Aging Clin Exp Res DOI 10.1007/s40520-014-0307-y
ORIGINAL ARTICLE
Effect of aerobic training and aerobic and resistance training on the inflammatory status of hypertensive older adults Leandra G. Lima • Jose´ M. T. Bonardi • Giulliard O. Campos • Rodrigo F. Bertani Luria M. L. Scher • Paulo Louzada-Junior • Ju´lio C. Moriguti • Eduardo Ferriolli • Nereida K. C. Lima
•
Received: 16 September 2014 / Accepted: 24 December 2014 Ó Springer International Publishing Switzerland 2015
Abstract There is a relationship between high levels of inflammatory markers and low adhesion to the practice of physical activity in the older population. The objective of the present study was to compare the effect of two types of exercise programs, i.e., aerobic training and aerobic plus resistance training on the plasma levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a) of elderly hypertensive subjects. Hypertensive older volunteers in use of antihypertensive drugs were randomized to three groups: aerobic group (AG), resistance and aerobic group (RAG) and control group (CG). Training lasted 10 weeks, with sessions held three times a week. Blood samples were collected before training and 24 h after completion of the 30 sessions for the determination of serum IL-6 and TNF-a levels. Body mass index was obtained before and after 10 weeks. After intervention, BMI values were lower in AG and RAG compared to CG (p \ 0.001), IL-6 was reduced in AG compared to CG (p = 0.04), and TNF-a levels were lower only in RAG compared to CG
L. G. Lima J. M. T. Bonardi G. O. Campos R. F. Bertani L. M. L. Scher J. C. Moriguti E. Ferriolli N. K. C. Lima Division of General Internal Medicine and Geriatrics, School of Medicine of Ribeira˜o Preto, University of Sa˜o Paulo-FMRP-USP, Sa˜o Paulo, Brazil P. Louzada-Junior Division of Clinical Immunology, School of Medicine of Ribeira˜o Preto, University of Sa˜o Paulo-FMRP-USP, Sa˜o Paulo, Brazil N. K. C. Lima (&) Rua Mariana Casadio, 275, Jardim Canada´, Ribeira˜o Preto, SP 14024-360, Brazil e-mail: [email protected]
(p = 0.01). Concluding, both types of training were effective in reducing BMI values in hypertensive older subjects. Aerobic exercise produced the reduction of plasma IL-6 levels. However, the combination of aerobic and resistance exercise, which would be more indicated for the prevention of loss of functionality with aging, showed lower TNF-a mediator after training than control group and a greater fall of TNF-a levels associated to higher BMI reduction. Keywords Interleukin-6 Tumor necrosis factor alpha Aerobic training Resistance training Older adults
Backgrounds The aging process continues to be one of the concerns of humanity since the dawn of civilization [1]. There is consensus about the fact that the immune system changes during the aging process, becoming less efficient [2], with the occurrence of a two to fourfold increase in inflammatory markers including pro-inflammatory and anti-inflammatory cytokines, cytokine antagonists, and acute phase proteins [3, 4]. Changes in these pro-inflammatory markers may be associated with advancing age and with worsening of age-related chronic conditions such as arterial hypertension, functional capacity, muscle function, muscle fatigue, dementia, and many others [5–9]. The mechanism by which these mediators contribute to the functional decline of the aged is still uncertain but seems to be related to their catabolic effect, with reduction of muscle mass and strength [1, 10]. New studies showed an association between high levels of inflammatory markers and low adhesion to the practice
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of physical activity in the older population. The protective effect of exercise may be attributed to the anti-inflammatory effect of regular exercise, mediated via a reduction in visceral fat mass and/or by induction of an anti-inflammatory environment due to changes in monocyte phenotype, especially by a reduced production of immune cells of inflammatory mediators [9]. Pedersen et al. [11] have suggested that cytokines are produced, expressed, and released by muscle fibers and should be classified as ‘‘myokines’’. Such myokines may exert a direct effect on fat metabolism and there by result in indirect anti-inflammatory effects. It is suggested that contracting skeletal muscles release myokines, which work in a hormone-like fashion, exerting specific endocrine effects on visceral fat and other ectopic fat deposits. The first identified myokine is interleukin (IL-6). A number of studies have revealed that both type I and type II muscle fibers express the myokine IL-6 in response to muscle contractions. Subsequently IL-6 exert effects locally within the skeletal muscle, increasing locally fat oxidation and glucose uptake [12]. Although it has not been demonstrated that IL-6 has specific effects on visceral fat mass, it does appear to play an important role in lipid metabolism. The cytokine response to exercise differs from that elicited by severe infections. Classical pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-a) and IL-1b, in general do not increase with exercise, indicating that the cytokine cascade induced by exercise is markedly different from the cytokine cascade induced by infections [12]. Thus, studies associating and comparing the different effects of aerobic and anaerobic exercise on the chronic inflammatory process observed in the older adults have become relevant. As aerobic exercise is recommended to all hypertensive individuals, the objective of the present study was to evaluate the effect of isolated aerobic training and combined aerobic and resistive training on the inflammatory status of older subjects.
Methods Experimental approach to the problem The aim of this study was to compare the effect of two types of physical exercise programs, i.e., aerobic training and aerobic plus resistance training, over a period of 10 weeks, on the plasma levels of interleukin-6 (IL-6) and TNF-a of older adults. IL-6 was evaluated because it was the first myokine studied and has an indirect anti-inflammatory effect, and TNF-a is a classical pro-inflammatory cytokine.
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Subjects We selected 44 volunteers aged 60–75 years who were regularly taking antihypertensive medication (hydrochlorothiazide, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers). Volunteers performed all the basic and instrumental activities of daily living, with normal cognition, without current depression, and had adequate social condition. Exclusion criteria were: mean systolic blood pressure (SBP) above 160 mmHg and mean diastolic blood pressure (DBP) above 105 mmHg; use of beta blocker medication or presence of arrhythmia; smokers or ex-smokers for less than 5 years; presence of cardiac or respiratory problems; ethanol intake of more than 168 g per week; history or a previous diagnosis of acute myocardial infarction, stroke, secondary hypertension due to renal damage, diabetes mellitus, degenerative neurocognitive deficits, uncontrolled hypothyroidism or hyperthyroidism; hemoglobin values of less than 11 g/dL; changes in the treadmill test or echocardiogram; limiting osteoarthritis; acute inflammatory or infectious diseases; grade II and III obesity (body mass index (BMI) of 34.99 kg/m2 or more) or peripheral vascular obstruction; participation in other programs or practice of regular physical activity more than twice a week, or refusal to participate in the study. The study was approved by the Research Ethics Committee of the Public Health Center of the School of Medicine of Ribeira˜o Preto, protocol No. 367/CEP/CSEFMRP-USP, and all subjects gave written informed consent to participate. Procedures All volunteers were evaluated by a multidisciplinary team and answered a structured screening questionnaire. Blood and urine samples were collected for general tests (fasting glycaemia, glycated hemoglobin, blood count, serum lipids, creatinine, urea, sodium, potassium, thyroid stimulating hormone (TSH) and routine urinalysis) to exclude diabetes, renal failure, hypothyroidism or hyperthyroidism. The volunteers were instructed to not self-medicate and to contact the doctor in charge of the study in cases of fever, acute infection, use of new medications or increase of the habitual dose of any medication. They were asked to not change the habitual diet. The concentrations of the inflammatory markers studied: interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a) were measured in a blood sample collected during the week preceding the interventions from resting subjects after an overnight fast at 8:00–09:00 a.m. Blood samples from all individuals were harvested in the morning and placed in test tubes with anticoagulant (EDTA) and kept on ice until
Aging Clin Exp Res
1 hour. Subsequently, the plasma was obtained by centrifugation at 400 g, and stored at -70 °C. The measurement of IL-6 and TNF was performed by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s instructions. Samples were assessed in duplicate. The detection limit of BDNF was 5 pg/mL. The intra-assay and inter-assay coefficients of variation (CV) were below 5 and 10 %, respectively. The volunteers were submitted to fundoscopic examination, to a treadmill test and to echocardiography to detect retinal or cardiac diseases that would contraindicate physical training. Weight and height were measured for the calculation of BMI. The treadmill test was also applied to determine maximum aerobic capacity. Based on the maximum oxygen consumption (VO2max) values obtained in the treadmill test, the individuals were classified as active or sedentary. VO2max was estimated by the formula of the American College of Sports Medicine [13]: VO2max = {[(maximum speed 9 16.66) 0.1] ? 3.5} ? {[(maximum slope/100) 9 (maximum speed 9 16.66)] 1.8}. After the subjects were classified in terms of physical conditioning, their working heart rate (HR) was determined by the following formula: Training HR = (maximum HR - resting HR) 9 % ? resting HR. Maximum HR was established by the maximum treadmill test, and resting HR was measured before the test. Two percentages were used for the lower and upper limits of the training range: 50 and 70 % for the sedentary volunteers and 60 and 80 % for conditioned volunteers, respectively. We opted for different percentages for sedentary and active volunteers to avoid under- and overestimating physical ability according to the guidelines for prescribing aerobic exercise. To determine the load imposed during resisted exercise we used the one repetition maximum test (1RM), with progressive increments being inserted for each muscle groups exercised in the protocol. Four trials were performed to determine the 1RM value. The final weight successfully lifted was recorded as the absolute value, 100 % or 1RM, and the individuals were trained with intensities of 50–60 % 1RM. On the basis of the planned objectives, nine resisted exercises were proposed to recruit muscle groups of the upper and lower limbs and of the trunk, selected in the following circuit order: (1) Leg Press 45°, (2) Chest Press, (3) Leg Extension, (4) Lat Pull Down, (5) Leg Curl, (6) Pulley Upright Row, (7) Seated Calf Raise, (8) Machine Seated Row, and (9) Abdominal Crunches. After the initial overall evaluation and the execution of the above procedures, the participants were randomized to three groups: aerobic group (AG), resistance and aerobic group (RAG) and control group (CG). Training lasted ten consecutive weeks, with sessions held three times a week on alternate days, for a total of 30 uninterrupted sessions. All sessions were held in the
morning in a fitness center located in the city of Ribeira˜o Preto. CG subjects did not engage in any type of training, maintaining their normal daily activities throughout the study period. AG subjects exercised on a treadmill. Each session started and ended with 5 min of stretching exercises. Twenty minutes of continuous aerobic exercise were performed from the 1st to the 4th week, with an increase to 30 min of continuous aerobic exercise from the 5th to the 10th week. During the execution of exercise, HR values were recorded every 5 min, as well as physical exertion values obtained using the revised Borg rating of perceived exertion scale [14]. RAG training also started and ended with 5 min of stretching, with the subjects sequentially completing one circuit lap (1st to 4th week) and progressing to two circuit laps (5th to 10th week) with intensity of 50–60 % RM. The time between stations (for each type of equipment) was 1 min, with each station consisting of exercised performed in series of 15 repetitions for the upper limbs and of 20 repetitions for the trunk and lower limbs. At the end of each station, HR and perceived exertion according to the Borg scale were recorded. After the resistance exercise protocol, the aerobic exercise was performed as described for the AG. Blood samples were collected 24 h after completion of the 30 sessions (chronic effect of exercise) for the determination of plasmatic IL-6 and TNF-a levels, with all procedures being identical to those performed in the preintervention period. Statistical analysis An exploratory analysis of the data was first carried out using descriptive statistics based on measurements of central tendency (mean and median) and of variability (standard deviation) using the SASÒ 9.0 software [15]. TNF-a and IL-6 variables were log transformed for residue adjustment using the SASÒ 9.0 software [15]. Orthogonal contrast post test was used for the comparisons. The co-variables age and sex were included and corrected according to the model. The Spearman correlation coefficient was used to determine correlations between the variables. Alpha level for significance: P \ 0.05.
Results The study was conducted on 44 individuals aged on average 68.5 ± 5.1 years, with no significant differences between groups (p = 0.44). There was a predominance of
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women (84 %) in all three groups (p = 0.32) (Table 1). Fifteen elderly subjects were assigned to the AG, 15 to the RAG and 14 to the CG. Pre-training BMI values were similar for all groups (p = 0.70). After intervention, BMI values were lower in AG and RAG compared to CG (p \ 0.001) (Fig. 1). Comparison of pre- and post-treatment revealed a significant BMI reduction for AG of 0.9 ± 0.3 kg/m2 (p = 0.01) and for RAG of 1.3 ± 0.3 kg/m2 (p = 0.01) and a BMI elevation for CG of 0.9 ± 0.3 kg/m2 (p = 0.01), with no difference between AG and RAG. Baseline plasma IL-6 levels were higher in AG than in RAG (p = 0.01) and CG (p = 0.01) subjects, a fact that was not observed in the comparison of RAG vs. CG. After treatment, IL-6 was lower in AG compared to CG (p = 0.04) (Fig. 2). When comparing pre and post-training IL-6 levels, there was a reduction of 18.7 ± 4.8 pg/mL in AG (p \ 0.001). Initial TNF-a values did not differ between groups (AG: 30.1 ± 41.1 pg/mL, RAG: 17.1 ± 21.0 pg/mL, and CG: 42.4 ± 56.0 pg/mL; p [ 0.05). After the 10 weeks of the protocol, TNF-a levels were lower only in RAG compared to CG (RAG: 11.8 ± 8.2 pg/mL; CG: 49.3 ± 86.4 pg/mL, p = 0.01), with no significant difference for the comparisons AG (21.5 ± 20.2 pg/mL) vs. CG and AG vs. RAG after training. However, comparison of pre- and posttreatment TNF-a levels did not show differences for groups. When the correlation between BMI, IL-6 and TNF-a was calculated for the three groups, no association was detected between TNF-a and age, BMI, and IL-6, for AG and CG subjects. Among RAG subjects, the same was observed regarding age and IL-6, but a positive correlation was observed between the changes in TNF-a pre and posttraining and the difference between BMI pre and posttraining (p = 0.02 and r = 0.58) (Fig. 3). IL-6 had no association to variables age, BMI and TNF-a, in all groups.
Fig. 1 Box-plot shows the body mass index (BMI) before and after training in aerobic group (AG), combined resistance and aerobic group (RAG), and control group (CG). *p = 0.01 AG after vs. AG before, #p = 0.01 RAG after vs. RAG before, and &p = 0.01 CG after vs. CG before training. The bottom and the top of the box are the first and third quartile, the line inside the box is the second quartile (the median), black dots represent means, and white dots are outliers
Discussion In the present study, we observed a significant reduction in basal plasma IL-6 levels after aerobic training even though Table 1 Clinical characteristics of the groups before training Characteristics
AG
RAG
CG
N
15
15
14
Age (years)
67.8 ± 4.3
67.8 ± 5.2
69.9 ± 5.5
Sex (male/female)
1/14
2/13
2/12
28.9 ± 3.5
28.0 ± 3.2
27.6 ± 3.4
2
BMI (kg/m )
Data are reported as mean ± SD. P [ 0.05 for age, sex and BMI N number of individuals, BMI body mass index (weight/height2)
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Fig. 2 Box-plot shows interleukin-6 (IL-6) levels before and after training in aerobic group (AG), combined resistance and aerobic group (RAG), and control group (CG). *p \ 0.001 AG after vs. AG before training. The bottom and the top of the box are the first and third quartile, the line inside the box is the second quartile (the median), black dots represent means, and white dots are outliers
Aging Clin Exp Res
Fig. 3 Correlation between tumor necrosis factor alpha (TNF-a) delta and body mass index (BMI) delta pre and post-training in combined resistance and aerobic group (RAG)
this group had higher baseline levels than the other groups. Typically, IL-6 is the first cytokine released into the circulation during exercise. The level of circulating IL-6 increases in an exponential fashion (up to100 fold) in response to exercise and declines in the post-exercise period. The circulating levels of well-known anti-inflammatory cytokines such as IL-1ra and IL-10 increase after exercise [16]. Several observational studies have reported a negative association between the amount of regular physical activity and resting plasma IL-6 levels. In other words, the more active the individual, the lower the basal IL-6 [16]. On the other hand, high plasma levels of IL-6 are closely associated with physical inactivity and the metabolic syndrome. Intervention studies show that basal levels of IL-6 are reduced after training [16]. However, while plasma-IL-6 appears to be down regulated by training, the muscular expression of the IL-6 receptor (IL-6R) is up regulated. Moreover, the basal IL-6R mRNA content in trained skeletal muscle is increased compared to untrained conditions [17], suggesting that the sensitivity to IL-6 is increased. The elevated circulating levels of IL-6 that accompany obesity and physical inactivity may represent a compensatory mechanism. A fall in IL-6 in RAG subjects was not detected in this study. This cytokine is linked to the intensity and duration of exercise [18], when the low concentration of muscle glycogen stimulates its production. Then, it would be waited that the fall in IL-6 levels occurred in RAG. Maybe
the higher variability of the IL-6 values had influenced in the results. A lower pro-inflammatory cytokine TNF-a was observed only in RAG subjects compared to CG subjects after intervention with exercise. A high TNF-a concentration may be related to intolerance of exercise and to a sedentary condition since adipose tissue is responsible for its release [19, 20]. The present study found a positive correlation between the decrease of TNF-a and decrease in BMI in individuals RAG, indicating that the effects of exercise on TNF-a RAG may be mediated by the reduction in fat mass. Some studies have demonstrated more significant results in the reduction of mediators when aerobic exercises were performed, because there is a greater loss of body fat and body weight compared to the application of exclusive resistance exercises [21, 22]. On the other hand, resistance activity could provide a greater gain of muscle mass and strength and a greater loss of adipose mass when added to aerobic training. We detected similar reduction in BMI in older subjects submitted to aerobic exercise and those submitted to aerobic plus resistance exercise when compared to control subjects. Different results have been reported in study [23], in which elderly subjects submitted to aerobic and resistance exercise did not show any change in body weight. The authors evaluated the effects of 12 weeks of aerobic and resistance exercise and of 12 weeks of weight loss (diet and behavioral therapy) on the reduction of inflammation in older adults. They observed that IL-6 and TNF-a levels were reduced by 50 % and fat-free mass was increased in the group submitted to exercise training compared to the group allocated to the diet. Complementary results have been reported in a study [24], in which older subjects were submitted to a long time of physical activity associated with a diet. In the LIFE study, reduction of IL-6 was observed after 12 months of physical activity of moderate intensity (aerobic and resisted exercise, equilibrium and flexibility) in 424 elderly subjects [25]. In agreement, some investigators [5], noted that, after 24 weeks of moderate physical exercise with duration of 60 min and a frequency of 3 times a week, there was a fall in IL-6 and TNF-a, but not in IL-10. Controversial findings were obtained in another investigation [9], in which only IL-8 was affected by exercise after 12 months of physical activity, whereas no effect was observed on IL-6 or TNF-a. In a study using a protocol of resistance exercise and functional performance applied to older adults during 10 weeks, with 30 sessions, at a frequency of 3 times per week, results were similar to ours, with no reduction of IL6 levels after resistance exercise. No significant changes
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were also found in soluble tumor necrosis factor receptor-1 [26]. Important aspects to be considered are the intensity, duration, frequency and modality of physical exercise, which are very important variables that can modify the results obtained regarding the inflammatory process in older adults. Although several studies have reported and emphasized the importance of physical activity for the reduction of inflammation, not all of them have shown these positive effects, with many gaps still existing regarding the effect of physical exercise on the inflammatory biomarkers, especially in the older population, which may show marked signs of senility. Despite the small number of participants in each group of this study, the training protocol tested in the present study was effective in reducing the levels of inflammatory cytokines and could be reproduced in medical practice for the treatment of hypertensive older subjects. Concluding, both types of training used in the present study were effective in reducing BMI values in independent hypertensive older adults. Ten continuous weeks of aerobic exercise produced more expressive fall of plasma IL-6 levels than the combination of aerobic and resistance exercise in these older subjects. However, this combination of exercises, which would be more indicated for the prevention of loss of functionality with aging, showed a lower TNF-a mediator after training than control group and an association between greater fall of BMI and more expressive TNF-a reduction. Acknowledgments This study was supported by the Research Foundation of the State of Sa˜o Paulo (FAPESP) and the National Council for Scientific and Technological Development (CNPq). Conflict of interest
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Authors declare no conflict of interest. 19.
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ORIGINAL ARTICLE
Effect of aerobic training and aerobic and resistance training on the inflammatory status of hypertensive older adults Leandra G. Lima • Jose´ M. T. Bonardi • Giulliard O. Campos • Rodrigo F. Bertani Luria M. L. Scher • Paulo Louzada-Junior • Ju´lio C. Moriguti • Eduardo Ferriolli • Nereida K. C. Lima
•
Received: 16 September 2014 / Accepted: 24 December 2014 Ó Springer International Publishing Switzerland 2015
Abstract There is a relationship between high levels of inflammatory markers and low adhesion to the practice of physical activity in the older population. The objective of the present study was to compare the effect of two types of exercise programs, i.e., aerobic training and aerobic plus resistance training on the plasma levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a) of elderly hypertensive subjects. Hypertensive older volunteers in use of antihypertensive drugs were randomized to three groups: aerobic group (AG), resistance and aerobic group (RAG) and control group (CG). Training lasted 10 weeks, with sessions held three times a week. Blood samples were collected before training and 24 h after completion of the 30 sessions for the determination of serum IL-6 and TNF-a levels. Body mass index was obtained before and after 10 weeks. After intervention, BMI values were lower in AG and RAG compared to CG (p \ 0.001), IL-6 was reduced in AG compared to CG (p = 0.04), and TNF-a levels were lower only in RAG compared to CG
L. G. Lima J. M. T. Bonardi G. O. Campos R. F. Bertani L. M. L. Scher J. C. Moriguti E. Ferriolli N. K. C. Lima Division of General Internal Medicine and Geriatrics, School of Medicine of Ribeira˜o Preto, University of Sa˜o Paulo-FMRP-USP, Sa˜o Paulo, Brazil P. Louzada-Junior Division of Clinical Immunology, School of Medicine of Ribeira˜o Preto, University of Sa˜o Paulo-FMRP-USP, Sa˜o Paulo, Brazil N. K. C. Lima (&) Rua Mariana Casadio, 275, Jardim Canada´, Ribeira˜o Preto, SP 14024-360, Brazil e-mail: [email protected]
(p = 0.01). Concluding, both types of training were effective in reducing BMI values in hypertensive older subjects. Aerobic exercise produced the reduction of plasma IL-6 levels. However, the combination of aerobic and resistance exercise, which would be more indicated for the prevention of loss of functionality with aging, showed lower TNF-a mediator after training than control group and a greater fall of TNF-a levels associated to higher BMI reduction. Keywords Interleukin-6 Tumor necrosis factor alpha Aerobic training Resistance training Older adults
Backgrounds The aging process continues to be one of the concerns of humanity since the dawn of civilization [1]. There is consensus about the fact that the immune system changes during the aging process, becoming less efficient [2], with the occurrence of a two to fourfold increase in inflammatory markers including pro-inflammatory and anti-inflammatory cytokines, cytokine antagonists, and acute phase proteins [3, 4]. Changes in these pro-inflammatory markers may be associated with advancing age and with worsening of age-related chronic conditions such as arterial hypertension, functional capacity, muscle function, muscle fatigue, dementia, and many others [5–9]. The mechanism by which these mediators contribute to the functional decline of the aged is still uncertain but seems to be related to their catabolic effect, with reduction of muscle mass and strength [1, 10]. New studies showed an association between high levels of inflammatory markers and low adhesion to the practice
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of physical activity in the older population. The protective effect of exercise may be attributed to the anti-inflammatory effect of regular exercise, mediated via a reduction in visceral fat mass and/or by induction of an anti-inflammatory environment due to changes in monocyte phenotype, especially by a reduced production of immune cells of inflammatory mediators [9]. Pedersen et al. [11] have suggested that cytokines are produced, expressed, and released by muscle fibers and should be classified as ‘‘myokines’’. Such myokines may exert a direct effect on fat metabolism and there by result in indirect anti-inflammatory effects. It is suggested that contracting skeletal muscles release myokines, which work in a hormone-like fashion, exerting specific endocrine effects on visceral fat and other ectopic fat deposits. The first identified myokine is interleukin (IL-6). A number of studies have revealed that both type I and type II muscle fibers express the myokine IL-6 in response to muscle contractions. Subsequently IL-6 exert effects locally within the skeletal muscle, increasing locally fat oxidation and glucose uptake [12]. Although it has not been demonstrated that IL-6 has specific effects on visceral fat mass, it does appear to play an important role in lipid metabolism. The cytokine response to exercise differs from that elicited by severe infections. Classical pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-a) and IL-1b, in general do not increase with exercise, indicating that the cytokine cascade induced by exercise is markedly different from the cytokine cascade induced by infections [12]. Thus, studies associating and comparing the different effects of aerobic and anaerobic exercise on the chronic inflammatory process observed in the older adults have become relevant. As aerobic exercise is recommended to all hypertensive individuals, the objective of the present study was to evaluate the effect of isolated aerobic training and combined aerobic and resistive training on the inflammatory status of older subjects.
Methods Experimental approach to the problem The aim of this study was to compare the effect of two types of physical exercise programs, i.e., aerobic training and aerobic plus resistance training, over a period of 10 weeks, on the plasma levels of interleukin-6 (IL-6) and TNF-a of older adults. IL-6 was evaluated because it was the first myokine studied and has an indirect anti-inflammatory effect, and TNF-a is a classical pro-inflammatory cytokine.
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Subjects We selected 44 volunteers aged 60–75 years who were regularly taking antihypertensive medication (hydrochlorothiazide, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers). Volunteers performed all the basic and instrumental activities of daily living, with normal cognition, without current depression, and had adequate social condition. Exclusion criteria were: mean systolic blood pressure (SBP) above 160 mmHg and mean diastolic blood pressure (DBP) above 105 mmHg; use of beta blocker medication or presence of arrhythmia; smokers or ex-smokers for less than 5 years; presence of cardiac or respiratory problems; ethanol intake of more than 168 g per week; history or a previous diagnosis of acute myocardial infarction, stroke, secondary hypertension due to renal damage, diabetes mellitus, degenerative neurocognitive deficits, uncontrolled hypothyroidism or hyperthyroidism; hemoglobin values of less than 11 g/dL; changes in the treadmill test or echocardiogram; limiting osteoarthritis; acute inflammatory or infectious diseases; grade II and III obesity (body mass index (BMI) of 34.99 kg/m2 or more) or peripheral vascular obstruction; participation in other programs or practice of regular physical activity more than twice a week, or refusal to participate in the study. The study was approved by the Research Ethics Committee of the Public Health Center of the School of Medicine of Ribeira˜o Preto, protocol No. 367/CEP/CSEFMRP-USP, and all subjects gave written informed consent to participate. Procedures All volunteers were evaluated by a multidisciplinary team and answered a structured screening questionnaire. Blood and urine samples were collected for general tests (fasting glycaemia, glycated hemoglobin, blood count, serum lipids, creatinine, urea, sodium, potassium, thyroid stimulating hormone (TSH) and routine urinalysis) to exclude diabetes, renal failure, hypothyroidism or hyperthyroidism. The volunteers were instructed to not self-medicate and to contact the doctor in charge of the study in cases of fever, acute infection, use of new medications or increase of the habitual dose of any medication. They were asked to not change the habitual diet. The concentrations of the inflammatory markers studied: interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a) were measured in a blood sample collected during the week preceding the interventions from resting subjects after an overnight fast at 8:00–09:00 a.m. Blood samples from all individuals were harvested in the morning and placed in test tubes with anticoagulant (EDTA) and kept on ice until
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1 hour. Subsequently, the plasma was obtained by centrifugation at 400 g, and stored at -70 °C. The measurement of IL-6 and TNF was performed by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s instructions. Samples were assessed in duplicate. The detection limit of BDNF was 5 pg/mL. The intra-assay and inter-assay coefficients of variation (CV) were below 5 and 10 %, respectively. The volunteers were submitted to fundoscopic examination, to a treadmill test and to echocardiography to detect retinal or cardiac diseases that would contraindicate physical training. Weight and height were measured for the calculation of BMI. The treadmill test was also applied to determine maximum aerobic capacity. Based on the maximum oxygen consumption (VO2max) values obtained in the treadmill test, the individuals were classified as active or sedentary. VO2max was estimated by the formula of the American College of Sports Medicine [13]: VO2max = {[(maximum speed 9 16.66) 0.1] ? 3.5} ? {[(maximum slope/100) 9 (maximum speed 9 16.66)] 1.8}. After the subjects were classified in terms of physical conditioning, their working heart rate (HR) was determined by the following formula: Training HR = (maximum HR - resting HR) 9 % ? resting HR. Maximum HR was established by the maximum treadmill test, and resting HR was measured before the test. Two percentages were used for the lower and upper limits of the training range: 50 and 70 % for the sedentary volunteers and 60 and 80 % for conditioned volunteers, respectively. We opted for different percentages for sedentary and active volunteers to avoid under- and overestimating physical ability according to the guidelines for prescribing aerobic exercise. To determine the load imposed during resisted exercise we used the one repetition maximum test (1RM), with progressive increments being inserted for each muscle groups exercised in the protocol. Four trials were performed to determine the 1RM value. The final weight successfully lifted was recorded as the absolute value, 100 % or 1RM, and the individuals were trained with intensities of 50–60 % 1RM. On the basis of the planned objectives, nine resisted exercises were proposed to recruit muscle groups of the upper and lower limbs and of the trunk, selected in the following circuit order: (1) Leg Press 45°, (2) Chest Press, (3) Leg Extension, (4) Lat Pull Down, (5) Leg Curl, (6) Pulley Upright Row, (7) Seated Calf Raise, (8) Machine Seated Row, and (9) Abdominal Crunches. After the initial overall evaluation and the execution of the above procedures, the participants were randomized to three groups: aerobic group (AG), resistance and aerobic group (RAG) and control group (CG). Training lasted ten consecutive weeks, with sessions held three times a week on alternate days, for a total of 30 uninterrupted sessions. All sessions were held in the
morning in a fitness center located in the city of Ribeira˜o Preto. CG subjects did not engage in any type of training, maintaining their normal daily activities throughout the study period. AG subjects exercised on a treadmill. Each session started and ended with 5 min of stretching exercises. Twenty minutes of continuous aerobic exercise were performed from the 1st to the 4th week, with an increase to 30 min of continuous aerobic exercise from the 5th to the 10th week. During the execution of exercise, HR values were recorded every 5 min, as well as physical exertion values obtained using the revised Borg rating of perceived exertion scale [14]. RAG training also started and ended with 5 min of stretching, with the subjects sequentially completing one circuit lap (1st to 4th week) and progressing to two circuit laps (5th to 10th week) with intensity of 50–60 % RM. The time between stations (for each type of equipment) was 1 min, with each station consisting of exercised performed in series of 15 repetitions for the upper limbs and of 20 repetitions for the trunk and lower limbs. At the end of each station, HR and perceived exertion according to the Borg scale were recorded. After the resistance exercise protocol, the aerobic exercise was performed as described for the AG. Blood samples were collected 24 h after completion of the 30 sessions (chronic effect of exercise) for the determination of plasmatic IL-6 and TNF-a levels, with all procedures being identical to those performed in the preintervention period. Statistical analysis An exploratory analysis of the data was first carried out using descriptive statistics based on measurements of central tendency (mean and median) and of variability (standard deviation) using the SASÒ 9.0 software [15]. TNF-a and IL-6 variables were log transformed for residue adjustment using the SASÒ 9.0 software [15]. Orthogonal contrast post test was used for the comparisons. The co-variables age and sex were included and corrected according to the model. The Spearman correlation coefficient was used to determine correlations between the variables. Alpha level for significance: P \ 0.05.
Results The study was conducted on 44 individuals aged on average 68.5 ± 5.1 years, with no significant differences between groups (p = 0.44). There was a predominance of
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women (84 %) in all three groups (p = 0.32) (Table 1). Fifteen elderly subjects were assigned to the AG, 15 to the RAG and 14 to the CG. Pre-training BMI values were similar for all groups (p = 0.70). After intervention, BMI values were lower in AG and RAG compared to CG (p \ 0.001) (Fig. 1). Comparison of pre- and post-treatment revealed a significant BMI reduction for AG of 0.9 ± 0.3 kg/m2 (p = 0.01) and for RAG of 1.3 ± 0.3 kg/m2 (p = 0.01) and a BMI elevation for CG of 0.9 ± 0.3 kg/m2 (p = 0.01), with no difference between AG and RAG. Baseline plasma IL-6 levels were higher in AG than in RAG (p = 0.01) and CG (p = 0.01) subjects, a fact that was not observed in the comparison of RAG vs. CG. After treatment, IL-6 was lower in AG compared to CG (p = 0.04) (Fig. 2). When comparing pre and post-training IL-6 levels, there was a reduction of 18.7 ± 4.8 pg/mL in AG (p \ 0.001). Initial TNF-a values did not differ between groups (AG: 30.1 ± 41.1 pg/mL, RAG: 17.1 ± 21.0 pg/mL, and CG: 42.4 ± 56.0 pg/mL; p [ 0.05). After the 10 weeks of the protocol, TNF-a levels were lower only in RAG compared to CG (RAG: 11.8 ± 8.2 pg/mL; CG: 49.3 ± 86.4 pg/mL, p = 0.01), with no significant difference for the comparisons AG (21.5 ± 20.2 pg/mL) vs. CG and AG vs. RAG after training. However, comparison of pre- and posttreatment TNF-a levels did not show differences for groups. When the correlation between BMI, IL-6 and TNF-a was calculated for the three groups, no association was detected between TNF-a and age, BMI, and IL-6, for AG and CG subjects. Among RAG subjects, the same was observed regarding age and IL-6, but a positive correlation was observed between the changes in TNF-a pre and posttraining and the difference between BMI pre and posttraining (p = 0.02 and r = 0.58) (Fig. 3). IL-6 had no association to variables age, BMI and TNF-a, in all groups.
Fig. 1 Box-plot shows the body mass index (BMI) before and after training in aerobic group (AG), combined resistance and aerobic group (RAG), and control group (CG). *p = 0.01 AG after vs. AG before, #p = 0.01 RAG after vs. RAG before, and &p = 0.01 CG after vs. CG before training. The bottom and the top of the box are the first and third quartile, the line inside the box is the second quartile (the median), black dots represent means, and white dots are outliers
Discussion In the present study, we observed a significant reduction in basal plasma IL-6 levels after aerobic training even though Table 1 Clinical characteristics of the groups before training Characteristics
AG
RAG
CG
N
15
15
14
Age (years)
67.8 ± 4.3
67.8 ± 5.2
69.9 ± 5.5
Sex (male/female)
1/14
2/13
2/12
28.9 ± 3.5
28.0 ± 3.2
27.6 ± 3.4
2
BMI (kg/m )
Data are reported as mean ± SD. P [ 0.05 for age, sex and BMI N number of individuals, BMI body mass index (weight/height2)
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Fig. 2 Box-plot shows interleukin-6 (IL-6) levels before and after training in aerobic group (AG), combined resistance and aerobic group (RAG), and control group (CG). *p \ 0.001 AG after vs. AG before training. The bottom and the top of the box are the first and third quartile, the line inside the box is the second quartile (the median), black dots represent means, and white dots are outliers
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Fig. 3 Correlation between tumor necrosis factor alpha (TNF-a) delta and body mass index (BMI) delta pre and post-training in combined resistance and aerobic group (RAG)
this group had higher baseline levels than the other groups. Typically, IL-6 is the first cytokine released into the circulation during exercise. The level of circulating IL-6 increases in an exponential fashion (up to100 fold) in response to exercise and declines in the post-exercise period. The circulating levels of well-known anti-inflammatory cytokines such as IL-1ra and IL-10 increase after exercise [16]. Several observational studies have reported a negative association between the amount of regular physical activity and resting plasma IL-6 levels. In other words, the more active the individual, the lower the basal IL-6 [16]. On the other hand, high plasma levels of IL-6 are closely associated with physical inactivity and the metabolic syndrome. Intervention studies show that basal levels of IL-6 are reduced after training [16]. However, while plasma-IL-6 appears to be down regulated by training, the muscular expression of the IL-6 receptor (IL-6R) is up regulated. Moreover, the basal IL-6R mRNA content in trained skeletal muscle is increased compared to untrained conditions [17], suggesting that the sensitivity to IL-6 is increased. The elevated circulating levels of IL-6 that accompany obesity and physical inactivity may represent a compensatory mechanism. A fall in IL-6 in RAG subjects was not detected in this study. This cytokine is linked to the intensity and duration of exercise [18], when the low concentration of muscle glycogen stimulates its production. Then, it would be waited that the fall in IL-6 levels occurred in RAG. Maybe
the higher variability of the IL-6 values had influenced in the results. A lower pro-inflammatory cytokine TNF-a was observed only in RAG subjects compared to CG subjects after intervention with exercise. A high TNF-a concentration may be related to intolerance of exercise and to a sedentary condition since adipose tissue is responsible for its release [19, 20]. The present study found a positive correlation between the decrease of TNF-a and decrease in BMI in individuals RAG, indicating that the effects of exercise on TNF-a RAG may be mediated by the reduction in fat mass. Some studies have demonstrated more significant results in the reduction of mediators when aerobic exercises were performed, because there is a greater loss of body fat and body weight compared to the application of exclusive resistance exercises [21, 22]. On the other hand, resistance activity could provide a greater gain of muscle mass and strength and a greater loss of adipose mass when added to aerobic training. We detected similar reduction in BMI in older subjects submitted to aerobic exercise and those submitted to aerobic plus resistance exercise when compared to control subjects. Different results have been reported in study [23], in which elderly subjects submitted to aerobic and resistance exercise did not show any change in body weight. The authors evaluated the effects of 12 weeks of aerobic and resistance exercise and of 12 weeks of weight loss (diet and behavioral therapy) on the reduction of inflammation in older adults. They observed that IL-6 and TNF-a levels were reduced by 50 % and fat-free mass was increased in the group submitted to exercise training compared to the group allocated to the diet. Complementary results have been reported in a study [24], in which older subjects were submitted to a long time of physical activity associated with a diet. In the LIFE study, reduction of IL-6 was observed after 12 months of physical activity of moderate intensity (aerobic and resisted exercise, equilibrium and flexibility) in 424 elderly subjects [25]. In agreement, some investigators [5], noted that, after 24 weeks of moderate physical exercise with duration of 60 min and a frequency of 3 times a week, there was a fall in IL-6 and TNF-a, but not in IL-10. Controversial findings were obtained in another investigation [9], in which only IL-8 was affected by exercise after 12 months of physical activity, whereas no effect was observed on IL-6 or TNF-a. In a study using a protocol of resistance exercise and functional performance applied to older adults during 10 weeks, with 30 sessions, at a frequency of 3 times per week, results were similar to ours, with no reduction of IL6 levels after resistance exercise. No significant changes
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were also found in soluble tumor necrosis factor receptor-1 [26]. Important aspects to be considered are the intensity, duration, frequency and modality of physical exercise, which are very important variables that can modify the results obtained regarding the inflammatory process in older adults. Although several studies have reported and emphasized the importance of physical activity for the reduction of inflammation, not all of them have shown these positive effects, with many gaps still existing regarding the effect of physical exercise on the inflammatory biomarkers, especially in the older population, which may show marked signs of senility. Despite the small number of participants in each group of this study, the training protocol tested in the present study was effective in reducing the levels of inflammatory cytokines and could be reproduced in medical practice for the treatment of hypertensive older subjects. Concluding, both types of training used in the present study were effective in reducing BMI values in independent hypertensive older adults. Ten continuous weeks of aerobic exercise produced more expressive fall of plasma IL-6 levels than the combination of aerobic and resistance exercise in these older subjects. However, this combination of exercises, which would be more indicated for the prevention of loss of functionality with aging, showed a lower TNF-a mediator after training than control group and an association between greater fall of BMI and more expressive TNF-a reduction. Acknowledgments This study was supported by the Research Foundation of the State of Sa˜o Paulo (FAPESP) and the National Council for Scientific and Technological Development (CNPq). Conflict of interest
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14. 15. 16. 17.
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Authors declare no conflict of interest. 19.
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