two exercise training groups (immediate treatment and delayed treatment), that performed a twice-weekly (60 m/session) during 12 or 6 months, both groups exhibited increases in lean mass and the results were more expressed in the immediate treatment group, whereas the delayed treatment group did not show differences in lean mass across the study period [34]. Courneya et al. [65] obtained similar results after randomizing into three groups 242 patients with breast cancer receiving ongoing treatments. An exercise group that performed AET with different ergometers of moderate-to-vigorous intensity 45 min/day three times weekly, another exercise group that performed RET involving two sets of 8/12 repetitions in different muscle groups three times weekly, and a control group. Both exercise training groups showed significant results relating to the increased lean mass, after 17 weeks, more expressed in women who received RET treatment [66].

Animal studies have also highlighted the benefits of exercise against the depletion of muscle mass in the cancer context. Al-Majid et al. [67] described the benefits of REX program in the lower limb muscles of tumor-bearing animals subjected to eight sessions of electrical stimulation modeling RET. Puppa et al. [55] also reported the beneficial effects of moderate-intensity REX in the treadmill for 55 min/day 6 days/week for 11 weeks on muscle mass, in cancer-induced cachectic animals overexpressing systemic IL-6.

The study of Franjacomo et al. [68] aimed to examine if the studies involving cachexia could use the model of mammary neoplasms. They determined that the model, involving Ehrlich carcinoma cells inoculation could feature systemic inflammation and the muscle wasting of cachexia in a less aggressive manner suitable for studying new pharmacological approaches. Nevertheless, using an inoculation model of Walker-256 cancer cells subjected rats to a 6-week RET program, Padilha et al. [69] concluded that RET performed prior to tumor implantation prevented the development of cachexia by attenuating tumor-induced systemic proinflammatory conditions, oxidative stress, and damage in the muscles, which suggest the advantages of exercise training prior to tumor onset.

Above the heterogeneity of results and research designs in animal models and clinical conditions, it seems that the severity and incidence of cachexia depend on a reasonable range of factors and can vary according to the site and mass of the tumor, tumor type, interindividual differences in susceptibility to cachexia, and abnormal metabolism or reductions in food intake [70].

Evidence from animal studies demonstrates that RPA/REX might play an important role in attenuating cancer-induced muscle wasting by regulating or inhibiting, if not both, several factors at a molecular level. Apparently, exercise activates a network of transcription factors, kinases, and coregulator proteins that cap change in gene expression and prompt increases in mitochondrial biogenesis, which in turn cause metabolic reprogramming in skeletal muscle. Consistent evidence shows that endurance training induces mitochondrial biogenesis and a fast-to-slow fiber-type switch in skeletal muscles, expressed in type 1 and type 2A fibers [71].

Clearly, additional studies are needed in the context of cancer-induced muscle wasting, to date, no medical intervention has completely reversed cachexia, and no approved drug therapies are available [72]. Nevertheless, according to recent data [73], molecular mechanisms underlying such beneficial effect of exercise seems to be by the contribution of TNF-like weak inducer of apoptosis (TWEAK) signaling to cancer-induced skeletal muscle wasting. The authors concluded that exercise training prevented tumor-induced TWEAK/NF-jB signaling in skeletal muscle with a beneficial impact on fiber cross-sectional area and metabolism. Indeed, 35 weeks of exercise training promoted the upregulation of oxidative complexes. An active lifestyle for the prevention of muscle wasting secondary to breast cancer, highlighting TWEAK/NF-jB signaling as a potential therapeutic target for the preservation of muscle mass.

#### **6. Conclusion**

The diversity of designs and protocols of exercise training used in the reviewed documents, create serious difficulties to achieve a clear understanding of the best exercise training designs that better suit greater outcomes for breast cancer patients.

More powerful studies involving similar protocols could enhance the knowledge of the ideal amount of exercise needed in clinical contexts. However, despite the diversity of results reported, evidence of the benefits of exercising after a breast cancer diagnosis does exist.

Exposure to programs of regular exercise training combining AET and RET seems to promote better results along with the moderate-to-vigorous intensity through which the exercise is performed.

Exercise programs to breast cancer patients should include organized and supervised activities, considering a symptom-based approach, tailored to each patient.

Performing vigorous exercise 85 min/week can reduce the levels of systemic inflammation and improve circulating in sex hormone levels in animals, but in human populations, such evidence needs to be supported with more studies. The present chapter has some limitations mainly related to the studies included. The difference in study designs along with the lack of published information in some of them creates a difficult understanding and a more accurate analysis. Future studies should be performed with the knowledge already achieved in mind reporting, when published, the necessary information that allows their replication.

#### **Acknowledgements**

The authors gratefully acknowledge the financial support from the Portuguese Foundation for Science and Technology, I.P., Grant/Award Number UIDP/04748/2020 and UIB/00617/2020, from the Polytechnic Institute of Setúbal and from the School of Education.

*Exercise Training in the Spectrum of Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.102427*

#### **Author details**

Ana Cristina Corrêa Figueira1,2\*, Ana Pereira1,3, Luis Leitão1,3, Rita Ferreira2,4 and José Alberto Duarte2

1 Department of Sciences and Technologies/Sport Sciences, Polytechnic Institute of Setúbal, School of Education, Setúbal, Portugal

2 CIAFEL, Research Center in Physical Activity, Exercise, Leisure and Health, Faculty of Sport, University of Porto, Porto, Portugal

3 Life Quality Research Center, Rio Maior, Portugal

4 QOPNA, Department of Chemistry, University of Aveiro, Aveiro, Portugal

\*Address all correspondence to: ana.figueira@ese.ips.pt

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA: A Cancer Journal for Clinicians. 2017;**67**:7-30

[2] Kolak A, Kaminska M, Sygit K, Budny A, Surdyka D, Kukielka-Budny B, et al. Primary and secondary prevention of breast cancer. Annals of Agricultural and Environmental Medicine. 2017;**24**:549-553

[3] Singletary SE. Rating the risk factors for breast cancer. Annals of Surgery. 2003;**237**:474-482

[4] Weinberg R. The Biology of Cancer. Second Edition. New York: Taylor & Francis Group; 2014

[5] Jayasekara H, MacInnis RJ, Room R, English DR. Long-term alcohol consumption and breast, upper aerodigestive tract and colorectal Cancer risk: A systematic review and Metaanalysis. Alcohol and Alcoholism. 2016;**51**:315-330

[6] Catsburg C, Miller AB, Rohan TE. Active cigarette smoking and risk of breast cancer. International Journal of Cancer. 2015;**136**:2204-2209

[7] Michels KB, Mohllajee AP, Roset-Bahmanyar E, Beehler GP, Moysich KB. Diet and breast cancer: A review of the prospective observational studies. Cancer. 2007;**109**:2712-2749

[8] Friedenreich CM, Cust AE. Physical activity and breast cancer risk: Impact of timing, type and dose of activity and population subgroup effects. British Journal of Sports Medicine. 2008;**42**:636-647

[9] Ratnasinghe LD, Modali RV, Seddon MB, Lehman TA. Physical activity and reduced breast cancer risk: A multinational study. Nutrition and Cancer. 2010;**62**:425-435

[10] Friedenreich CM, Neilson HK, Lynch BM. State of the epidemiological evidence on physical activity and cancer prevention. European Journal of Cancer. 2010;**46**:2593-2604

[11] Schmitz KH, Holtzman J, Courneya KS, Masse LC, Duval S, Kane R. Controlled physical activity trials in cancer survivors: A systematic review and meta-analysis. Cancer Epidemiology, Biomarkers & Prevention. 2005;**14**:1588-1595

[12] Campbell KL, McTiernan A. Exercise and biomarkers for cancer prevention studies. The Journal of Nutrition. 2007;**137**:161S-169S

[13] McTiernan A. Mechanisms linking physical activity with cancer. Nature Reviews. Cancer. 2008;**8**:205-211

[14] Courneya KS, McKenzie DC, Mackey JR, Gelmon K, Friedenreich CM, Yasui Y, et al. Effects of exercise dose and type during breast cancer chemotherapy: Multicenter randomized trial. Journal of the National Cancer Institute. 2013;**105**:1821-1192

[15] Sweegers MG, Altenburg TM, Chinapaw MJ, Kalter J, Verdonck-de Leeuw IM, Courneya KS, et al. Which exercise prescriptions improve quality of life and physical function in patients with cancer during and following treatment? A systematic review and meta-analysis of randomized controlled trials. British Journal of Sports Medicine. 2017;**52**:(8)

[16] Sorlie T. Molecular portraits of breast cancer: Tumor subtypes as distinct disease entities. European Journal of Cancer. 2004;**40**:2667-2675

[17] Lynch BM, Neilson HK, Friedenreich CM. Physical activity and breast cancer prevention. Recent Results in Cancer Research. 2011;**186**:13-42

[18] Rock CL, Doyle C, Demark-Wahnefried W, Meyerhardt J, Courneya KS, Schwartz AL, et al. Nutrition and physical activity guidelines for cancer survivors. CA: a Cancer Journal for Clinicians. 2012;**62**:243-274

[19] Schmitz KH, Courneya KS, Matthews C, Demark-Wahnefried W, Galvao DA, Pinto BM, et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Medicine and Science in Sports and Exercise. 2010;**42**: 309-1426

[20] Newton RU, Galvao DA. Exercise in prevention and management of cancer. Current Treatment Options in Oncology. 2008;**9**:135-146

[21] McNeely ML, Campbell KL, Rowe BH, Klassen TP, Mackey JR, Courneya KS. Effects of exercise on breast cancer patients and survivors: A systematic review and meta-analysis. CMAJ. 2006;**33**:34-41

[22] Holick CN, Newcomb PA, Trentham-Dietz A, Titus-Ernstoff L, Bersch AJ, Stampfer MJ, et al. Physical activity and survival after diagnosis of invasive breast cancer. Cancer Epidemiology, Biomarkers & Prevention. 2008;**17**:379-386

[23] Peel JB, Sui X, Adams SA, Hebert JR, Hardin JW, Blair SN. A prospective study of cardiorespiratory fitness and breast cancer mortality. Medicine and Science in Sports and Exercise. 2009;**41**:742-748

[24] Ibrahim EM, Al-Homaidh A. Physical activity and survival after breast cancer diagnosis: meta-analysis of published studies. Medical Oncology. 2011;**28**:753-765

[25] Lahart IM, Metsios GS, Nevill AM, Carmichael AR. Physical activity, risk of death and recurrence in breast cancer survivors: A systematic review and meta-analysis of epidemiological studies. Acta Oncologica. 2015;**54**: 635-654

[26] Lipsett A, Barrett S, Haruna F, Mustian K, O'Donovan A. The impact of exercise during adjuvant radiotherapy for breast cancer on fatigue and quality of life: A systematic review and metaanalysis. Breast. 2017;**32**:144-155

[27] Westerlind KC, McCarty HL, Schultheiss PC, Story R, Reed AH, Baier ML, et al. Moderate exercise training slows mammary tumour growth in adolescent rats. European Journal of Cancer Prevention. 2003;**12**:281-287

[28] Malicka I, Siewierska K, Pula B, Kobierzycki C, Haus D, Paslawska U, et al. The effect of physical training on the N-methyl-N-nitrosourea-induced mammary carcinogenesis of Sprague-Dawley rats. Experimental Biology and Medicine. 2015;**240**:308-1415

[29] Courneya KS, Friedenreich CM. Physical activity and cancer: An introduction. Recent Results in Cancer Research. 2011;**186**:1-10

[30] Warburg O. On the origin of cancer cells. Science. 1956;**123**:309-314

[31] Irwin ML, Varma K, Alvarez-Reeves M, Cadmus L, Wiley A, Chung GG, et al. Randomized controlled trial of aerobic exercise on insulin and insulin-like growth factors in breast cancer survivors: The Yale exercise and survivorship study. Cancer Epidemiology, Biomarkers & Prevention. 2009;**18**:306-335

[32] Fairey AS, Courneya KS, Field CJ, Bell GJ, Jones LW, Mackey JR. Effects of exercise training on fasting insulin,

insulin resistance, insulin-like growth factors, and insulin-like growth factor binding proteins in postmenopausal breast cancer survivors: A randomized controlled trial. Cancer Epidemiology, Biomarkers & Prevention. 2003;**12**:721-727

[33] Schernhammer ES, Holly JM, Hunter DJ, Pollak MN, Hankinson SE. Insulin-like growth factor-I, its binding proteins (IGFBP-1 and IGFBP-3), and growth hormone and breast cancer risk in the nurses health study II. Endocrine-Related Cancer. 2006;**13**:583-592

[34] Schmitz KH, Ahmed RL, Hannan PJ, Yee D. Safety and efficacy of weight training in recent breast cancer survivors to alter body composition, insulin, and insulin-like growth factor axis proteins. Cancer Epidemiology, Biomarkers & Prevention. 2005;**14**:1672-1162

[35] Ligibel JA, Campbell N, Partridge A, Chen WY, Salinardi T, Chen H, et al. Impact of a mixed strength and endurance exercise intervention on insulin levels in breast cancer survivors. Journal of Clinical Oncology. 2008;**26**:907-912

[36] Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: Overview and recent insights. Endocrine Reviews. 2007;**28**:20-47

[37] Guinan E, Hussey J, Broderick JM, Lithander FE, O'Donnell D, Kennedy MJ, et al. The effect of aerobic exercise on metabolic and inflammatory markers in breast cancer survivors--a pilot study. Support Care Cancer. 2013;**21**:1983-1992

[38] Thomas GA, Alvarez-Reeves M, Lu L, Yu H, Irwin ML. Effect of exercise on metabolic syndrome variables in breast cancer survivors. International Journal of Endocrinology. 2013;**2013**:168797

[39] Meneses-Echavez JF, Jimenez EG, Rio-Valle JS, Correa-Bautista JE, Izquierdo M, Ramirez-Velez R. The insulin-like growth factor system is modulated by exercise in breast cancer survivors: A systematic review and meta-analysis. BMC Cancer. 2016;**16**:682

[40] Kang DW, Lee J, Suh SH, Ligibel J, Courneya KS, Jeon JY. Effects of exercise on insulin, IGF Axis, Adipocytokines, and inflammatory markers in breast Cancer survivors: A systematic review and Meta-analysis. Cancer Epidemiology, Biomarkers & Prevention. 2017;**26**:355-365

[41] Zhu Z, Jiang W, Zacher JH, Neil ES, McGinley JN, Thompson HJ. Effects of energy restriction and wheel running on mammary carcinogenesis and host systemic factors in a rat model. Cancer Prevention Research. 2012;**5**:414-422

[42] Gillette CA, Zhu Z, Westerlind KC, Melby CL, Wolfe P, Thompson HJ. Energy availability and mammary carcinogenesis: Effects of calorie restriction and exercise. Carcinogenesis. 1997;**18**:119-1188

[43] Pierce BL, Neuhouser ML, Wener MH, Bernstein L, Baumgartner RN, Ballard-Barbash R, et al. Correlates of circulating C-reactive protein and serum amyloid a concentrations in breast cancer survivors. Breast Cancer Research and Treatment. 2009;**32**:155-167

[44] Fairey AS, Courneya KS, Field CJ, Bell GJ, Jones LW, Martin BS, et al. Effect of exercise training on C-reactive protein in postmenopausal breast cancer survivors: A randomized controlled trial. Brain, Behavior, and Immunity. 2005;**19**:381-388

[45] Hutnick NA, Williams NI, Kraemer WJ, Orsega-Smith E, Dixon RH, Bleznak AD, et al. Exercise and lymphocyte activation following chemotherapy for breast cancer.

*Exercise Training in the Spectrum of Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.102427*

Medicine and Science in Sports and Exercise. 2005;**37**:1827-1195

[46] Gomez AM, Martinez C, Fiuza-Luces C, Herrero F, Perez M, Madero L, et al. Exercise training and cytokines in breast cancer survivors. International Journal of Sports Medicine. 2011;**32**:461-467

[47] Rogers LQ, Fogleman A, Trammell R, Hopkins-Price P, Vicari S, Rao K, et al. Effects of a physical activity behavior change intervention on inflammation and related health outcomes in breast cancer survivors: Pilot randomized trial. Integrative Cancer Therapies. 2013;**12**:323-335

[48] Campbell KL, Van Patten CL, Neil SE, Kirkham AA, Gotay CC, Gelmon KA, et al. Feasibility of a lifestyle intervention on body weight and serum biomarkers in breast cancer survivors with overweight and obesity. Journal of the Academy of Nutrition and Dietetics. 2012;**20**:559-567

[49] Meneses-Echavez JF, Correa-Bautista JE, Gonzalez-Jimenez E, Schmidt Rio-Valle J, Elkins MR, Lobelo F, et al. The effect of exercise training on mediators of inflammation in breast Cancer survivors: A systematic review with Meta-analysis. Cancer Epidemiology, Biomarkers & Prevention. 2016;**25**:1009-1017

[50] Goh J, Tsai J, Bammler TK, Farin FM, Endicott E, Ladiges WC. Exercise training in transgenic mice is associated with attenuation of early breast cancer growth in a dosedependent manner. PLoS One. 2013;**8**:e2123

[51] Thompson HJ, Wolfe P, McTiernan A, Jiang W, Zhu Z. Wheel running-induced changes in plasma biomarkers and carcinogenic response in the 1-methyl-1-nitrosourea-induced rat model for breast cancer. Cancer Prevention Research. 2010;**3**:344-1492

[52] Lewis-Wambi JS, Jordan VC. Estrogen regulation of apoptosis: How can one hormone stimulate and inhibit? Breast Cancer Research. 2009;**11**:206

[53] Sternfeld B, Weltzien E, Quesenberry CP Jr, Castillo AL, Kwan M, Slattery ML, et al. Physical activity and risk of recurrence and mortality in breast cancer survivors: Findings from the LACE study. Cancer Epidemiology, Biomarkers & Prevention. 2009;**18**:87-95

[54] Irwin ML, McTiernan A, Manson JE, Thomson CA, Sternfeld B, Stefanick ML, et al. Physical activity and survival in postmenopausal women with breast cancer: Results from the women's health initiative. Cancer Prevention Research (Philadelphia, Pa.). 2011;**4**:522-529

[55] Chen X, Lu W, Zheng W, Gu K, Matthews CE, Chen Z, et al. Exercise after diagnosis of breast cancer in association with survival. Cancer Prevention Research (Philadelphia, Pa.). 2011;**4**:309-1418

[56] McTiernan A, Rajan KB, Tworoger SS, Irwin M, Bernstein L, Baumgartner R, et al. Adiposity and sex hormones in postmenopausal breast cancer survivors. Journal of Clinical Oncology. 2003;**21**:1961-1966

[57] Isanejad A, Alizadeh AM, Amani Shalamzari S, Khodayari H, Khodayari S, Khori V, et al. MicroRNA-206, let-7a and microRNA-21 pathways involved in the anti-angiogenesis effects of the interval exercise training and hormone therapy in breast cancer. Life Sciences. 2016;**151**: 30-40

[58] Faustino-Rocha AI, Gama A, Oliveira PA, Alvarado A, Neuparth MJ, Ferreira R, et al. Effects of lifelong exercise training on mammary tumorigenesis induced by MNU in female Sprague-Dawley rats. Clinical and Experimental Medicine. 2016;**17**:151-160

[59] Figueira A, Cortinhas A, Soares JP, Leitão FC, Ferreira RP, Duarte JA. Exercise-induced changes in systemic biomarkers of breast cancer: Systematic review with meta-analysis. International Journal of Sports Medicine. 2018;**39**(05):327-342

[60] Al-Majid S, Waters H. The biological mechanisms of cancer-related skeletal muscle wasting: The role of progressive resistance exercise. Biological Research for Nursing. 2008;**10**:7-20

[61] Argiles JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Manas L. Skeletal muscle regulates metabolism via Interorgan crosstalk: Roles in health and disease. Journal of the American Medical Directors Association. 2016;**17**(9):789-796

[62] Sandri M. Signaling in muscle atrophy and hypertrophy. Physiology (Bethesda). 2008;**23**:160-170

[63] Allred DC. Issues and updates: Evaluating estrogen receptor-alpha, progesterone receptor, and HER2 in breast cancer. Modern Pathology. 2010;**23**(Suppl 2):S52-S59

[64] Bowen TS, Schuler G, Adams V. Skeletal muscle wasting in cachexia and sarcopenia: Molecular pathophysiology and impact of exercise training. Journal of Cachexia, Sarcopenia and Muscle. 2015;**6**:197-128

[65] Courneya KS, Segal RJ, Mackey JR, Gelmon K, Reid RD, Friedenreich CM, et al. Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: A multicenter randomized controlled trial. Journal of Clinical Oncology. 2007;**25**:4396-4404

[66] al-Majid S, McCarthy DO. Resistance exercise training attenuates wasting of the extensor digitorum longus muscle in mice bearing the

colon-26 adenocarcinoma. Biological Research for Nursing. 2001;**2**:155-166

[67] Puppa MJ, White JP, Velazquez KT, Baltgalvis KA, Sato S, Baynes JW, et al. The effect of exercise on IL-6-induced cachexia in the Apc (min/+) mouse. Journal of Cachexia, Sarcopenia and Muscle. 2012;**3**:117-137

[68] Frajacomo FT, de Souza Padilha C, Marinello PC, Guarnier FA, Cecchini R, Duarte JA, et al. Solid Ehrlich carcinoma reproduces functional and biological characteristics of cancer cachexia. Life Sciences. 2016;**162**:47-53

[69] Padilha CS, Borges FH, Mendes C, da Silva LE, Frajacomo FTT, Jordao AA, et al. Resistance exercise attenuates skeletal muscle oxidative stress, systemic pro-inflammatory state, and cachexia in Walker-256 tumor-bearing rats. Applied Physiology, Nutrition, and Metabolism. 2017;**42**:916-923

[70] Argiles JM, Busquets S, Lopez-Soriano FJ, Costelli P, Penna F. Are there any benefits of exercise training in cancer cachexia? Journal of Cachexia, Sarcopenia and Muscle. 2012;**3**:73-76

[71] Arany Z, Lebrasseur N, Morris C, Smith E, Yang W, Ma Y, et al. The transcriptional coactivator PGC-1beta drives the formation of oxidative type IIX fibers in skeletal muscle. Cell Metabolism. 2007;**5**:35-46

[72] Baracos VE. Bridging the gap: Are animal models consistent with clinical cancer cachexia? Nature Reviews. Clinical Oncology. 2018;**15**:197-198

[73] Padrão AI, Figueira ACC, Faustino-Rocha AI, Gama A, Loureiro MM, Neuparth MJ, et al. Long-term exercise training prevents mammary tumorigenesis-induced muscle wasting in rats through the regulation of TWEAK signaling. Acta Physiologica (Oxford, England). 2017;**219**:23-813

#### **Chapter 12**

## Physical Activity and Vaccine Response

*Kotaro Suzuki*

#### **Abstract**

Over the past decade, numerous research studies have shown that the immune system's capacity for creating antibodies after getting vaccinated is better in those who exercise are physically active. Authoritative studies show that exercise is an important ally of the vaccine, amplifying its effectiveness. The immune response to vaccines is usually lower in the elderly population. Several strategies have been used to help overcome this problem. Recently, studies in humans and animals have shown that exercise increases antigen-specific blood antibody levels following vaccination. Exercise has been considered as an effective way to improve vaccine response in the elderly population. In this chapter, we will discuss the effect of exercise on vaccine response. This study summarizes the current understanding of exercise and antibody production. In order to develop intervention strategies, it will be necessary to further elucidate the predisposing factors and mechanisms behind exercise induce antibody response.

**Keywords:** exercise, physical activity, vaccine response, antibody

#### **1. Introduction**

In our daily life, there are harmful viruses, bacteria, and other microorganisms that can invade the human body and cause illness. However, the human body has a mechanism to prevent pathogens from causing disease once they have invaded the body. This mechanism is called "immunity." Immunity is a powerful defense mechanism that protects us from disease by recognizing pathogens in the body and killing them. Vaccines make use of this mechanism.

Vaccination is one of the most successful public health interventions in preventing infectious diseases and reducing the mortality and morbidity associated with these diseases. The main aim of vaccination is to prevent pathogen-specific infections. The result is to prevent people from becoming seriously ill and dying. On the other hand, aging is the biggest risk factor for impaired immunological health and reduced vaccine efficacy. To enhance the vaccine response, the vaccine itself needs to be modified or behavioral interventions need to be found that alter host factors to enhance the vaccine response.

Exercise improves antibody response to vaccine in human study [1]. Despite the potential beneficial role of exercise on immune responses to vaccination, the underlying mechanisms remain understudied. Based on the studies above, it is generally accepted that prolonged intense exercise is detrimental [2], whilst continuous moderate-intensity exercise is beneficial to immune function [3]. Exercise is a costeffective behavioral intervention to enhance immune function. Exercise may have a

beneficial effect on the immune response to vaccination in elderly population. The two main questions of interest are: (1) how does exercise benefit the effectiveness of vaccination; and (2) what kind of exercise, for how long and at what intensity, would be beneficial in elderly population?

The primary goal of the review presented in this chapter is to provide a better understanding of exercise and vaccine response. This chapter is divided into three parts, with the first section summarizing basic knowledge about vaccines and antibody production. In the second part, we focus on the latest insights into the mechanism of exercise-induced increase in antibody concentration. This section describes the intensity of exercise, the duration of exercise, endogenous opioids, IgG half-life that are modulated by exercise. The third part presents information on our current understanding on immune senescence and effects of exercise on vaccine response in older adult.

#### **2. Vaccination**

#### **2.1 What is in a vaccine?**

Vaccination is regarded one of the greatest medical discoveries of modern civilization. The eradication of smallpox is one of the most important contribution toward for human and best examples of how vaccination stopped a deadly disease and saved millions of lives [4]. A vaccine is a complex biological product that can be used to safely induce an immune response that confers protection against infection and disease on subsequent exposure to a pathogen.

Vaccine adjuvants usually improve the vaccine response by stimulating the innate immune system, which provides for the rapid first line of defense against infection. Regardless of whether the vaccine is made up of the antigen itself, this weakened version will not cause the disease in the person receiving the vaccine, but it will prompt their immune system to respond much as it would have on its first reaction to the actual pathogen. To achieve this, vaccines are made from pathogenic viruses and bacteria that have been rendered less virulent by reducing their virulence. An essential component of most vaccines is one or more protein antigens that elicit an immune response that provides protection.

#### **2.2 Vaccines induce antibodies**

Vaccination response can be understood as a measure of integrated immune function, elicited by antigen exposure and measured by antibody titer and cellmediated response [4]. The adaptive immune response is mediated by B cells that produce antibodies (humoral immunity) and by T cells (cellular immunity). All vaccines in routine use are thought to mainly confer protection through the induction of antibodies. Immune responses to antigens may be categorized as primary or secondary responses (**Figure 1**). After vaccination, B-lymphocytes detect the antigens and respond as if a real infectious agent has invaded the body, proliferating to form identical cells that can respond to the vaccine antigens. This response from immune system, generated by the B lymphocytes, is known as the primary response.

After initial antigen exposure, it takes several days for this adaptive response to become active. After the first exposure to a pathogen, immune activity rises and then levels off and declines. Since the initial immune response is slow, it does not prevent disease. Antibody levels in the circulation wane after primary vaccination, often to a level below that required for protection. During subsequent exposures to

#### **Figure 1.**

*During the primary response, naive B cell differentiation and antibody production occur several days after antigen encounter (initial exposure). In contrast, following secondary antigenic exposure, B cells expand with a shortened lag phase and produce larger quantities of antibodies. The difference between the primary and secondary exposures is the presence of memory B cells and pre-existing antigen-specific antibody. Memory cells differentiate into antibody-secreting plasma cells that output a greater amount of antibody for a longer period of time.*

the same pathogen, the immune system can respond rapidly, and activity reaches higher levels. The secondary immune responses can usually prevent disease. In encountering a pathogen, the immune system of an individual who has been vaccinated against that specific pathogen is able to mount a protective immune response more rapidly and more robustly. Immune memory is important feature of vaccineinduced protection. Memory of the infection is reinforced, and long-lived antibodies remain in circulation. It takes several days to build to maximum intensity, and the antibody concentration in the blood peaks at about 14 days [5].

Some infections, such as chickenpox, induce a life-long memory of infection [6]. Other infections, such as influenza, vary from season to season to such an extent that even an adult is unable to adapt [7]. Seasonal influenza A and B viruses are constantly evolving in nature, often resulting in antigenic change or "drift" [8]. The composition of influenza vaccines is updated annually to keep pace with antigenic drift [9]. Whether immune memory can protect against a future pathogen encounter depends on the incubation time of the infection, the quality of the memory response and the level of antibodies induced by memory B cells.

#### **3. Exercise and antibody response**

#### **3.1 Exercise induces antibody production**

The immune response is a complex mechanism, but it is important to understand this in order to consider the possibility that it may be modulated by exercise. Liu and Wang [10] examined exercise-induced blood antibody levels in mice. They examined the plasma antibody levels of mice after infected with *Salmonella typhi*. The results showed that the antibody titer of the exercising mice was significantly higher (2.76 times higher) than that of the non-exercising group during the experiment. The antibody titer of the exercising mice was 2.76 times higher than that of the control group (**Figure 2**). Authors observed that after the initial immunization,

#### **Figure 2.**

*Effects of physical training on the murine immunological response. Serum antibody levels in active (exercise) and control (non-exercise) mice (modified from Douglass [11]).*

a primary antibody response occurred. After booster immunization, the antibody levels increased and then remained high in the blood. This result means that maintenance of long-term antibody responses is critical for protective immunity against many pathogens. After this study, effects of exercise on secondary antibody responses have been tested in young mice [12] and rats [13]. Several studies have been conducted on exercise-induced elevation of blood antibody, focusing mainly on the secondary antibody response. Exercise immunologists were intrigued by the dramatic changes in secondary antibody responses in exercising mice.

Moderate exercise, such as voluntary wheel running exercise [12] or exercise (8–15 m/minutes) on a treadmill [14], has been shown to have a marked effect on the increase in antibody levels after booster immunization. These findings have proved to be valuable information that prompted exercise immunologists to investigate. Thus, since the early days, the effect of exercise on the increase in blood antibody concentration after booster immunization has been investigated. Moderate exercise may be a powerful adjuvant to vaccination.

The rodent model is known to affect the antibody response after booster immunization. In mice, the primary IgG response to the antigen was not enhanced, but in mice subjected to exercise, the IgG response was enhanced after booster immunization [12]. Subsequent reports also showed that antibody production in exercising mice was enhanced after booster immunization [10, 11, 15]. It is unclear why moderate exercise affects the antibody response after booster immunization, while it does not affect antibody production after initial immunization.

#### **3.2 Effect of moderate intensity physical exercise on antibody response**

Both moderate and vigorous-intensity physical activity improve antibody response. Moderate-intensity physical exercises stimulate cellular immunity, while prolonged or high-intensity practices without appropriate rest can trigger decreased cellular immunity, increasing the propensity for infectious diseases [14]. Furthermore, acute and intensive exercise, more common among athletes such

#### *Physical Activity and Vaccine Response DOI: http://dx.doi.org/10.5772/intechopen.102531*

as marathon runners, can lead to transient immunodepression [16]. According to the International Society for Exercise and Immunology (ISEI), the immunological decrease occurs after the practice of prolonged physical exercise, that is, after 90 minutes of moderate- to high-intensity physical activity [17].

In contrast, moderate intensity physical activity is responsible for providing an increase in the immune response. As an example, elderly women participating in a moderate intensity physical exercise program aerobic exercises were performed between 60 and 70% of VO2max, involving at least 30 minutes of exercises in step, jump coordination, and rhythmic movements sometimes dance for at least 12 months (1 hour exercise sessions 4 times a week) produced higher levels of antiinfluenza (IgM and IgG) antibodies compared to sedentary women [18]. Another study showed that elderly subjects who performed physical exercised at 65–75% heart rate reserve (HRR), 25–30 minutes, 3 days per week, for 10 months also confirmed that the exercise increased the concentration of antibodies against the influenza vaccine [19].

Moderate-intensity exercise was also effective in increasing the effectiveness of the pneumococcal vaccine. When young adults immunized with pneumococcal vaccine were given 15 minutes of moderate exercise (30 seconds of exercise followed by 30 seconds of rest), they showed higher antibody production than those who did not exercise [20]. Thus, moderate physical exercise helps our body trigger the antigen specific antibody response to effectively.

#### **3.3 Effect of exercise term on secondary antibody response**

How long exercise does it take to be effective exercise induce secondary antibody response? Moderate exercise conducted over a 2- to 8-week period enhances secondary antibody response and is mediated. Kapasi et al. compared different duration of moderate exercise training on antibody immune responses in young mice [21]. Female C57BL/6 mice were randomized into 2 to 8-week exercise training or sedentary control group. Mice with 2 weeks of exercise showed a significant increase in antibodies after the additional immunization, comparable to mice with 8 weeks of exercise. Studies on the effect of moderate exercise on increased antibody levels after additional immunization will be reviewed in a later section. A moderate exercise program of 2 weeks may be sufficient to improve secondary antibody production. The author proposed that may be a useful strategy to enhance antibody response to vaccinations in humans.

#### **3.4 Effect of exercise on antigen-specific antibody producing B cell and T cell**

Factors responsible for the enhance antibody level after booster immunization have been investigated in detail by Suzuki and Tagami [12]. They examined the effect of exercise on antigen-specific IgG-producing cells in splenic lymphocytes by Enzyme-Linked ImmunoSpot [22]. The antigen-specific IgG-producing cells were significantly higher in the exercising group than in the sedentary group. Authors proposed that effects of voluntary wheel-running exercise on the number of cells which produce tetanus toxoid (TT)-specific IgG producing cells (**Figure 3**). Voluntary exercise of moderate intensity (60–70% VO2max) increases the immune response of CD4+ T cells in healthy mice after vaccination [23]. Rogers et al. reported that exercised C57BL/6 mice with OVA intranasally immunization, and significantly increased CD4+ T cells (collected in spleen, mesentery lymph nodes, and Peyer's patches), TNF-α OVA-specific, and IL-5 were significantly increased. These reports suggest that exercise also effect on B cell and T cell responses.

#### *Exercise Physiology*

#### **Figure 3.**

*Effects of physical training on the murine immunological response. Antigen specific antibody levels in active (exercise) and control (non-exercise) mice (modified from Suzuki and Tagami [12]).*

#### **3.5 Effects of exercise on endogenous opioids**

*Beta*-endorphin, an opioid peptide is released into the blood after moderate exercise [24]. However, this phenomenon varies among individuals. Furthermore, endorphin levels in the blood are maintained for 15–60 minutes after exercise [25]. The role of endogenous opioids in exercise-induced increases in secondary antibody concentrations is unknown [12]. It has been suggested that endogenous opioids are involved in the increase in exercise-induced secondary antibody concentrations. Endogenous opioids have been implicated in exercise-induced increases in secondary antibody concentrations. Enkephalins were first observed in the brain and endocrine system. Both endorphins and enkephalins are important regulators of pain. Endorphins have been implicated in immune function [13], pain relief [26], and response to exercise [27–29]. The role of endogenous opioids in modulating exercise-induced increases in secondary antibody concentrations, especially at the cellular level, needs to be elucidated.

Kapasi et al. [30] initially immunized mice with antigens and administered placebo or an opioid antagonist (naltrexone), while untreated mice received no intervention. The mice were then subjected to exercising for 8 weeks, followed by booster immunization. After the booster immunization, the antibody levels increased in the exercising mice. On the other hand, there was no increase in antibody levels in the mice that received the antagonist. The increase in antibody concentration by endogenous opioids was dose-dependent of intravenous injection [31]. The production of antibodies occurs as a result of the interaction of antigens retained on follicular dendritic cells with B and Th lymphocytes [32, 33].

The mechanism of exercise-induced antibody concentration is activated by the binding of opioids to specific receptors on B cells and T cells [33]. Endogenous opioids also affect the antibody response through receptors on Th (CD4+) cells and by stimulating proliferation [34, 35]. These cascades are the result of induced IL-4 production, and IL-4 increases the viability of splenic B cells [36]. Further research is needed to determine if the effect of exercise is due to increased antibody levels.

#### **3.6 Effects of exercise on IgG half-life**

The mechanism that induces exercise-induced increases in blood antibody concentrations is related to the half-life of IgG [12]. The clearance rate of IgG in

#### *Physical Activity and Vaccine Response DOI: http://dx.doi.org/10.5772/intechopen.102531*

blood has been found to be highly dependent on its concentration in plasma [37]. The half-life of IgG in blood at physiological concentrations is about 10-fold longer than at IgG higher concentrations [37]. IgG proteins are endocytosed [38]. IgG is induced at the cell surface and released into plasma or interstitial fluid. FcRn regulates IgG epithelial transport and recycling. FcRn binds to IgG in a pH-dependent manner binding to IgG [39, 40]. In an acidic environment, IgG binds strongly to FcRn; the IgG-FcRn complex is transported by lysosomes to the cell surface where it fuses with the cell membrane [41]. At physiological pH, the FcRn receptor has little affinity for IgG. When sorting vesicles fuse to the plasma membrane, IgG dissociates from the receptor and is rapidly released into the extracellular fluid. Clearance of IgG is increased approximately 10-fold, and the efficiency of IgG recycling is over 90% in wild-type animals expressing FcRn [40].

The effect of exercising mice on IgG clearance has been reported [42]. The clearance of IgG with exercise has been reported by Suzuki and Tagami [12]. They investigated for factors that would reduce the clearance of non-specific 125I-IgG in the blood after booster immunization (**Figure 4**). High blood antibody levels may result in low clearance of antibodies. The reason for the low clearance of 125I-IgG in the blood of exercising mice has not yet been elucidated; the homeostasis mechanism of IgG depends on the Fc region of IgG [42]. A possible cause of the decreased clearance is the FcRn receptor, which is expressed in the vascular endothelium in mice and has an IgG protective function [43].

The FcRn molecule is dependent on dimerization with β2-microglobulin (β2m) [43]. In β2m-deficient mice, a shortening of the half-life of IgG occurs and homeostatic IgG levels are reduced [44]. Suzuki et al. reported on the effects of intraperitoneal immunization of mice with TT to induce primary and secondary antibody responses, protection from IgG catabolism in the liver and β2m expression. The authors reported an exercise-induced increase in blood antibody concentrations and a prolonged half-life of antigen-specific IgG in active mice [45]. Exercising mice had higher levels of radiolabeled IgG in the liver. This phenomenon was also confirmed by immunohistochemical analysis. The expression of the β2m gene was up regulated in the liver of exercised mice. There was a significant correlation between the amount of IgG accumulated in the liver and the concentration of IgG in the blood. There was also a significant correlation between total liver IgG and liver β2m.

#### **Figure 4.**

*Clearance of radiolabeled IgG from exercise (black circles) and non-exercise (white circles) mice (modified from Suzuki and Tagami [12]).*

#### **4. Exercise and vaccine in older population**

#### **4.1 Immune senescence in old adults**

Preventive medicine is the most effective and feasible strategy to protect health in old subjects and vaccination against the most common infectious diseases is the most indicated approach. Most currently used vaccines are less immunogenic and effective in the elderly compared to younger adults [46]. This is due to several factors, including immune aging and a different immune response in children and young adults than in older adults with a history of infection. Almost all vaccines are specifically designed for children and young adults. The mechanisms of immune senescence are multiple but seem to be driven largely by changes in T cell-mediated immunity. There are fewer antigen-naïve T cells in the peripheral blood of aged individuals than there are in younger individuals [47].

Aging is a natural process and is described as "immune senescence." Immune senescence is associated with a decline in the immune system [48]. An important sign of immune senescence is the decline in immune function. Decline in immune function can lead to the development of opportunistic infections [49]. Immune senescence also results in a reduced vaccine response [50], leading to an increased incidence of infectious diseases. Improving immune function is expected to reduce the incidence of infections in the elderly and have beneficial effects in maintaining health. Moderate exercise has been used as an intervention to combat the aging of the immune system.

Aging is associated with declines in humoral and cellular immunity [51], and therefore reduced immune function. The decline in immunity due to aging is more pronounced in acquired immunity than in natural immunity. The capacity of this acquired immunity peaks around the age of 20s and declines to about half of that in the 40s. The main cause of immune senescence thought to be the change in the quality of T cells due to the decline in the function of the thymus gland.

The age-related decline in the function of major cells that take part in the antibody response are reflected by the secondary antibody response [52]. Kapasi et al. focused on age-related changes in immune function and the effects of exercise, and their study clearly showed that older mice exhibited a secondary antibody response similar to that seen in young control mice after exercise [15]. Thus, intense exercise exerts positive effects on the secondary antibody response in older animals. This, exercise-induced attenuation of immune senescence might help to improve immune responses to vaccination. Therefore, the health of the elderly is closely related to the maintenance of immune function. Therefore, the health of the elderly is closely related to the maintenance of the immune system. Thus, exercise has a positive effect on the secondary antibody response in older animals. This suggests that exercise in older animals may contribute to the immune response to vaccination. Hence, the health of the elderly is closely related to the maintenance of immune function.

#### **4.2 Effects of exercise on vaccine response in older adult**

Recently, several strategies have been tested to improve the efficacy of a vaccine in older adults. Regular exercise has been associated with enhanced vaccination responses [51, 52]. In contrast, acute exercise had no detrimental effect on vaccination response in healthy older adults [53]. Exercise-induced elevation of antibody concentrations is a tool against infectious diseases. The use of exercise-induced elevation of antibody concentrations to combat infectious diseases in humans has been investigated, and positive results have been observed [19]. Moderate aerobic

#### *Physical Activity and Vaccine Response DOI: http://dx.doi.org/10.5772/intechopen.102531*

exercise in the elderly [19] and resistance exercise have been shown to enhance the immune response to influenza vaccination [54, 55]. In addition, several crosssectional studies have found that physically fit [56] and active older adults [57] have higher antibody responses to booster immunization. Shuler et al. [58] examined antibody titers to influenza vaccination in the elderly. There was no association between physical activity level and the degree of antibody concentration. However, this study did not measure antigen-specific antibodies.

Cross-sectional studies in elderly populations have all reported increased antibody concentrations after booster immunization in participants with high physical fitness [56, 59] or physical activity [57, 58, 60]. This effect of exercise-induced increases in antibody concentrations after vaccination in an elderly population was exemplified by Smith et al. [60]. They compared antibody levels in exerciseinduced antibody production by immunizing with keyhole limpet hemocyanin (KLH). The results showed that antibody responses and cell-mediated responses to KLH were stronger in active elderly men than in sedentary elderly men.

Woods et al. demonstrated that 10 months of aerobic exercise (60–70% maximal oxygen uptake, 45–60 minutes, 3 times per week) in previously sedentary elderly subjects resulted in increased blood antibody levels compared to participants who only participated in flexibility training during the same period [61]. Elevated antibody concentrations to antigens have also been observed after chronic exercise; after KLH vaccination, IgG1 and IgM concentrations were higher in participants who completed a 10-month cardiovascular training program than in control participants [62]. Previously reported studies supported the hypothesis that regular exercise improves immune function in the elderly. This is reflected in the increased concentration of antigen-specific antibodies after vaccination, especially in the elderly.

#### **5. Conclusion**

In this review, we presented to improve vaccine response through moderate exercise. Currently available evidence shows that moderate exercise impacts upon the secondary antibody response but not the primary response. These effects are mediated by a diverse range of factors, including the functions of antibody producing cells, proliferation of CD4+ T cells, endogenous opioids, and IgG half-life. Over 2-week period enhances secondary antibody response is mediated. Most exercise studies have focused on antibody production, with more work required in this area. Almost all studies have investigated the effects of moderate exercise on immune function. This will provide insight into vaccination that is improved by exercise. The incorporation of molecular biological methods into the field of exercise immunology should improve our understanding of the activation of cells involved in exercise-induced increases in antibody concentrations after booster immunization.

#### **Acknowledgements**

I would like to express my heartfelt gratitude to my advisor, Dr. Kazumi Tagami, for her guidance and encouragement throughout my PhD. Dr. Tagami was always happy with me when I succeeded and worked with me to find the cause of my failures. This study was supported in part by grants from the Daiwa Securities Health Foundation and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (No. 16650154 to KT). This paper is a revised and enhanced version of the authors' recent publication [12, 45].

## **Abbreviations**


## **Author details**

Kotaro Suzuki Faculty of Health and Sports Sciences, University of Tsukuba, tsukubai-shi, ibaraki-ken, Japan

\*Address all correspondence to: koutarousuzuki55@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Physical Activity and Vaccine Response DOI: http://dx.doi.org/10.5772/intechopen.102531*

### **References**

[1] Havers F, Sokolow L, Shay DK, Farley MM, Monroe M, Meek J, et al. Case-control study of vaccine effectiveness in preventing laboratoryconfirmed influenza hospitalizations in older adults, United States, 2010-2011. Clinical Infectious Diseases. 2016;**63**(10):1304-1311

[2] Campbell JP, Turner JE. Debunking the myth of exercise-induced immune suppression: Redefining the impact of exercise on immunological health across the lifespan. Frontiers in Immunology. 2018;**9**:648

[3] Khammassi M, Ouerghi N, Said M, Feki M, Khammassi Y, Pereira B, et al. Continuous moderate-intensity but not high-intensity interval training improves immune function biomarkers in healthy young men. Journal of Strength and Conditioning Research. 2020;**34**(1):249-256

[4] WHO. Summary report on first, second and third generation smallpox vaccines. WHO Report. 2013. p. 33

[5] Stratton K, Ford A, Rusch E, Clayton EW. Adverse Effects of Vaccines: Evidence and Causality. Washington DC: The National Academies Press; 2012. pp. 1-894

[6] Gershon AA, Breuer J, Cohen JI, Cohrs RJ, Gershon MD, Gilden D, et al. Varicella zoster virus infection. Nature Reviews. Disease Primers. 2015;**1**:1-19

[7] WHO. Evaluation of Influenza Vaccine Effectiveness: A Guide to the Design and Interpretation of Observational Studies. Geneva, Switzerland: World Health Organization; 2017

[8] Petrova VN, Russell CA. The evolution of seasonal influenza viruses. Nature Reviews. Microbiology. 2018;**16**(1):47-60

[9] Paules C, Subbarao K. Influenza. The Lancet. 2017;**390**(10095):697-708

[10] Liu YG, Wang SY. The enhancing effect of exercise on the production of antibody to *Salmonella typhi* in mice. Immunology Letters. 1987;**14**(2):117-120

[11] Douglass JH. The effects of physical tracing on the immunological response in mice. The Journal of Sports Medicine and Physical Fitness. 1974;**14**(1):48-54

[12] Suzuki K, Tagami K. Voluntary wheel-running exercise enhances antigen-specific antibody-producing splenic B cell response and prolongs IgG half-life in the blood. European Journal of Applied Physiology. 2005;**94**(5-6): 514-519

[13] Kaufman JC, Harris TJ, Higgins J, Maisel AS. Exercise-induced enhancement of immune function in the rat. Circulation. 1994;**90**(1):525-532

[14] Pedersen BK, Hoffman-Goetz L. Exercise and the immune system: Regulation, integration, and adaptation. Physiological Reviews. 2000;**80**(3): 1055-1081

[15] Kapasi ZF, Catlin PA, Joyner DR, Lewis ML, Schwartz AL, Townsend EL. The effects of intense physical exercise on secondary antibody response in young and old mice. Physical Therapy. 2000;**80**(11):1076-1086

[16] Cox AJ, Gleeson M, Pyne DB, Callister R, Hopkins WG, Fricker PA. Clinical and laboratory evaluation of upper respiratory symptoms in elite athletes. Clinical Journal of Sport Medicine. 2008;**18**(5):438-445

[17] Walsh NP, Gleeson M, Pyne DB, Nieman DC, Dhabhar FS, Shephard RJ, et al. Position statement. Part two: Maintaining immune health. Exercise Immunology Review. 2011;**17**:64-103

[18] Bachi ALL, Suguri VM, Ramos LR, Mariano M, Vaisberg M, Lopes JD. Increased production of autoantibodies and specific antibodies in response to influenza virus vaccination in physically active older individuals. Results in Immunology. 2013;**3**:10-16

[19] Kohut ML, Arntson BA, Lee W, Rozeboom K, Yoon K-J, Cunnick JE, et al. Moderate exercise improves antibody response to influenza immunization in older adults. Vaccine. 2004;**22**(17-18):2298-2306

[20] Edwards KM, Pung MA, Tomfohr LM, Ziegler MG, Campbell JP, Drayson MT, et al. Acute exercise enhancement of pneumococcal vaccination response: A randomised controlled trial of weaker and stronger immune response. Vaccine. 2012;**30**(45):6389-6395

[21] Kapasi ZF, Catlin PA, Adams MA, Glass EG, McDonald BW, Nancarrow AC. Effect of duration of a moderate exercise program on primary and secondary immune responses in mice. Physical Therapy. 2003;**83**(7):638-647

[22] Czerkinsky C, Andersson G, Ekre HP, Nilsson LA, Klareskog L, Ouchterlony O. Reverse ELISPOT assay for clonal analysis of cytokine production. I. Enumeration of gammainterferon-secreting cells. Journal of Immunological Methods. 1988;**110**(1):29-36

[23] Rogers CJ, Zaharoff DA, Hance KW, Perkins SN, Hursting SD, Schlom J, et al. Exercise enhances vaccine-induced antigen-specific T cell responses. Vaccine. 2008;**26**(42):5407-5415

[24] Pilozzi A, Carro C, Huang X. Peran β-Endorphin dalam Stres, Perilaku, Peradangan Neuroin, dan Metabolisme. International Journal of Molecular Sciences. 2021;**22**(1):338-362

[25] Sforzo GA. Opioids and exercise. An update. Sports Medicine. 1989;**7**(2):109-124

[26] Sommers DK, Loots JM, Simpson SF, Meyer EC, Dettweiler A, Human JR. Circulating met-enkephalin in trained athletes during rest, exhaustive treadmill exercise and marathon running. European Journal of Clinical Pharmacology. 1990;**38**(4): 391-392

[27] Jamurtas AZ, Goldfarb AH, Chung SC, Hegde S, Marino C. Betaendorphin infusion during exercise in rats: Blood metabolic effects. Medicine and Science in Sports and Exercise. 2000;**32**(9):1570-1575

[28] Nauli SM, Maher TJ, Pearce WJ, Ally A. Effects of opioid receptor activation on cardiovascular responses and extracellular monoamines within the rostral ventrolateral medulla during static contraction of skeletal muscle. Neuroscience Research. 2001;**41**(4):373-383

[29] Tsuchimochi H, McCord JL, Kaufman MP. Peripheral mu-opioid receptors attenuate the augmented exercise pressor reflex in rats with chronic femoral artery occlusion. American Journal of Physiology. Heart and Circulatory Physiology. 2010;**299**(2):H557-H565

[30] Kapasi ZF, Catlin PA, Beck J, Roehling T, Smith K. The role of endogenous opioids in moderate exercise training-induced enhancement of the secondary antibody response in mice. Physical Therapy. 2001;**81**(11):1801-1809

[31] Janković BD, Marić D. Enkephalins and immunity. I: In vivo suppression and potentiation of humoral immune response. Annals of the New York Academy of Sciences. 1987;**496**: 115-125

*Physical Activity and Vaccine Response DOI: http://dx.doi.org/10.5772/intechopen.102531*

[32] Mousa SA, Zhang Q, Sitte N, Ji R, Stein C. Beta-endorphin-containing memory-cells and mu-opioid receptors undergo transport to peripheral inflamed tissue. Journal of Neuroimmunology. 2001;**115**(1-2):71-78

[33] Tew JG, Kosco MH, Burton GF, Szakal AK. Follicular dendritic cells as accessory cells. Immunological Reviews. 1990;**117**:185-211

[34] Kamphuis S, Eriksson F, Kavelaars A, Zijlstra J, van de Pol M, Kuis W, et al. Role of endogenous pro-enkephalin A-derived peptides in human T cell proliferation and monocyte IL-6 production. Journal of Neuroimmunology. 1998;**84**(1):53-60

[35] Sharp BM, Li MD, Matta SG, McAllen K, Shahabi NA. Expression of delta opioid receptors and transcripts by splenic T cells. Annals of the New York Academy of Sciences. 2000;**917**:764-770

[36] Mori M, Morris SC, Orekhova T, Marinaro M, Giannini E, Finkelman FD. IL-4 promotes the migration of circulating B cells to the spleen and increases splenic B cell survival. Journal of Immunology. 2000;**164**(11): 5704-5712

[37] Waldmann TA, Strober W. Metabolism of immunoglobulins. Progress in Allergy. 1969;**13**:1-110

[38] Jones DH, Nusbacher J, Anderson CL. Fc receptor-mediated binding and endocytosis by human mononuclear phagocytes: Monomeric IgG is not endocytosed by U937 cells and monocytes. The Journal of Cell Biology. 1985;**100**(2):558-564

[39] Brambell FW, Hemmings WA, Morris IG. A theoretical model of gamma-globulin catabolism. Nature. 1964;**203**:1352-1354

[40] Junghans RP. Finally! The Brambell receptor (FcRB). Mediator of

transmission of immunity and protection from catabolism for IgG. Immunologic Research. 1997;**16**(1):29-57

[41] Qiao S-W, Kobayashi K, Johansen F-E, Sollid LM, Andersen JT, Milford E, et al. Dependence of antibody-mediated presentation of antigen on FcRn. Proceedings of the National Academy of Sciences of the United States of America. 2008;**105**(27):9337-9342

[42] Ghetie V, Hubbard JG, Kim JK, Tsen MF, Lee Y, Ward ES. Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice. European Journal of Immunology. 1996;**26**(3):690-696

[43] Wani MA, Haynes LD, Kim J, Bronson CL, Chaudhury C, Mohanty S, et al. Familial hypercatabolic hypoproteinemia caused by deficiency of the neonatal Fc receptor, FcRn, due to a mutant beta2-microglobulin gene. Proceedings of the National Academy of Sciences of the United States of America. 2006;**103**(13):5084-5089

[44] Christianson GJ, Brooks W, Vekasi S, Manolfi EA, Niles J, Roopenian SL, et al. Beta 2-microglobulin-deficient mice are protected from hypergammaglobulinemia and have defective antibody responses because of increased IgG catabolism. Journal of Immunology. 1997;**159**(10):4781-4792

[45] Suzuki K, Suk PJ, Hong C, Imaizumi S, Tagami K. Exerciseinduced liver beta2-microglobulin expression is related to lower IgG clearance in the blood. Brain, Behavior, and Immunity. 2007;**21**(7):946-952

[46] Jefferson T, Rivetti D, Rivetti A, Rudin M, Di Pietrantonj C, Demicheli V. Efficacy and effectiveness of influenza vaccines in elderly people: A systematic review. The Lancet. 2005;**366**(9492): 1165-1174

[47] Suchard M. Immunosenescence: Ageing of the immune system. South African Pharmaceutical Journal. 2015;**82**:28-31

[48] Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. The Journal of Pathology. 2007;**211**(2):144-156

[49] Pawelec G, Adibzadeh M, Pohla H, Schaudt K. Immunosenescence: Ageing of the immune system. Immunology Today. 1995;**16**:420-422

[50] Kumar R, Burns EA. Age-related decline in immunity: Implications for vaccine responsiveness. Expert Review of Vaccines. 2008;**7**(4):467-479

[51] Hodes RJ. Aging and the immune system. Immunological Reviews. 1997;**160**:5-8

[52] Szakal AK, Kapasi ZF, Masuda A, Tew JG. Follicular dendritic cells in the alternative antigen transport pathway: Microenvironment, cellular events, age and retrovirus related alterations. Seminars in Immunology. 1992;**4**(4): 257-265

[53] Bohn-Goldbaum E, Pascoe A, Singh MF, Singh N, Kok J, Dwyer DE, et al. Acute exercise decreases vaccine reactions following influenza vaccination among older adults. Brain, Behavior, & Immunity - Health. 2020;**1**:100009

[54] Schuler PB, Lloyd LK, Leblanc PA, Clapp TA, Abadie BR, Collins RK. The effect of physical activity and fitness on specific antibody production in college students. The Journal of Sports Medicine and Physical Fitness. 1999;**39**(3):233-239

[55] Edwards KM, Burns VE, Allen LM, McPhee JS, Bosch JA, Carroll D, et al. Eccentric exercise as an adjuvant to influenza vaccination in humans. Brain, Behavior, and Immunity. 2007;**21**(2): 209-217

[56] Keylock KT, Lowder T, Leifheit KA, Cook M, Mariani RA, Ross K, et al. Higher antibody, but not cell-mediated, responses to vaccination in high physically fit elderly. Journal of Applied Physiology. 2007;**102**(3):1090-1098

[57] Kohut ML, Cooper MM, Nickolaus MS, Russell DR, Cunnick JE. Exercise and psychosocial factors modulate immunity to influenza vaccine in elderly individuals. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2002;**57**(9):M557-M562

[58] Schuler PB, Leblanc PA, Marzilli TS. Effect of physical activity on the production of specific antibody in response to the 1998-99 influenza virus vaccine in older adults. The Journal of Sports Medicine and Physical Fitness. 2003;**43**(3):404

[59] Brydak LB, Tadeusz S, Magdalena M. Antibody response to influenza vaccination in healthy adults. Viral Immunology. 2004;**17**(4):609-615

[60] Smith TP, Kennedy SL, Fleshner M. Influence of age and physical activity on the primary in vivo antibody and T cell-mediated responses in men. Journal of Applied Physiology. 2004;**97**(2): 491-498

[61] Woods JA, Keylock KT, Lowder T, Vieira VJ, Zelkovich W, Dumich S, et al. Cardiovascular exercise training extends influenza vaccine seroprotection in sedentary older adults: The immune function intervention trial. Journal of the American Geriatrics Society. 2009;**57**(12):2183-2191

[62] Grant RW, Mariani RA, Vieira VJ, Fleshner M, Smith TP, Keylock KT, et al. Cardiovascular exercise intervention improves the primary antibody response to keyhole limpet hemocyanin (KLH) in previously sedentary older adults. Brain, Behavior, and Immunity. 2008;**22**(6):923-932

*Edited by Ricardo Ferraz, Henrique Neiva, Daniel A. Marinho, José E. Teixeira, Pedro Forte and Luís Branquinho*

Exercise physiology is one of the most researched sports sciences, with practical implications for health, well-being and sports performance. This book brings together emerging research in this area, presenting the main findings and criticisms, as well as considering the future of exercise physiology.

Published in London, UK © 2022 IntechOpen © Moussa81 / iStock

Exercise Physiology

Exercise Physiology

*Edited by Ricardo Ferraz, Henrique Neiva, Daniel A. Marinho, José E. Teixeira,* 

*Pedro Forte and Luís Branquinho*