Secondary Logo

Journal Logo

Monocyte and T-Cell Responses to Exercise Training in Elderly Subjects

Shimizu, Kazuhiro; Suzuki, Natsumi; Imai, Tomoko; Aizawa, Katsuji; Nanba, Hideyuki; Hanaoka, Yukichi; Kuno, Shinya; Mesaki, Noboru; Kono, Ichiro; Akama, Takao

Journal of Strength and Conditioning Research: September 2011 - Volume 25 - Issue 9 - p 2565-2572
doi: 10.1519/JSC.0b013e3181fc5e67
Original Research
Free

Shimizu, K, Suzuki, N, Imai, T, Aizawa, K, Nanba, H, Hanaoka, Y, Kuno, S, Mesaki, N, Kono, I, and Akama, T. Monocyte and T-cell responses to exercise training in elderly subjects. J Strength Cond Res 25(9): 2565-2572, 2011—The purpose of this study was to examine the effects of exercise training on age-related impairment of immune parameters related to T-cell activation in elderly individuals. Twenty-four elderly subjects were assigned to an exercise training group (EXC: 3 men, 9 women; age 61-76 years) or a nonexercise control group (CON: 4 men, 8 women; age 62-79 years). Subjects in EXC participated in exercise sessions 2 d·wk−1 for 12 weeks. The training session included stretching and endurance exercise (10 minutes), resistance training comprised leg extension, leg press, hip abduction, and hip adduction using exercise machine and each subject's body weight. Subjects in CON maintained their normal physical activity levels during the study period. Blood samples were collected before and after the training period. Samples were measured for the numbers of leukocytes, lymphocytes, and monocytes, and for CD3+, CD4+, CD8+, CD28+CD4+, CD28+CD8+, TRL-4+CD14+, and CD80+CD14+ cells. The number of leukocytes, lymphocytes, monocytes, CD3+, CD4+, and CD8+ cells did not change after 12 weeks in either EXC or CON. The number of CD28+CD8+ cells increased significantly after training in EXC (p ≤ 0.05), although CON showed no significant change. In the EXC group, CD80+CD14+ cell counts were significantly higher after training (p ≤ 0.05), but the TLR-4+CD14+ cell counts were unchanged. In the CON group, no significant alteration existed in TLR-4+CD14+ and CD80+CD14+ cell numbers. In conclusion, exercise training in elderly people is associated with increased CD28-expressing Tc cells and CD80-expressing monocytes. Therefore, exercise training might upregulate monocyte and T-cell-mediated immunity in elderly people.

1Faculty of Sport Sciences, Waseda University, Saitama, Japan; 2Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan; 3Japan Institute of Sports Sciences, Tokyo, Japan; 4Laboratory of Regenerative Medical Engineering, Center for Disease Biology and Integrative Medicine Graduate School of Medicine, The University of Tokyo, Japan; and 5Faculty of Community Health Care, Teikyo Heisei University, Chiba, Japan

Address correspondence to Kazuhiro Shimizu, shimikazu@aoni.waseda.jp.

This study was supported by a Grant-in-Aid for Science Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (19300228 to I.K.).

Back to Top | Article Outline

Introduction

It is generally believed that immune function undergoes adverse changes with aging that are explainable by impaired function of, or diminished regulation of, the immune system (31). This immune senescence potentially engenders an increased susceptibility to infectious diseases, malignancy, and autoimmune disorders in elderly people (27). In fact, cancer, malignancy, and pneumonia infection rank among the most frequent causes of death among elderly people in both Japan and the United States (12,35). By this immunosenescence, as the thymus involutes, T cells, which play a central role in cellular immune function, show the largest age-related alterations in distribution and function (4,16).

An important alteration in T-cell profiles that takes place with aging is impaired expression of CD28 (38). In fact, CD28 regularly expresses on the surface of T cells (23). Ligation of CD28 with its cognate receptor (CD80), which expresses on the surface of antigen-presenting cells (e.g., monocytes), is both necessary and sufficient, along with T-cell receptor signaling, to induce T-cell activation (13,19). Toll-like receptors (TLRs), which express on the surface of monocytes, play a role in detecting infectious microorganisms and control the expression of costimulatory molecules such as CD80 (1,17,18,25,41). Therefore, TLRs on monocytes have an important role in T-cell activation. Toll-like receptor 4 (TLR-4), which is a TLR stimulated by lipopolysaccharide (LPS), mediates the production of cytokines and T-cell activation. Previous investigators suggested that aging did not alter TLR-4 expression on monocytes (7,34). However, Renshaw et al. (30) reported a decrease in TLR-4 mRNA and suggested that TLR-4 expression was lower in macrophages from aged mice. Additionally, cytokine production in response to LPS via TLR-4 is lower in older adults than in young people, suggesting that monocyte function is impaired with age (7).

Reportedly, T cells lacking CD28 are detected in patients with autoimmune diseases such as rheumatoid arthritis and HIV-1 infection (15). In other words, low CD28 expression might induce high susceptibility to infection. The CD28-deficient mice are susceptible to pneumocystis carinii infection (6). In fact, TLR-4-deficient mice are more susceptible to infection by tuberculosis than wild-type mice are (9). Consequently, absence of the CD28 and TLR expressions might be a contributing factor to the increased incidence of infection in elderly people.

In recent years, the effect of exercise on human immune function has received considerable attention. Earlier evidence suggests that 6 months of combined exercise training (resistance exercise using subjects' body weight and 30-minute endurance exercise at 50% V̇O2max) increases CD28-expressing CD4+ cells in elderly people (32). In animal studies, 8 weeks of endurance training reportedly increased the concentration of cytokines including interleukin-2 (IL-2) and interferon-gamma (IFN-γ) in older mice (20,22). Because costimulation via CD80 and CD28 enhances production of IL-2 and IFN-γ in T cells activated by antigens or mitogens, the possibility exists that exercise affects CD28 expression. However, Raso et al. (29) showed that 12 months of resistance exercise (54.9 ± 2.4% 1 repetition maximum [1RM]) provided elderly subjects no change of T-cell subsets and the CD28-expressing CD4+ and CD8+ cells. Therefore, resistance training might have little or no impact on CD28 expression in elderly people. Stewart et al. (34) reported that 12 weeks of resistance exercise (50% 1RM) and endurance exercise (60-70 HR, 20 minutes) reduced TLR-4 expression on monocytes in elderly subjects, although they did not determine costimulatory molecules such as CD28 and CD80. Therefore, a combined exercise program including light-moderate resistance exercise and 20- to 30-minute endurance exercise might alter expressions of CD28 and TLRs in elderly people. However, their effects on immune function, especially on CD28 and TLRs, which relate to T-cell activation, have been poorly investigated. Moreover, no report describes a study examining the effects of light-moderate exercise training on CD80-expressing monocytes in elderly people. Demonstration of a relation between exercise training and immune parameters might contribute to establishment of effective exercise training recommendations in terms of improvement of immune function in elderly individuals.

This study was undertaken to determine the effects of 12 weeks of resistance exercise with endurance exercise on CD28-expressing T cells, and TLR-4, and CD80-expressing monocytes in elderly subjects. We hypothesized that exercise training increases CD28-expressing T cells and CD80-expressing monocytes, and decreases TLR-4-expressing monocytes in elderly subjects.

Back to Top | Article Outline

Methods

Experimental Approach to the Problem

Immune function undergoes adverse changes with aging, especially CD28, CD80, and TLRs. This immune senescence might induce an increased susceptibility to infections in elderly people. This study evaluates lymphocyte subsets such as CD28-expressing T cells and TLR-4 and CD80-expressing monocytes in response to exercise training programs during 12 weeks in elderly subjects.

Back to Top | Article Outline

Subjects

Healthy, sedentary, elderly subjects living independently in Japan were recruited using municipal advertisements and separated into 2 groups: an exercise training group (EXC; 3 men, 9 women; age 67.1 ± 1.0 years) and a nonexercise control group (CON; 4 men, 8 women; age 67.5 ± 0.7 years). Potential subjects were given a detailed explanation of the risks, stress, and potential benefits of the study before they signed an informed consent form. Based on the results of medical examinations within 6 months before the study and self-reported medical histories, the following exclusion criteria were determined for all subjects: hormone replacements, acute illness from infection within the preceding 3 months, metabolic disorders, and major surgery during the preceding 6 months. In addition, all subjects had to have passed a complete medical examination during the prior year and must have received written permission from a sports doctor to be included in the study. No subject had been treated with any drug that was known to affect immune function. The EXC subjects participated in an exercise program for 12 weeks. We asked CON subjects not to participate in any formal exercise but merely to continue their daily activities. All participants took part in the study for 12 weeks. This study, which conforms to the principles outlined in the Declaration of Helsinki, was approved by the Ethic Committees of the Institute of Health and Sport Sciences and by the Institute of Clinical Medicine of University of Tsukuba before any data collection.

Back to Top | Article Outline

Strength Assessment

During week 0 (PRE), week 4, week 8, and week 12 (POST), maximum strength was assessed by 1RM strength tests on leg extension, leg press, hip abduction, and hip adduction machines (Nautilus Nitro; Nautilus Inc., Vancouver, Canada). Subjects first performed a brief light-resistance warm-up. Then, they were encouraged to meet their 1RM within 5 trials of incrementally increasing resistance; it was retested and adjusted every 4 weeks for all exercises. No injuries were observed or reported during 1RM testing.

Back to Top | Article Outline

Exercise Program

Subjects in the EXC group participated in exercise sessions 2 d·wk−1 for 12 weeks. They were supervised by experienced instructors who conducted tests and who were responsible for measuring their heart rate (HR). The training program involved 10 minutes of stretching and 10 minutes doing cycle-ergometer (EZ101; Combi Wellness Corp., Tokyo, Japan) exercise at 90-100 b·min−1 HR for warm-up, resistance training, and 10 minutes of stretching for cool-down. The resistance training session comprised leg-extension, leg press, hip abduction, and hip adduction using an exercise machine (Nautilus Nitro; Nautilus Inc.), and back extension, trunk curl, and chest-press using their body weight (3 sets of 10 repetitions). Initially, EXC subjects performed machine exercises at 20% 1RM (1 set of 15 repetitions) during 1-2 weeks. During 3-4 weeks, they exercised 30% 1RM (2 sets of 15 repetitions). During 5-12 weeks, they exercised 40% 1RM (2 sets of 15 repetitions). The intensities and repetitions of machine exercise were referred to the American College of Sports Medicine's recommendation (3). In addition to exercise sessions, EXC subjects were instructed to perform back extension, trunk curl, and chest press by moving their body weight (3 sets of 10 repetitions) at home for 3 days or more per week. As a result, they performed their body-weight exercises 3.64 ± 0.68 times per week at home. Subjects in the CON group did not participate in exercise sessions; during the study, they simply maintained their normal levels of physical activity.

Back to Top | Article Outline

Blood Collection

Blood samples were obtained in the morning (8:30-9:30) both PRE and POST. Subjects refrained from any exercise for at least 24 hours before blood sampling. Additionally, subjects were asked to refrain from consuming any food or liquid from 22:00 pm the previous day of measurement. They came to our experimental laboratory in the fasted state. Samples were collected in vacutainers containing sodium ethylenediaminetetraacetic acid (EDTA). We quantified total leukocytes, lymphocytes, and monocytes from whole-blood samples using a multichannel hemocyte analysis system (SE-9000; Sysmex Corp, Hyogo, Japan).

Back to Top | Article Outline

Determination of Lymphocyte and Monocyte Subpopulations

We used a whole-blood staining method (32) to label the lymphocytes with fluorescent dye: fluorescein isothiocyanate (FITC), R-phycoerythrin (RPE), and allophycocyanin (APC). The surface antibodies used for subset identification were CD3+ for T cells, CD4+ for Th cells, CD8+ for Tc cells, CD28+CD4+ for CD28+Th cells, CD28+CD8+ for CD28+Tc cells, TLR-4+CD14+ for TLR-4+ monocytes, and CD80+CD14+ for CD80+ monocytes. Cell surfaces were stained with 3 monoclonal antibodies: CD3 (FITC, clone: UCHT1; DakoCytomation, Glostrup, Denmark), CD4 (APC, clone: 13B8.2; Immunotech, Marseille, France), CD8 (RPE, clone: DK25; DakoCytomation), CD28 (FITC, clone: CD28.2; BD Biosciences, San Jose, CA, USA), CD14 (APC, clone: RMO52; Immunotech), CD80 (RPE, clone: 2D10.4; DakoCytomation), and TLR-4 (FITC, clone: HTA125; MBL Co. Ltd., Tokyo, Japan). The mouse IgG1 antibody (clone: DAK-GO1; DakoCytomation) was used as an isotypic control. The FITC-conjugated, PE-conjugated, and APC-conjugated antibody were pipetted into a tube. Then 100 μL of whole blood was added and incubated for 15 minutes in the dark at room temperature. After incubation, 1 ml of lysing solution (0.15 M NH4Cl, 10 mM KHCO3, 0.1 mM EDTA-2Na) was added to each of the tubes and incubated for 10 minutes in the dark at room temperature for erythrocyte lysing. Tubes were centrifuged for 5 minutes at 3,000 rpm. The supernatant was vacuum aspirated. Then the cell pellet was washed with 1 mL of 0.1% bovine serum albumin (BSA)/0.1% NaN3/phosphate-buffered saline (PBS), centrifuged and vacuum aspirated again. The pellet was suspended in 300 μL of 0.1%BSA/0.1% NaN3/PBS. Labeled cells were analyzed using flow cytometry with a fluorescence-activated cell sorter analyzer (FACSCalibur; BD Biosciences).

Back to Top | Article Outline

Flow Cytometry Analysis

Immunophenotyping by flow cytometry has become standard practice for identification of human leukocyte subpopulations. A previous study demonstrated this method's repeatability and reliability (11). The usual quantity of cells scanned was 10,000 cells per sample. The data were analyzed using software (CELLQuest; BD Biosciences) to determine proportions of fluorescent-labeled lymphocytes and monocytes. Absolute quantities of cells in specific cell subsets were calculated using the total number of cells multiplied by the percentage of positive cells within the subset of interest.

Back to Top | Article Outline

Statistical Analyses

All data were represented as mean ± SE. For all analyses, p ≤ 0.05 was considered statistically significant. Comparison between the EXC and CON groups for the baseline criterion measures was made using Student's t-test. Then 2-way analysis of variance (ANOVA) for 2 (group, EXC and CON groups) × 2 (time, PRE and POST) repeated measures was used to determine the effect of exercise training on immune parameters during the 12-week period between each group. Then, ANOVA was conducted with the treatment group used as the dependent variable and anthropometric data or immune parameters as independent variables. A Tukey-Kramer post hoc test was performed whenever a significant effect was found using ANOVA. Time effects of intervention within each group were analyzed using Student's t-test. An intraclass correlation (ICC Rs) was calculated for each measurement to examine the reliability of each test. Reliability ICC Rs for the dependent variables was 0.76-0.97. Additionally, the effect size (ES) was calculated as the difference between means. An ES of 0.2 is considered small, 0.5 is moderate, and 0.8 is large (14).

Back to Top | Article Outline

Results

Table 1 presents physical characteristics for the EXC and the CON group. Results show that the EXC group and the CON group were of a similar age and body composition before the study period. The body mass (ES: 0.15) and body mass index (ES: 0.18) decreased significantly during the study period in EXC (p ≤ 0.05), although CON showed no significant change. In the EXC group, the resistive exercise training induced an increase in muscle strength scores (Table 2).

Table 1

Table 1

Table 2

Table 2

As Table 3 shows, the subjects in both the EXC and the CON groups had similar leukocyte, lymphocyte, and monocyte numbers in whole blood before the study period. These numbers did not change significantly after the study period in either EXC or CON.

Table 3

Table 3

The absolute numbers of CD3+, CD4+, and CD8+ cells at PRE showed no intergroup differences between EXC and CON (Table 3). No significant group × time interaction in absolute numbers of CD3+, CD4+, and CD8+ cells was found. These cells did not change in either group after the study period.

Figure 1 presents changes in the absolute numbers of CD28+CD4+ and CD28+CD8+ cells in both EXC and CON. The absolute number of CD28+CD4+ cells at PRE showed no intergroup differences between EXC and CON. No significant group × time interaction was found in the absolute number of CD28+CD4+ cells. The CD28+CD4+ cells did not change in either group after the study period. The absolute number of CD28+CD8+ cells at PRE showed no intergroup differences between EXC and CON. Although no significant group × time interaction was found in the absolute number of CD28+CD8+ cells, EXC showed a significant increase in CD28+CD8+ cells after the training (p ≤ 0.05; ES: 0.29). On the other hand, CON showed no significant change.

Figure 1

Figure 1

Figure 2 shows changes in the absolute number of TLR-4+CD14+ and CD80+CD14+ cells in both EXC and CON. The absolute numbers of TLR-4+CD14+ cells at PRE in EXC and CON were not significantly different. No significant group × time interaction was found in TLR-4+CD14+ cells. In addition, the absolute number of TLR-4+CD4+ cells did not change significantly after 12 weeks in either EXC or CON. The absolute numbers of CD80+CD14+ cells at PRE in EXC and CON were not significantly different. The group × time interaction for CD80+CD14+ cells was significant (p ≤ 0.05). Within the EXC group, the absolute number of CD80+CD14+ cells was increased significantly after the training (p ≤ 0.05; ES: 0.32), although CON showed no significant change.

Figure 2

Figure 2

Back to Top | Article Outline

Discussion

This study analyzed the immunological responses of elderly subjects after 12 weeks of resistance training using an exercise machine (20-40% of 1RM) and each subject's body weight with 10 minutes of endurance training. The primary finding of our investigation was that exercise training, which yielded significant strength improvements, increased CD28-expressing CD8+ cells and CD80-expressing CD14+ cells in elderly subjects. These results suggest that regular resistance with a small amount of endurance exercise can bolster T-cell-mediated immunity in elderly people.

The CD28 molecule plays a crucial role in orchestrating immune responses, including upregulation of cytokines synthesis and T-cell activation (23). The CD28 expression on T cells decreases with age; this decline is shown predominantly in the CD8+ cells (8). Consequently, decreases in the level of CD28 expression contribute to degraded functions of T cells, leading to an increased incidence of infections and autoimmune diseases in elderly people (6,15,38). In this study, resistance training (machine exercise - 3 sets of 10 repetitions at 40% 1RM, 2 times per week; body-weight exercise—10 repetitions, 3.64 ± 0.68 times per week during 12 weeks) and 10 minutes of endurance exercise (90-100 b·min−1 HR, 2 times per week) increased CD28+CD8+ cells in elderly subjects. Raso et al. (29) reported that resistance training (3 sets of 12 repetitions at 54.9 ± 2.4% 1RM, 3 times per week during 12 months) did not change CD28-expressing CD8+ cells in elderly subjects. Miles et al. (26) suggested that different intensities of resistance training might be associated with increased strength and workload but not with alternations of T-cell proliferation responses in young women. The effects of exercise on CD28 expression might depend on the exercise type: endurance exercise despite the volumes of resistance training. In this study, subjects conducted endurance exercise as a warm-up, although they spent 10 minutes in exercise sessions. In other words, resistance training might show favorable effects on immune function in elderly people by the addition to 10 minutes and more of endurance training. Specifically, moderate endurance training or combined training including endurance exercise might upregulate CD28 expression on CD8+ cells in elderly people. Raso et al. (29) reported that 6 months of resistance training provided elderly subjects no benefits related to T-cell subsets and CD28-expressing CD4+ cells. In our previous study, 6 months of resistance exercise (3 sets of 10 repetitions using one's body weight) and 30 minutes of endurance exercise (50% V̇O2max) 5 times per week increased CD4+ cells and CD28+CD4+ cells in elderly subjects (32). In this study, CD28+CD4+ cells show no significant change after exercise training, although CD28+CD8+ cells increased significantly. Therefore, the terms and duration of exercise in this study might be inadequate to alter the CD28-expressing CD4+ cells: 30 minutes and more of in session and 6 months and more terms of endurance exercise might show favorable effects on CD28 expression on CD4+ cells in elderly people. Simpson et al. (33) reported that exhaustive endurance exercise decreased CD28+CD3+CD8+ cells, although CD28+CD3+CD4+ cells did not change. Therefore, sensitivity of CD28 expression in response to exercise might be higher in CD8+ cells than in CD4+ cells. Future studies must elucidate clearly what training volumes of endurance and resistance contribute to upregulation of CD28-expressing T cells in elderly people. More effective health-related programming can be established to enhance immune function in elderly people if these volumes were clarified.

In fact, TLR-4 is related to mediation of the cytokine production and T-cell activation (36). Some investigators have reported that age does not influence TLR-4 expression (7,34). Others showed that it was decreased with age (30). Stewart et al. (34) reported that 12 weeks of exercise training reduced TLR-4 expression in elderly subjects, suggesting that downregulation of TLR-4 with exercise training might help explain the anti-inflammatory effects of exercise. In this study, however, TLR-4-expressing CD14 cells showed no significant change in elderly people. In the previous study of Stewart et al. (34), elderly subjects performed 50% 1RM of resistance training and 60-70 HR of endurance training (20 minutes) for 3 times per week for 12 weeks. Therefore, the intensity and duration of exercise used for this study might be inadequate to alter the expression of TLR-4 in elderly people. The TLRs control the generation of T-cell activation through induction of costimulatory molecules such as CD80. Actually, van Duin et al. (39) reported that CD80 expression on monocytes in response to TLR stimulation was lower in elderly people than in young people. Results of this study show that CD80-expressing CD14 cells were increased significantly after exercise training in elderly people. Although TLR-4 did not change after exercise training, TLR functions such as modulation of CD80 expression might be upregulated by exercise training. Therefore, exercise training might improve monocyte function in elderly people.

In this study, CD28-expressing CD8+ cells and CD80-expressing monocytes increased after exercise training in elderly people. Previous reports have also described that endurance exercise training increased IL-2 receptor (IL-2R) expression on T cells in elderly human (21) and IL-2 production in older mice (20,22), which are upregulated by signaling from antigen-presenting cells such as monocytes. Consequently, exercise training in elderly individuals might increase CD80 and CD28 expressions, and might then upregulate cosignaling from monocytes to T cells via CD80 and CD28, leading to enhancement of IL-2R expression and IL-2 production as T-cell activation.

The molecular mechanisms underlying the increase of CD28 and CD80 expressions through exercise training have not been clarified. The possibility is related to reactive oxygen species and proinflammatory cytokine such as tumor necrosis factor-α (TNF-α). Oxidative stress and TNF-α level increase with age and downregulate CD28 expression (10,24). Reportedly, regular exercise training reduces oxidative stress and TNF-α levels (5,37). It is therefore possible that the exercise-induced decrease of chronic oxidative stress and inflammation is linked to upregulation of CD28 expression in elderly people. Upregulated CD80 expression requires NF-κB activation (42); NF-κB activity is negatively regulated by glucocorticoids (2). However, 16 weeks of resistance training was reported not to change peripheral glucocorticoids such as cortisol in elderly women (28). Future studies are necessary to determine these parameters so that the process of exercise-induced T-cell activation can be examined closely.

This study has the following study limitations: male and female subjects were combined in the analysis. Moreover, the smaller sample size does not allow appropriate analysis of gender effects. Although the influence of gender differences on CD28, TLRs and CD80 in response to exercise in elderly people is unclear, previous reports of studies have described that no significant gender difference was found in the number of CD4+ and CD8+ cells in response to active (mental arithmetic) and passive (cold pressor) stresses (40). Future studies must examine the influence of gender difference on CD28-expressing T cells and CD80 and TLR-expressing monocytes in light-moderate exercise training in elderly people. Second, no control subjects with only resistance exercise or endurance exercise participated in this study. The exercise program in this study included endurance exercise, although this program included mainly resistance exercise. Future studies must compare the effects of resistance exercise, endurance exercise, and combined exercise (resistance and endurance) on immune parameters in elderly subjects.

In conclusion, results show that 12 weeks of resistance training with a small amount of endurance training significantly increased CD28-expressing Tc cells and CD80-expressing monocytes in elderly subjects. Regular exercise can enhance CD28 and CD80 expression, leading to upregulation of monocyte and T-cell-mediated immune function including T-cell proliferation and differentiation in elderly people.

Back to Top | Article Outline

Practical Applications

In general, resistance training improves muscular strength and endurance and increases muscle mass in elderly people. However, its effects on immune function, especially CD28, TLRs, and CD80, which relate to T-cell activation, have been inadequately investigated. Results of a previous study suggest that resistance training provided elderly people no benefits related to T cells such as CD28 expression (29). However, present results showed that resistance exercise with prior endurance exercise (90-100 b·min−1 HR for 10 minutes) added during each session might increase CD28-expressing CD8+ cells and CD80-expressing monocytes, consequently improving monocyte and T-cell-mediated immunity in elderly people. Additionally, previous report showed that resistance training (50% 1RM) with prior endurance exercise (60-70 b·min−1 HR for 20 minutes) added each session altered the expression of TLR-4 in elderly people (34). Therefore, we recommend appending an endurance exercise session (60-100 b·min−1 HR for >10-20 minutes) to a resistance exercise program for elderly people in incremental steps to enhance immune function in addition to muscle mass and muscle strength, leading to decreased susceptibility to infection. Further work needs to demonstrate optimal resistance and endurance training prescriptions (e.g., intensity, duration, frequency, periods, and timing) for upregulated immune function in elderly.

Back to Top | Article Outline

Acknowledgments

We thank all participants in this study, Dr. Takayuki Akimoto (Laboratory of Regenerative Medical Engineering, Center for Disease Biology and Integrative Medicine Graduate School of Medicine, The University of Tokyo), and Dr. Fuminori Kimura (Graduate School of Comprehensive Human Sciences, University of Tsukuba) for critical comments. This study was supported by a Grant-in-Aid for Science Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (19300228 to I. K.). The authors have no conflict of interest related to this study.

Back to Top | Article Outline

References

1. Alexopoulou, L, Holt, AC, Medzhitov, R, and Flavell, RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413: 732-738, 2001.
2. Almawi, WY, Abou Jaoude, MM, and Li, XC. Transcriptional and post-transcriptional mechanisms of glucocorticoid antiproliferative effects. Hematol Oncol 20: 17-32, 2002.
3. American College of Sports Medicine. American College of Sports Medicine position stand. Progression models in resistance training for healthy adults. Med Sci Sports Exerc 41: 687-708, 2009.
4. Aspinall, R and Andrew, D. Thymic involution in aging. J Clin Immunol 20: 250-256, 2000.
5. Avula, CP, Muthukumar, AR, Zaman, K, McCarter, R, and Fernandes, G. Inhibitory effects of voluntary wheel exercise on apoptosis in splenic lymphocyte subsets of C57BL/6 mice. J Appl Physiol 91: 2546-2552, 2001.
6. Beck, JM, Blackmon, MB, Rose, CM, Kimzey, SL, Preston, AM, and Green, JM. T cell costimulatory molecule function determines susceptibility to infection with pneumocystis carinii in mice. J Immunol 171: 1969-1977, 2003.
7. Boehmer, ED, Goral, J, Faunce, DE, and Kovacs, EJ. Age-dependent decrease in Toll-like receptor 4-mediated proinflammatory cytokine production and mitogen-activated protein kinase expression. J Leukoc Biol 75: 342-349, 2004.
8. Boucher, N, Dufeu-Duchesne, T, Vicaut, E, Farge, D, Efros, RB, and Schächter, F. CD28 expression in T cell aging and human longevity. Exp Gerontol 33: 267-282, 1998.
9. Branger, J, Leemans, JC, Florquin, S, Weijer, S, Speelman, P, and Van Der Poll, T. Toll-like receptor 4 plays a protective role in pulmonary tuberculosis in mice. Int Immunol 16: 509-516, 2004.
10. Bryl, E, Vallejo, AN, Weyand, CM, and Goronzy, JJ. Down-regulation of CD28 expression by TNF-alpha. J Immunol 167: 3231-3238, 2001.
11. Catellier, DJ, Aleksic, N, Folsom, AR, and Boerwinkle, E. Atherosclerosis risk in communities (ARIC) carotid MRI flow cytometry study of monocyte and platelet markers: intraindividual variability and reliability. Clin Chem 54: 1363-1371, 2008.
12. Centers for Disease Control and Prevention. Deaths: Leading Causes for 2006. Natl Vital Stat Rep 58: 10-11, 2009.
13. Cerdan, C, Martin, Y, Courcoul, M, Brailly, H, Mawas, C, Birg, F, and Olive, D. Prolonged IL-2 receptor α/CD25 expression after T cell activation via the adhesion molecules CD2 and CD28. Demonstration of combined transcriptional and post-transcriptional regulation. J Immunol 149: 2255-2261, 1992.
14. Cohen, J. Statistical power analysis for the behavioral sciences (2nd ed.). New York, NY: Academic Press, 1988. pp. 75-95.
15. Effros, BR. Costimulatory mechanisms in the elderly. Vaccine 18: 1661-1665, 2000.
16. Engwerda, CR, Handwerger, BS, and Fox, BS. Aged T cells are hyporesponsive to costimulation mediated by CD28. J Immunol 152: 3740-3747, 1994.
17. Hayashi, F, Smith, KD, Ozinsky, A, Hawn, TR, Yi, EC, Goodlett, DR, Eng, JK, Akira, S, Underhill, DM, and Aderem, A. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410: 1099-1103, 2001.
18. Hemmi, H, Takeuchi, O, Kawai, T, Kaisho, T, Sato, S, Sanjo, H, Matsumoto, M, Hoshino, K, Wagner, H, Takeda, K, and Akira, S. A Toll-like receptor recognizes bacterial DNA. Nature 408: 740-745, 2000.
19. Jenkins, MK, Taylor, PS, Norton, SD, and Urdahl, KB. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol 147: 2461-2466, 1991.
20. Kohut, ML, Boehm, GW, and Moynihan, JA. Moderate exercise is associated with enhanced antigen-specific cytokine, but not IgM antibody production in aged mice. Mech Ageing Dev 122: 1135-1150, 2001.
21. Kohut, ML and Senchina, DS. Reversing age-associated immunosenescence via exercise. Exerc Immunol Rev 10: 6-41, 2004.
22. Kohut, ML, Thompson, JR, Lee, W, and Cunnick, JE. Exercise training-induced adaptations of immune response are mediated by beta-adrenergic receptors in aged but not young mice. J Appl Physiol 96: 1312-1322, 2004.
23. Lenschow, DJ, Walunas, TL, and Bluestone, JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol 14: 233-258, 1996.
24. Ma, S, Ochi, H, Cui, L, Zhang, J, and He, W. Hydrogen peroxide induced down-regulation of CD28 expression of jurkat cells is associated with a change of site α-specific nuclear factor binding activity and the activation of caspase-3. Exp Gerontol 38: 1109-1118, 2003.
25. Medzhitov, R, Preston-Hurlburt, P, and Janeway, Jr CA. A human homologue of the Drosophilia Toll protein signals activation of adaptive immunity. Nature 388: 394-397, 1997.
26. Miles, MP, Kraemer, WJ, Nindl, BC, Grove, DS, Leach, SK, Dohi, K, Marx, JO, Volek, JS, and Mastro, AM. Strength, workload, anaerobic intensity and the immune response to resistance exercise in women. Acta Physiol Scand 178: 155-163, 2003.
27. Nieman, DC, Henson, DA, Gusewitch, G, Warren, BJ, Dotson, RC, Butterworth, DE, and Nehlsen-Cannarella, SL. Physical activity and immune function in elderly women. Med Sci Sports Exerc 25: 823-831, 1993.
28. Orsatti, FL, Nahas, EA, Maesta, N, Nahas-Neto, J, and Burini, RC. Plasma hormones, muscle mass and strengthen in resistance-trained postmenopausal women. Maturitas 59: 394-404, 2008.
29. Raso, V, Benard, G, Da Silva Duarte, AJ, and Natale, VM. Effect of resistance training on immunological parameters of healthy elderly women. Med Sci Sports Exerc 39: 2152-2159, 2007.
30. Renshaw, M, Rockwell, J, Engleman, C, Gewirtz, A, Katz, J, and Sambhara, S. Cutting edge: impaired Toll-like receptor expression and function in aging. J Immunol 169: 4697-4701, 2002.
31. Shephard, RJ and Shek, PN. Exercise, aging and immune function. Int J Sports Med 16: 1-6, 1995.
32. Shimizu, K, Kimura, F, Akimoto, T, Akama, T, Tanabe, K, Nishijima, T, Kuno, S, and Kono, I. Effect of moderate exercise training on T-helper subpopulations in elderly people. Exerc Immunol Rev 14: 24-37, 2008.
33. Simpson, RJ, Cosgrove, C, Ingram, LA, Florida-James, GD, Whyte, GP, Pircher, H, and Guy, K. Senescent T-lymphocytes are mobilized into the peripheral blood compartment in young and older humans after exhaustive exercise. Brain Behav Immun 22: 544-551, 2008.
34. Stewart, LK, Flynn, MG, Campbell, WW, Craig, BA. Robinson, JP, McFarlin, BK, Timmerman, KL, Coen, PM, Felker, J, and Talbert, EJ, and Talbert, E. Influence of exercise training and age on CD14+ cell-surface expression of toll-like receptor 2 and 4. Brain Behav Immun 19: 389-397, 2005.
35. The Japan Ministry of Health, Labour and Welfare (ed) Vital Statistics of Japan 2008. Tokyo, Health and Welfare Statistics Association, 256-257, 2010.
36. Triantafilou, M and Triantafilou, K. Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. Trends Immunol 23: 301-304, 2002.
37. Tsukui, S, Kanda, T, Nara, M, Nishino, M, Kondo, T, and Kobayashi, I. Moderate-intensity regular exercise decreases serum tumor nec rosis factor-alpha and HbA1c levels in healthy women. Int J Obes Relat Metab Disord 24: 1207-1211, 2000.
38. Vallejo, AN. CD28 extinction in human T cells: Altered functions and the program of T-cell senescence. Immunol Rev 205: 158-169, 2005.
39. van Duin, D, Allore, HG, Mohanty, S, Ginter, S, Newman, FK, Belshe, RB, Medzhitov, R, and Shaw, AC. Prevaccine determination of the expression of costimulatory B7 molecules in activated monocytes predicts influenza vaccine responses in young and older adults. J Infect Dis 195: 1590-1597, 2007.
40. Willemsen, G, Carroll, D, Ring, C, and Drayson, M. Cellular and mucosal immune reactions to mental and cold stress: associations with gender and cardiovascular reactivity. Psychophysiology 39: 222-228, 2002.
41. Yamamoto, M, Sato, S, Hemmi, H, Sanjo, H, Uematsu, S, Kaisho, T, Hoshino, K, Takeuchi, O, Kobayashi, M, Fujita, T, Takeda, K, and Akira, S. Essential role for TIRAP in activation of the signaling cascade shared by TLR2 and TLR4. Nature 420: 324-329, 2002.
42. Yoshimura, S, Bondeson, J, Brennan, FM, Foxwell, BM, and Feldmann, M. Role of NFkappaB in antigen presentation and development of regulatory T cells elucidated by treatment of dendritic cells with the proteasome inhibitor PSI. Eur J Immunol 31: 1883-1893, 2001.
Keywords:

resistance training; CD28; TLRs; older people

Copyright © 2011 by the National Strength & Conditioning Association.