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Exercise
Immune benefits of exercise
physical medicine

Definition

Exercise garners much publicity for the positive benefits it provides for weight control and stress management. However, only recently has much attention been paid to the advantages that regular exercise provides to immune function. Even a single bout of exercise can trigger increased activity in certain cells within the immune system. Researchers have found that both young and older adults experience this beneficial response at measurable levels. Studies on the influence of moderate exercise training on host protection and immune function have shown that near-daily brisk walking compared with inactivity reduced the number of sickness days by half over a 12- to 15-week period without change in resting immune function. Research in the area of cancer risk and prevention have found that physical activity is associated with a reduced risk of all-cause and colonic cancers, and it seems to exert a weaker effect on the risk of breast, lung and reproductive tract tumours.


footnotes

Friedenreich CM, Thune I, Brinton LA, Albanes D. Epidemiologic issues related to the association between physical activity and breast cancer. Cancer 1998 Aug 1;83(3 Suppl):600-610. (Review)
Abstract: A workshop on physical activity and breast cancer was held in November 1997 to review previous epidemiologic research on this topic and to identify new areas for research. This article is the first of three summaries of the workshop's activities. The
material reviewed included 21 studies that reported a measure of physical activity in relation to breast cancer outcomes and were published by December 1997. They were identified in a computerized literature search and a "by-hand" review of journals. The study designs, populations, data collection methods, and results were examined and the strengths and limitations of the studies identified. The strengths and limitations are discussed herein, as are recommendations for future research. Fifteen of the 21 studies suggested that physical activity reduces the risk of breast cancer, whereas four studies found no association and two studies found an increased risk of breast cancer associated with physical activity. Specific subgroups of the population may experience a greater decrease in breast cancer with increased levels of physical activity. These include women
who are lean, parous, and premenopausal. Some examination of confounding and effect modification was undertaken. Hypothesized biologic mechanisms for this putative association include an effect of physical activity on endogenous hormones, energy balance, and the immune system. The overall evidence supports a reduction in breast cancer risk with increased physical activity. However, numerous questions remain regarding this putative association. These include the underlying biologic model and the parameters of physical activity that are associated with risk, such as the types of activity (occupational, recreational, and household), the components of activity (frequency, intensity, and duration), the time periods in life that are associated with risk reduction, and the important confounders and effect modifiers of this association. Use of intermediate endpoints for breast cancer may be useful in such investigations.

Malm C, Lenkei R, Sjodin B. Effects of eccentric exercise on the immune system in men. J Appl Physiol 1999 Feb;86(2):461-468.
Abstract: The effects of eccentric exercise on changes in numbers of circulating leukocytes, cell activation, cell adhesion, and cellular memory function were investigated in 12 men, aged 22-35 yr. The immunologic effects of postexercise epidermal treatment with monochromatic, infrared light were also evaluated. Blood was drawn before and 6, 24, and 48 h after exercise for phenotyping and analysis of creatine kinase activity. There was an increase in leukocyte, monocyte, and neutrophil number, no change in the number of basophils, eosinophils, B cells, and T cells, and a decrease in natural killer cell number postexercise. Some markers of lymphocyte and monocyte activation remained unchanged or decreased, whereas the expression of adhesion molecules 62L and 11b increased on monocytes. It is concluded that eccentric exercise induced decreased activation, and increased cell adhesion capacity, of monocytes. Altered trafficking of cells between lymphoid tissue and blood, selective apoptosis, or attachment/detachment from the endothelial wall can explain the observed phenotypic changes. Treatment with monochromatic, infrared light did not significantly affect any of the investigated variables. Correlations between immunologic and physiological parameters indicate a role of the immune system in adaptation to physical exercise.

Mazzeo RS, Rajkumar C, Rolland J, Blaher B, Jennings G, Esler M. Immune response to a single bout of exercise in young and elderly subjects. Mech Ageing Dev 1998 Jan 30;100(2):121-132.
Abstract: The purpose of this investigation was to examine alterations in lymphocyte proliferation activity and T cell subsets following an acute bout of exercise in young and old subjects. Six young (26+/-3 years) and nine old (69+/-5 years) male subjects were tested at rest and immediately after 20 min of submaximal exercise at 50% peak work capacity. Arterial blood was sampled from an indwelling catheter for catecholamine and immunology assays. Peripheral blood lymphocytes were isolated for mitogen-induced phytohemagglutinin (PHA) proliferation capacity. Lymphocyte subsets were analyzed by dual-labeled flow cytometry. As has been shown in previous studies, baseline proliferative responsiveness was significantly lower in the old (down 22%) compared to the young subjects. In response to submaximal exercise, proliferative responsiveness to PHA increased significantly in the young subjects (up 55%), however, for the old subjects this response did not differ significantly from resting values (up 18%). The number of total lymphocytes, as well as CD4+ and CD8+ T cell subsets, at rest were lower for old subjects compared with young. Exercise-induced increases in T cell subset populations were similar across age groups. It was concluded that, while having lower initial T cell numbers and PHA responsiveness, immunoresponsiveness during a single bout of exercise is, in general, maintained in old when compared to young individuals.

McTiernan A, Ulrich C, Slate S, Potter J. Physical activity and cancer etiology: associations and mechanisms. Cancer Causes Control 1998 Oct;9(5):487-509.
Abstract: OBJECTIVES: This paper reviews the epidemiologic data of associations between physical activity and cancer risk, describes potential mechanisms for a physical activity cancer link, and proposes future directions for research. METHODS: We reviewed English-language published papers on physical activity and cancer through Medline searches for epidemiologic studies, and through references on individual reports. We reviewed general texts on effects of exercise on human biology and applied the concepts to the biology of cancer in humans to describe potential mechanisms for a physical activity-cancer association. RESULTS: Considerable epidemiologic evidence has accrued linking increased physical activity with reduced occurrence of cancers of the breast and colon. The association between physical activity and cancers of other sites is unclear. Potential mechanisms for the association between physical activity and reduced risk for breast and colon cancer are varied: they range from bias due to physical activity's strong correlations with other health factors (e.g., diet, smoking, alcohol use, use of medications) to the metabolic effects resulting from increased physical activity and fitness, such as reduced obesity, hormonal and reproductive effects, mechanical effects, and enhancement of the immune system. CONCLUSIONS: The elucidation of biologic mechanisms for an association between physical activity and cancer may provide biological support for the association. It will contribute information to determine the type, frequency, and duration of exercise needed to maximize protection. This information will be needed before large-scale community interventions are begun, in order to choose the correct interventions for the desired effect of reduced incidence of the most common cancers.

Nieman DC, Pedersen BK. Exercise and immune function. Recent developments. Sports Med 1999 Feb;27(2):73-80.
Abstract: Comparison of immune function in athletes and nonathletes reveals that the adaptive immune system is largely unaffected by athletic endeavour. The innate immune system appears to respond differentially to the chronic stress of intensive exercise, with natural killer cell activity tending to be enhanced while neutrophil function is suppressed. However, even when significant changes in the level and functional activity of immune parameters have been observed in athletes, investigators have had little success in linking these to a higher incidence of infection and illness. Many components of the immune system exhibit change after prolonged heavy exertion. During this 'open window' of altered immunity (which may last between 3 and 72 hours, depending on the parameter measured), viruses and bacteria may gain a foothold, increasing the risk of subclinical and clinical infection. However, no serious attempt has been made by investigators to demonstrate that athletes showing the most extreme post-exercise immunosuppression are those that contract an infection during the ensuing 1 to 2 weeks. This link must be established before the 'open window' theory can be wholly accepted. The influence of nutritional supplements, primarily zinc, vitamin C, glutamin and carbohydrate, on the acute immune response to prolonged exercise has been measured in endurance athletes. Vitamin C and glutamine have received much attention, but the data thus far are inconclusive. The most impressive results have been reported in the carbohydrate supplementation studies. Carbohydrate beverage ingestion has been associated with higher plasma glucose levels, an attenuated cortisol and growth hormone response, fewer perturbations in blood immune cell counts, lower granulocyte and monocyte phagocytosis and oxidative burst activity, and a diminished pro- and anti-inflammatory cytokine response. It remains to be shown whether carbohydrate supplementation diminishes the frequency of infections in the recovery period after strenuous exercise. Studies on the influence of moderate exercise training on host protection and immune function have shown that near-daily brisk walking compared with inactivity reduced the number of sickness days by half over a 12- to 15-week period without change in resting immune function. Positive effects on immunosurveillance and host protection that come with moderate exercise training are probably related to a summation effect from acute positive changes that occur during each exercise bout. No convincing data exist that moderate exercise training is linked with improved T helper cell counts in patients with HIV, or enhanced immunity in elderly participants.

Oliveria SA, Christos PJ. The epidemiology of physical activity and cancer. Ann N Y Acad Sci 1997 Dec 29;833:79-90. (Review)
Abstract: Experimental studies in animals and epidemiological studies in human populations support an inverse association between
exercise and the development of cancer. Physical activity has been shown to be protective against the development of breast
and colon cancer and may also be important for other kinds of cancer such as that of the prostate. The proposed biological
mechanisms for the physical activity--cancer association include exercise's effect on immune function, transit time of
digestion, hormones, and body fat. There has been little research on physical activity and the effect on progression of cancer,
although there are studies to suggest that it may slow the clinical course of the disease. Furthermore, exercise may be
beneficial in the treatment of cancer through mood elevation, decreased loss of lean tissue, and increased quality of life. Much
is still to be learned about the effect of exercise on cancer. The intensity, duration, frequency, and type of exercise that is
relevant need to be clarified. As well, the time period during life when exercise is important has not been determined. It
seems reasonable to conclude that exercise, a modifiable risk factor, is beneficial in preventing certain forms of cancer. Public
health interventions may hold promise for cancer prevention.


Scanga CB, Verde TJ, Paolone AM, Andersen RE, Wadden TA. Effects of weight loss and exercise training on natural killer cell activity in obese women. Med Sci Sports Exerc 1998 Dec;30(12):1666-71
Abstract: PURPOSE: The purposes of this study were two-fold: (1) to evaluate the effects of an 8-wk weight loss program on natural killer (NK) cell activity in obese women and 2) to determine whether an additional program of combined aerobic and resistance exercise training modified the effects of caloric restriction on immune function. METHODS: Twenty-two healthy obese women with a mean weight of 96.9 +/- 14 kg and age of 38 +/- 7 yr were randomly assigned to diet-alone (D) or diet-plus-exercise training (D + EX) conditions. Subjects consumed 950 kcal.d-1 using prepackaged portion-controlled foods.
Subjects in the D + EX group participated 3 times.wk-1 in a supervised program of light-to moderate-intensity aerobic activity and resistance training. Data were analyzed using a repeated measures ANOVA. RESULTS: After 8 wk of treatment, body weight decreased significantly in both groups (10.8% in D vs 11.4% in D + EX), whereas absolute and relative VO2peak increased in only D + EX (12.3% in D vs 57.7% in D + EX). Both groups experienced significant decreases in peripheral blood leukocytes and lymphocytes, although cell numbers remained within clinically normal range at week 8. NK cell (CD56+) proportion was unchanged in both groups after weight loss. The proportion of peripheral mononuclear cells expressing the interleukin-2 receptor-alpha (IL-2R alpha) (CD25+) decreased significantly (25.2%) in D and was unchanged in D + EX, resulting in a significant difference between groups at week 8. NK cell cytotoxicity was suppressed in D and unchanged in D + EX after treatment. Changes in NK cell activity were significantly correlated with proportional changes in (CD25+) (r = 0.584, P = 0.022), but not CD56+. CONCLUSIONS: A combined program of light- to moderate-intensity aerobic and resistance exercise offsets the apparent decrement in NK cell activity associated with weight loss.

Shephard RJ, Shek PN. Associations between physical activity and susceptibility to cancer: possible mechanisms. Sports Med 1998 Nov;26(5):293-315 .
Abstract: Physical activity is associated with a reduced risk of all-cause and colonic cancers, and it seems to exert a weaker effect on the risk of breast, lung and reproductive tract tumours. This review examines possible mechanisms behind the observed associations. Restriction of physical activity by pre-existing disease may contribute to the association with lung cancers, but seems a less likely explanation for other types of tumour. Indirect associations through activity-related differences in body build or susceptibility to trauma seem of minor importance. Potential dietary influences include overall energy balance and energy expenditure, the intake and/or bioavailability of minerals, antioxidant vitamins and fibre, and the relative proportions of protein and fat ingested. Links between regular exercise and other facets of lifestyle that influence cancer risks are not very strong, although endurance athletes are not usually smokers, and regular leisure activity is associated with a high socioeconomic status which tends to reduce exposure to airborne carcinogens, both at work and at home. Overall susceptibility to cancer shows a 'U'-shaped relationship to body mass index (mass/height2) reflecting, in part, the adverse influences of cigarette smoking and a tall body build for those with low body mass indices and, in part, the adverse effect of obesity at the opposite end of the body mass index distribution. Obesity seems a major component in the exercise-cancer relationship, with a particular influence on reproductive tract tumours; it alters the pathways of estradiol metabolism, decreases estradiol binding and facilitates the synthesis of estrogens. Among the hormonal influences on cancer risk, insulin-like growth factors promote tumour development and exercise-mediated increases in cortisol and prostaglandin levels may depress cellular components of immune function. However, the most important change is probably the suppression of the gonadotropic axis. Apparent gender differences in the benefits associated with regular exercise reflect gender differences in the hormonal milieu and also a failure to adapt activity questionnaires to traditional patterns of physical activity in females. The immune system is active at various stages of tumour initiation, growth and metastasis. However, acute and chronic changes in immune response induced by moderate exercise are rather small, and their practical importance remains debatable. At present, the oncologist is confronted by a plethora of interesting hypotheses, and further research is needed to decidewhich are of practical importance.

Shephard RJ. Exercise, immune function and HIV infection. Sports Med Phys Fitness 1998 Jun;38(2):101-110.
Abstract: The implications of HIV infection for exercise and sport are reviewed. HIV infection leads to impairment in a number of key elements of immune function, most obviously a progressive decline in the numbers of CD4+ T helper/inducer lymphocytes.
Nevertheless, patients with early through moderately advanced HIV-1 infection can engage in moderate sport and exercise without risk to themselves or other participants; the resulting gains of aerobic power and muscle strength are similar to those observed in healthy individuals of comparable initial fitness. In fully developed AIDS, the ability to exercise may be compromised by deteriorations in cardiorespiratory and neuromuscular function. Given the impairment of resting immune function, the potential immunosuppression from very intensive bouts of competitive exercise must be avoided. Review of all published papers to date provides a relatively limited data base. During a bout of moderate physical activity, HIV seropositive individuals apparently have an impaired ability to mobilize neutrophils, NK and LAK cells into the circulation. Nevertheless, programmes of moderate training can be sustained without any large change in CD4+ count or CD4+/CD8+ ratio. In some studies, training has also attenuated psychological stress, possibly for this reason checking the anticipated fall in CD4+ count. However, further large-scale randomized and long-term studies of HIV are needed, comparing the therapeutic value of exercise alone with that of psychotherapy or a combined programme of exercise and psychotherapy.

Silverman HG, Mazzeo RS. Hormonal responses to maximal and submaximal exercise in trained and untrained men of various ages. J Gerontol A Biol Sci Med Sci 1996 Jan;51(1):B30-37.
Abstract: Neuroendocrine adjustments to maximal and submaximal exercise were investigated in men as a function of age and training status. Twenty-four trained cyclists and 23 sedentary men constituting a young (M = 22.9 yrs, n = 16), middle-aged (M = 44.9 yrs, n = 16), and old (M = 65.5 yrs, n = 15) group performed both a maximal (GXT) and a 45-minute submaximal exercise test (cycle ergometer) at the workload corresponding to their lactate threshold. Plasma lactate, glucose, growth hormone, cortisol, norepinephrine, and epinephrine concentrations were analyzed both at rest and during exercise. Peak oxygen consumption (VO2 peak) was lower with age; however, all trained groups had higher values for VO2 peak compared to sedentary groups, regardless of age. Lactate threshold, when expressed in absolute terms, was lower with advancing age (sedentary decreases 9 and 26%: trained decreases 19 and 35% for middle-age and old, respectively, when compared to young). Pre-exercise plasma norepinephrine levels were higher with age in both trained and sedentary subjects. Cortisol levels were lower with age for sedentary subjects and were significantly elevated in trained subjects across all age groups. Endurance training resulted in increased hormonal responses, as measured by plasma concentrations, to both maximal and submaximal exercise across all age groups. However, regardless of training status, age-related declines were observed in peak responses for lactate, growth hormone, and cortisol during the GXT. During the 45-minute submaximal exercise test, these age-related differences that had been present in the GXT were abolished. This submaximal test represented a lower absolute work load for old compared to young as well as sedentary compared to trained subjects; however, individuals were working at similar relative exercise intensities. We conclude that older individuals are capable of similar hormonal responses to submaximal exercise of identical durations and intensities as their young and middle-aged counterparts, and that chronic endurance training can enhance the hormonal response to exercise in all age groups.

Woods JA. Exercise and resistance to neoplasia. Can J Physiol Pharmacol 1998 May;76(5):581-588. (Review)
Abstract: Epidemiological evidence has revealed an inverse relationship such that increased physical activity as measured directly subjective recall, job classification, former athletic status, or indirectly by physical fitness is associated with decreased incidence and (or) mortality rates for various cancers. The relationship appears strongest for colon cancer and female estrogen-dependent cancers of the breast, ovary, and endometrium. While some epidemiological studies have controlled for numerous confounding variables such as smoking, body mass index, and percent body fat, it is still difficult to ascertain whether physical activity exerts an independent effect on cancer above and beyond that associated with an improved lifestyle and numerous other potential confounding variables. Experimental studies performed in animals suggests that chronic exercise, especially when performed prior to tumorigenesis, can retard, delay, or prevent the incidence, progression, or spread of experimental tumors. There is also limited animal evidence suggesting that exercise may help ameliorate cancer cachexia. Exercise or physical activity may contribute to a reduction in site-specific cancers by different physiological mechanisms. Some purported mechanisms include decreased lifetime exposure to estrogen or other hormones, reduced body fat, enhanced gut motility, improved anti-oxidant defenses, and stimulation of anti-tumor immune defenses. Unfortunately, most animal studies have failed to account for plausible biological mechanisms as to how exercise might influence cancer. In addition, the exercise or activity dosage required to provide optimal protection from cancer is unclear. Interpretation of epidemiological studies is hampered by the numerous and sometimes inaccurate assessments of physical activity. Likewise, many animal studies have utilized unrealistic exercise protocols. Clearly, more research is needed to define appropriate
activity or exercise dosages definitively and to explore the mechanism(s) by which exercise helps protect against cancer. Nevertheless, moderate exercise appears to be a safe and effective means of aiding in the prevention of cancer and should be
adopted by the public in addition to other prudent behavioral practices such as proper diet. More research needs to be performed regarding the effects of exercise or physical activity on those who already have cancer to determine if exercise improves their prognosis.