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The Role of Physical Activity in Healthy Living
C H A P T E R
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The Role of Physical Activity in Healthy Living: Its Anti-Inflammatory Effects Cheri L. Gostic, Dawn Blatt Division of Rehabilitation Sciences, School of Health Technology and Management, Stony Brook University, NY, USA
INTRODUCTION Exercise and physical activity have long been associated with a healthy lifestyle, along with proper nutrition, adequate sleep, and stress management. A large body of evidence exists to support the benefits of regular physical activity and exercise in reducing morbidity and mortality through improvements in dyslipidemia, enhanced insulin sensitivity, a reduction in blood pressure, and beneficial changes in body mass and composition [1]. Physical fitness is associated with lower rates of cardiovascular disease, stroke, type 2 diabetes mellitus (T2DM), fractures due to osteoporosis, and breast and colon cancers [2]. Exercise attenuates the reduction in bone density and muscle mass that accompanies senescence, improves cognition, and reduces the risk of Alzheimer disease in the elderly [3]. Psychological benefits exist as well, and include improved self-esteem, mood, and stress relief via the release of endorphins by the pituitary gland in response to sustained exercise.
DAILY PHYSICAL ACTIVITY RECOMMENDATIONS Daily physical activity plays a fundamental role in energy balance, weight control, and overall health. Despite this fact, the US Department of Health and Human Services reports that only 20.6% of adults in the United States met physical activity guidelines in 2010 [4]. Although public health recommendations issued by the American College of Sports Medicine and the American Heart Association in 2007 advise adults to partake in a minimum of 30 min of moderate intensity aerobic activity 5 days a week, guidelines to prevent weight gain and
Inflammation, Advancing Age and Nutrition. http://dx.doi.org/10.1016/B978-0-12-397803-5.00023-X
weight regain are higher [5]. The International Association for the Study of Obesity concluded that 45-60 min of physical activity/day is required to prevent the transition to overweight and obesity in adults [2]. Additionally, for individuals who have lost a significant amount of weight, studies generally support the need for 60– 90 min of moderate intensity physical activity per day to prevent weight regain [6,7]. Individuals should allow adequate time to steadily progress to this recommended level of daily physical activity.
OVERWEIGHT AND OBESITY In adults, the health risks associated with increased adiposity are well established, and begin to rise at a body mass index (BMI) > 27 kg/m2 [8]. Obesity increases the risks of cardiovascular disease, stroke, diabetes, arthritis, gallbladder disease, certain cancers, and lung pathologies [9]. Overweight and obesity result from an imbalance involving elevated caloric intake relative to energy expenditure and are influenced by behavioral, genetic, metabolic, and socioeconomic factors. A review of the literature by Blair and Brodney demonstrates that regular physical activity attenuates many of the health risks associated with obesity. It found that overweight or obese individuals who are physically fit and active actually have lower mortality and morbidity than sedentary individuals of normal weight [10]. Research by Hu et al. concluded that a sedentary lifestyle and increased adiposity were strong, independent predictors of death, which together accounted for 31% of all premature deaths among the nonsmoking women in their study [11]. An inactive lifestyle promotes the accumulation of visceral fat, which results in an increased
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release of proinflammatory cytokines by adipocytes and the development of chronic low-grade systemic inflammation [12]. Exercise is a critical adjunct to diet and behavioral modification in a comprehensive weight loss program. It not only increases energy expenditure but has also been shown to diminish the loss of lean body mass and associated decline in resting metabolic rate that is characteristic of dieting alone [13]. Exercise improves the body’s ability to burn fat, thus enhancing the loss of adipose tissue [14]. In addition, it has been shown to improve dietary adherence while reducing anxiety, stress, and depression that can trigger overeating [15]. Research confirms that the combination of diet and exercise results in greater weight loss than diet or exercise alone [16], and that adherence to a lifestyle of physical activity and healthy nutrition are the greatest determinants of weight maintenance following weight loss [17–19].
TYPE 2 DIABETES The prevalence of diabetes has risen over recent decades due to the underlying association of T2DM with escalating rates of obesity. Exercise and physical activity are effective in addressing both of the principal modifiable risk factors of T2DM: obesity and a sedentary lifestyle [20]. Studies consistently indicate that an elevated BMI is one of the strongest risk factors for the development of diabetes, with an increased waist-to-hip ratio adding to a person’s risk [21]. A review of 10 prospective cohort studies by Jeon et al. indicates that people with an active lifestyle have an approximately 30% lower risk of developing diabetes than do individuals who are sedentary [22]. Insulin resistance, i.e. a reduction in the ability of the body to clear a glucose load from the blood in response to circulating insulin, is characteristic of T2DM and prediabetes. Physical activity is important in regulating plasma glucose levels, reducing the risk of insulin resistance, and decreasing excess fat deposition. Excess adiposity predisposes individuals to T2DM due to adipocyte production/release of free fatty acids and cytokines that interfere with insulin receptor signaling in muscle, adipose tissue, and the liver, leading to decreased glucose transport in genetically predisposed individuals. Cytokines released by adipocytes are associated with a proinflammatory effect and endothelial dysfunction that also increase the risk of metabolic dysfunction and cardiovascular disease in overweight individuals [23,34]. Exercise and physical activity have been shown to clearly influence the pathophysiological conditions underlying the development of T2DM and to improve insulin sensitivity. Aerobic exercise increases the lipid oxidative capacity of muscle cells, decreases the amount
of lipid products stored in skeletal muscle, increases glucose uptake by muscle during physical activity, and promotes the storage of glucose in muscle after exercise [25]. Glucose uptake into skeletal muscle has been shown to increase by up to 20-fold [26] during lower extremity exercise and is facilitated by an increase in blood flow to exercising muscles. Studies demonstrate a significant increase in glucose utilization and translocation of solute carrier family 2, facilitated glucose transporter member 4 [or insulin-regulated glucose transporter protein 4 (GLUT-4)] to the skeletal muscle cell membrane in both healthy individuals and individuals with T2DM with exercise [27,78]. Studies also reveal an improvement in insulin sensitivity that persists for several hours up to a few days after a single session of exercise in both healthy individuals and those with T2DM and obesity [29,30]. In contrast, several days without physical activity significantly decreases insulin sensitivity [31], reinforcing the need for regular physical activity as part of a healthy lifestyle. The protective mechanisms conferred by exercise and physical activity in preventing the onset of T2DM can be classified into acute versus chronic adaptations. Acute responses involve an increase in glucose uptake, glucose transport, and/or disposal of glucose that occurs during and appears to last for 12–48 h after the cessation of physical activity, depending on overall energy expenditure [32]. Chronic adaptations include increased mitochondrial biogenesis and fiber ratios [33]; improved endothelial function and capillarization [34]; improved muscular respiratory capacity and fatty acid oxidation [35]; and increased synthesis of GLUT-4 and enzymes that control the uptake and metabolism of glucose in skeletal muscle [36]. Exercise and physical activity play a crucial role in preventing or delaying the development of T2DM in those at risk by improving insulin sensitivity and, indirectly, by producing beneficial changes in body mass and body composition [37,78]. Both aerobic and resistive exercise have therapeutic value in preventing T2DM, largely independent of weight loss, and are both valuable components of an exercise program. Aerobic activity decreases adiposity, particularly in the visceral region, even in the absence of weight loss, and has greater effects on cardiorespiratory fitness [39]. Strength training increases muscle mass, elevates the resting metabolic rate, increases GLUT-4 protein content, and improves glucose metabolism through increased glycogen synthase activity within the trained muscle. In addition to improving muscle quality and insulin sensitivity, resistive exercise was shown to reduce C-reactive protein (CRP) levels and free fatty acids while increasing circulating adiponectin, changes that are all associated with improved metabolic control [40].
INFLAMMATION
METABOLIC SYNDROME Metabolic syndrome is a cluster of metabolically related abnormalities and cardiovascular risk factors that generally include abdominal obesity, insulin resistance, elevated triglycerides, reduced high-density lipoproteins, and hypertension. This diagnosis increases the risk of coronary heart disease twofold, and all-cause mortality by 40% [41]. Adults who did not participate in any leisure time physical activity were found to be 45% more likely to be diagnosed with metabolic syndrome when compared with active counterparts [42]. A body of evidence exists to support the benefits of exercise and physical activity in reducing the risks of metabolic syndrome and its associated risk factors [1,12–50].
HYPERTENSION Studies indicate that participating in a regular exercise program has a positive impact on blood pressure, thus decreasing one of the common criteria for metabolic syndrome. Welton et al. reviewed 54 randomized, controlled studies on aerobic exercise and its effect on blood pressure and found that physical inactivity led to a 30–50% increased risk of hypertension. Physical activity was found to decrease blood pressure in hypertensive and normotensive persons. Aerobic exercise led to a decrease in blood pressure for those with normal BMI scores as well. In addition, all forms of exercise appeared to have a positive impact on blood pressure measurements. Blood pressure was noted to decrease in trials independent of a change in body weight [51].
HYPERLIPIDEMIA Regular exercise significantly reduces triglyceride levels [52] and improves the blood lipid profile [53]. A review of randomized, controlled trials by Leon and Sanchez examined the effect of 12 weeks or more of exercise on hyperlipidemia. They found that programs consisting of moderate to vigorous intensity levels 3–5 days/week for at least 30 min/session resulted in an increase in high-density lipoprotein cholesterol levels in half of the studies [54].
INFLAMMATION Research aimed at understanding the pathophysiology of many common chronic diseases has shifted in recent decades from a focus on serum lipids and the proliferation of smooth muscle cells to the role of inflammation in chronic conditions such as T2DM, metabolic
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syndrome, and atherosclerosis. Low-grade systemic inflammation can be detected by an elevation in a variety of circulating inflammatory biomarkers including CRP and cytokines such as tumor necrosis factor (TNF-α) and interleukin-6 (IL-6). CRP is produced in the liver and regulated principally by the inflammatory cytokines IL-6 and TNF-α. Research has revealed a significant increase in CRP in individuals with atherosclerotic disease and metabolic syndrome [55,56]. Cytokines are small polypeptides produced by cells that regulate the body’s response to disease, trauma, and infection. Cytokines deemed “proinflammatory” act to accentuate disease processes, while anti-inflammatory cytokines serve to reduce inflammation and promote healing. Research since 2000 into exercise’s role in reducing low-grade systemic inflammation points to two potential mechanisms: a decrease in visceral adipose tissue and the release of anti-inflammatory cytokines from working skeletal muscle. In low-grade systemic inflammation, the cytokine TNF-α is released (mainly by adipose tissue) and stimulates the production of IL-6 in adipocytes and in mononuclear cells in the blood. IL-6, in turn, stimulates increased levels of plasma IL-1 receptor antagonist (IL-1ra), TNF receptor (TNFR), IL-10, and CRP by the liver [57]. The link between low-level chronic inflammation and illness related to atherosclerosis, obesity, metabolic syndrome, and diabetes appears to lie with TNF-α. Patients with T2DM possess high levels of TNF-α in skeletal muscle [58] and in the bloodstream [59–61], and research points to adipose tissue as the primary source of the elevated levels of TNF-α [62,23]. In these patients, studies suggest that TNF-α may have direct inhibitory effects on insulin signaling [64–66]. In patients with metabolic syndrome, high levels of TNF-α and IL-6 have been associated with abdominal obesity, and it is theorized that increases in TNF-α released by adipose tissue is responsible for the observed increase in s ystemic levels of IL-6. TNF-α is prevalent in atherosclerotic lesions, and elevated levels of TNF-α in the blood are predictive of a risk of myocardial infarction, the severity of peripheral arterial disease, and the degree of carotid artery atherosclerosis in healthy middle-aged men [67]. Chronic low-grade systemic inflammation is associated with advancing age, with circulating proinflammatory cytokines such as TNF-α, IL-6, and CRP typically measured at levels two to four times that of young adults, even in the absence of chronic disease [68]. Although age-related chronic disease plays a significant role in the low-grade inflammation observed in the elderly, the natural decline in immune function with age that promotes an inflammatory state is also believed to contribute as well [69]. In recent years, a direct association between physical activity and exercise and the release of cytokines with anti-inflammatory properties was revealed, which
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supports the benefit of regular physical activity in protecting individuals against certain chronic diseases [57]. During a bout of exercise, there is a transient increase in anti-inflammatory cytokines, a response that is markedly different from that seen with low-level inflammation or in response to disease or trauma: with exercise, muscle fiber production of IL-6 increases plasma levels of IL-6 by up to 100-fold [70–73], followed by an increase in anti-inflammatory cytokines and cytokine inhibitors such as IL-1ra, IL-10, and soluble TNFR (sTNFR) [74,45]. The plasma increase in IL-6 is related to exercise intensity, duration, and muscle mass recruited [70–72] and has the added benefit of inhibiting the production of the proinflammatory cytokine TNF-α [57]. The long-term effect of regular exercise is, thus, a reduction in basal levels of proinflammatory cytokines [76]. Although weight loss has been associated with a reduction in lowgrade inflammation due to a decrease in adiposity, studies also support a decrease in low-grade inflammation with exercise and/or diet, independent of weight loss [77], reflecting an anti-inflammatory effect of exercise itself.
REVIEW OF THE EVIDENCE ON THE EFFECT OF EXERCISE ON INFLAMMATORY MARKERS Recent studies that examine the effect of exercise and daily activity levels on inflammation can be categorized into observational and random control studies. In reviewing the literature of observational studies, most examined healthy subjects and relied on self-reported exercise and/or activity levels over the duration of the study [78–81]. Mora et al. followed a group of healthy women who were health professionals, ages 45 years and older, having them complete surveys and provide blood samples for CRP and fibrinogen. These women completed activity diaries for four separate weeks over the course of a year, estimating the amount of time spent in a variety of recreational activities and the number of flights of stairs climbed daily. A mean follow up of 10.9 ± 1.6 years found that women with an active lifestyle had lower risk factors for cardiovascular disease, including CRP and fibrinogen. The risk of cardiovascular disease showed a linear decrease with increasing levels of physical activity [78]. Mora et al. also investigated BMI and physical activity in the same group of women. BMI positively correlated with the inflammatory markers, CRP and fibrinogen, while physical activity negatively correlated with these biomarkers [79]. A group of 177 men, aged 40–75 years of age with BMIs between 25 and 35 kg/m2 who were being treated for hypertension, were randomly selected from the Hypertension High Risk Management Trial. They were asked
about the frequency and duration of all physical activities related to work, hobbies, home, leisure, transportation, regular exercise, and sedentary activities engaged in during the previous week. All participants were deemed sedentary, defined as performing regular exercise for < 1 hour/week. A fitness test was conducted for each subject using a bicycle and testing “time to exhaustion” as per the Borg Scale. This study revealed an inverse relationship between CRP and fitness, but no significant relationship was found between CRP and the level of physical activity in this population. The authors concluded that an increased level of physical fitness is beneficial in slowing the progression of cardiovascular disease in a sedentary population of drug-treated hypertensive men [80]. Kadoglou et al. studied 60 overweight subjects with T2DM, randomly assigning 30 participants to an exercise group and 30 to a control group. The exercise group completed aerobic exercise sessions four times/week for 45–60 min/session. At the end of the 6-month training period, the exercise group had large decreases in CRP and IL-18 plasma levels and small decreases in TNF-α compared to both the control group and baseline levels. These changes were attained without significant changes in body weight [81]. Exercise can be divided into two categories: endurance training and resistance training (RT). Many studies look at endurance exercise, while few focus on RT. RT, also referred to as strength training, is defined as exercise in which movement is performed against an external force. Single bouts of resistance exercise have shown a temporary increase in CRP levels, as well as an increase in IL-6, with long-term effects demonstrating a decrease in proinflammatory markers [82]. Calle and Fernandez followed a group of women performing an RT program twice weekly over the course of a year. The first 16 weeks were supervised and the remaining sessions were selfreported. At the end of the year, there was a decrease in CRP levels, but no change in IL-6 levels. The authors concluded that a decrease in CRP levels may be due to multiple factors and suggested that there may be a relationship between an individual’s level of training and their response to RT [83]. Phillips et al. utilized a randomized control design to examine a group of postmenopausal women over a 12-week period. The women, with an average age of 65.6 years, were split into two groups: one performed an RT program three times/week, involving three sets of 8–12 repetitions for 10 muscle groups, while the other group attended a program twice/week for stretching, knitting, and health information lectures. At the end of 12 weeks, the RT group had a decrease in CRP, leptin, and TNF-α plasma levels, with no change in body composition observed [84]. The results of the observational studies discussed above show a positive effect of exercise and physical activity on inflammatory markers in healthy subjects.
Review of the Evidence on the Effect of Exercise on Inflammatory Markers
In contrast, the results of randomized controlled studies that examined the impact of exercise on inflammation are mixed. These studies have often utilized subjects with various chronic conditions. Kohut et al. studied a group of 87 adults aged 64–87 years during a 10-month training program of either cardiovascular exercise or strength, balance, and flexibility exercises. The cardiovascular exercise program was performed three times/week, and consisted of a warmup, stretching, and 25–30 min of aerobic exercise on equipment, and finished with a cooldown consisting of stretching and balance exercises. The strength, flexibility, and balance training consisted of a 10-min warm up, stretching exercises targeting large muscle groups, and a 25–30-min exercise class including components of yoga, tai chi, weights, and stability balls, with a transition to weight machines for the second 5 months of the study. The session ended with a 10-min cooldown similar to that of the cardiovascular exercise group. At the end of the study, the cardiovascular exercise group had significant decreases in CRP, IL-6, and IL-18 levels, whereas the strength training group did not show these changes. Both groups had a reduction in TNF-α levels [85]. Walther et al. followed 101 men with coronary artery disease over 2 years, randomly assigning them into two groups: a group that performed 20 min of daily aerobic exercise and a group that underwent percutaneous coronary intervention (PCI) with stent placement. After 2 years, a significant decrease in CRP and IL-6 levels was observed in the exercise group, with no change noted in the PCI group. In addition, 78% of the group that p erformed regular exercise suffered no additional cardiac events, compared to 62% of subjects in the PCI group [86]. Nicklas et al. conducted a randomized controlled trial that looked at CRP and IL-6 levels over 12 months in 424 sedentary subjects, aged 70–89, assigned to either a physical activity group or a health education group. The successful aging health education group met weekly initially and then monthly for education on topics such as preventive health care, nutrition, medication, and foot care. Each session also included 5–10 min of upper extremity stretching. The physical activity group started with a supervised exercise program three times/week, decreased to two sessions/week after 2 months, and then, for the last 6 months, the participants exercised at home. The physical activity group focused on walking, with a goal of completing at least 150 min/week, and also completed lower extremity strengthening and stretching exercises. In addition, this group attended weekly behavioral counseling sessions for the first 10 weeks to encourage participation in the physical activity program. At the start of the program, the baseline measures of CRP and IL-6 were the same. After 12 months, the group that exercised had lower
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IL-6 concentrations, with no change noted in CRP concentration [87]. Martins et al. examined the effect of different types of exercise on an elderly adult population over the age of 64. The subjects were ambulatory and received medical clearance from their physicians. Some of the subjects had hypertension (47%), T2DM (16%), and angina pectoris (15%). They assigned the subjects into three groups: an aerobic training group (AT), a strength training group (ST), and a control group. The AT group undertook 16 weeks of supervised exercise, 45 min in duration, progressing from 40–50% of heart rate reserve to 71–85% heart rate reserve. The ST group performed eight supervised exercises, including calisthenics and resistance exercises with elastic bands, progressing from one set of 8 repeats to three sets of 15 repeats, three times/week. A significant decrease in CRP levels was observed in both groups, with a greater decrease noted in the AT group [88]. Recent randomized control studies have also examined the effect of exercise on inflammatory markers such as CRP, IL-6, or TNF-α and found no positive effect of exercise [89–92]. These studies were conducted on generally healthy subjects, as well as those with diagnoses such as breast cancer, chronic arthritis, and impaired insulin sensitivity. Whereas the benefits of exercise in improving health and fitness and in preventing cardiovascular disease are clear, research into the anti-inflammatory effects of exercise remains in its early stages. Due to a lack of consistent findings in the literature, more studies need to be conducted to determine the type and intensity of exercise that is most beneficial in increasing serum levels of inflammatory markers associated with atherosclerosis and chronic disease. In addition, research is needed to determine the benefits of exercise in positively influencing inflammatory markers in subjects with different health conditions and of different ages. Further research is also needed to better define the role of specific systemic markers of inflammation in the development of cardiovascular disease, so that these markers can be utilized more effectively in the prevention of chronic disease.
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Review of the Evidence on the Effect of Exercise on Inflammatory Markers
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The Role of Physical Activity in Healthy Living: Its Anti-Inflammatory Effects Cheri L. Gostic, Dawn Blatt Division of Rehabilitation Sciences, School of Health Technology and Management, Stony Brook University, NY, USA
INTRODUCTION Exercise and physical activity have long been associated with a healthy lifestyle, along with proper nutrition, adequate sleep, and stress management. A large body of evidence exists to support the benefits of regular physical activity and exercise in reducing morbidity and mortality through improvements in dyslipidemia, enhanced insulin sensitivity, a reduction in blood pressure, and beneficial changes in body mass and composition [1]. Physical fitness is associated with lower rates of cardiovascular disease, stroke, type 2 diabetes mellitus (T2DM), fractures due to osteoporosis, and breast and colon cancers [2]. Exercise attenuates the reduction in bone density and muscle mass that accompanies senescence, improves cognition, and reduces the risk of Alzheimer disease in the elderly [3]. Psychological benefits exist as well, and include improved self-esteem, mood, and stress relief via the release of endorphins by the pituitary gland in response to sustained exercise.
DAILY PHYSICAL ACTIVITY RECOMMENDATIONS Daily physical activity plays a fundamental role in energy balance, weight control, and overall health. Despite this fact, the US Department of Health and Human Services reports that only 20.6% of adults in the United States met physical activity guidelines in 2010 [4]. Although public health recommendations issued by the American College of Sports Medicine and the American Heart Association in 2007 advise adults to partake in a minimum of 30 min of moderate intensity aerobic activity 5 days a week, guidelines to prevent weight gain and
Inflammation, Advancing Age and Nutrition. http://dx.doi.org/10.1016/B978-0-12-397803-5.00023-X
weight regain are higher [5]. The International Association for the Study of Obesity concluded that 45-60 min of physical activity/day is required to prevent the transition to overweight and obesity in adults [2]. Additionally, for individuals who have lost a significant amount of weight, studies generally support the need for 60– 90 min of moderate intensity physical activity per day to prevent weight regain [6,7]. Individuals should allow adequate time to steadily progress to this recommended level of daily physical activity.
OVERWEIGHT AND OBESITY In adults, the health risks associated with increased adiposity are well established, and begin to rise at a body mass index (BMI) > 27 kg/m2 [8]. Obesity increases the risks of cardiovascular disease, stroke, diabetes, arthritis, gallbladder disease, certain cancers, and lung pathologies [9]. Overweight and obesity result from an imbalance involving elevated caloric intake relative to energy expenditure and are influenced by behavioral, genetic, metabolic, and socioeconomic factors. A review of the literature by Blair and Brodney demonstrates that regular physical activity attenuates many of the health risks associated with obesity. It found that overweight or obese individuals who are physically fit and active actually have lower mortality and morbidity than sedentary individuals of normal weight [10]. Research by Hu et al. concluded that a sedentary lifestyle and increased adiposity were strong, independent predictors of death, which together accounted for 31% of all premature deaths among the nonsmoking women in their study [11]. An inactive lifestyle promotes the accumulation of visceral fat, which results in an increased
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release of proinflammatory cytokines by adipocytes and the development of chronic low-grade systemic inflammation [12]. Exercise is a critical adjunct to diet and behavioral modification in a comprehensive weight loss program. It not only increases energy expenditure but has also been shown to diminish the loss of lean body mass and associated decline in resting metabolic rate that is characteristic of dieting alone [13]. Exercise improves the body’s ability to burn fat, thus enhancing the loss of adipose tissue [14]. In addition, it has been shown to improve dietary adherence while reducing anxiety, stress, and depression that can trigger overeating [15]. Research confirms that the combination of diet and exercise results in greater weight loss than diet or exercise alone [16], and that adherence to a lifestyle of physical activity and healthy nutrition are the greatest determinants of weight maintenance following weight loss [17–19].
TYPE 2 DIABETES The prevalence of diabetes has risen over recent decades due to the underlying association of T2DM with escalating rates of obesity. Exercise and physical activity are effective in addressing both of the principal modifiable risk factors of T2DM: obesity and a sedentary lifestyle [20]. Studies consistently indicate that an elevated BMI is one of the strongest risk factors for the development of diabetes, with an increased waist-to-hip ratio adding to a person’s risk [21]. A review of 10 prospective cohort studies by Jeon et al. indicates that people with an active lifestyle have an approximately 30% lower risk of developing diabetes than do individuals who are sedentary [22]. Insulin resistance, i.e. a reduction in the ability of the body to clear a glucose load from the blood in response to circulating insulin, is characteristic of T2DM and prediabetes. Physical activity is important in regulating plasma glucose levels, reducing the risk of insulin resistance, and decreasing excess fat deposition. Excess adiposity predisposes individuals to T2DM due to adipocyte production/release of free fatty acids and cytokines that interfere with insulin receptor signaling in muscle, adipose tissue, and the liver, leading to decreased glucose transport in genetically predisposed individuals. Cytokines released by adipocytes are associated with a proinflammatory effect and endothelial dysfunction that also increase the risk of metabolic dysfunction and cardiovascular disease in overweight individuals [23,34]. Exercise and physical activity have been shown to clearly influence the pathophysiological conditions underlying the development of T2DM and to improve insulin sensitivity. Aerobic exercise increases the lipid oxidative capacity of muscle cells, decreases the amount
of lipid products stored in skeletal muscle, increases glucose uptake by muscle during physical activity, and promotes the storage of glucose in muscle after exercise [25]. Glucose uptake into skeletal muscle has been shown to increase by up to 20-fold [26] during lower extremity exercise and is facilitated by an increase in blood flow to exercising muscles. Studies demonstrate a significant increase in glucose utilization and translocation of solute carrier family 2, facilitated glucose transporter member 4 [or insulin-regulated glucose transporter protein 4 (GLUT-4)] to the skeletal muscle cell membrane in both healthy individuals and individuals with T2DM with exercise [27,78]. Studies also reveal an improvement in insulin sensitivity that persists for several hours up to a few days after a single session of exercise in both healthy individuals and those with T2DM and obesity [29,30]. In contrast, several days without physical activity significantly decreases insulin sensitivity [31], reinforcing the need for regular physical activity as part of a healthy lifestyle. The protective mechanisms conferred by exercise and physical activity in preventing the onset of T2DM can be classified into acute versus chronic adaptations. Acute responses involve an increase in glucose uptake, glucose transport, and/or disposal of glucose that occurs during and appears to last for 12–48 h after the cessation of physical activity, depending on overall energy expenditure [32]. Chronic adaptations include increased mitochondrial biogenesis and fiber ratios [33]; improved endothelial function and capillarization [34]; improved muscular respiratory capacity and fatty acid oxidation [35]; and increased synthesis of GLUT-4 and enzymes that control the uptake and metabolism of glucose in skeletal muscle [36]. Exercise and physical activity play a crucial role in preventing or delaying the development of T2DM in those at risk by improving insulin sensitivity and, indirectly, by producing beneficial changes in body mass and body composition [37,78]. Both aerobic and resistive exercise have therapeutic value in preventing T2DM, largely independent of weight loss, and are both valuable components of an exercise program. Aerobic activity decreases adiposity, particularly in the visceral region, even in the absence of weight loss, and has greater effects on cardiorespiratory fitness [39]. Strength training increases muscle mass, elevates the resting metabolic rate, increases GLUT-4 protein content, and improves glucose metabolism through increased glycogen synthase activity within the trained muscle. In addition to improving muscle quality and insulin sensitivity, resistive exercise was shown to reduce C-reactive protein (CRP) levels and free fatty acids while increasing circulating adiponectin, changes that are all associated with improved metabolic control [40].
INFLAMMATION
METABOLIC SYNDROME Metabolic syndrome is a cluster of metabolically related abnormalities and cardiovascular risk factors that generally include abdominal obesity, insulin resistance, elevated triglycerides, reduced high-density lipoproteins, and hypertension. This diagnosis increases the risk of coronary heart disease twofold, and all-cause mortality by 40% [41]. Adults who did not participate in any leisure time physical activity were found to be 45% more likely to be diagnosed with metabolic syndrome when compared with active counterparts [42]. A body of evidence exists to support the benefits of exercise and physical activity in reducing the risks of metabolic syndrome and its associated risk factors [1,12–50].
HYPERTENSION Studies indicate that participating in a regular exercise program has a positive impact on blood pressure, thus decreasing one of the common criteria for metabolic syndrome. Welton et al. reviewed 54 randomized, controlled studies on aerobic exercise and its effect on blood pressure and found that physical inactivity led to a 30–50% increased risk of hypertension. Physical activity was found to decrease blood pressure in hypertensive and normotensive persons. Aerobic exercise led to a decrease in blood pressure for those with normal BMI scores as well. In addition, all forms of exercise appeared to have a positive impact on blood pressure measurements. Blood pressure was noted to decrease in trials independent of a change in body weight [51].
HYPERLIPIDEMIA Regular exercise significantly reduces triglyceride levels [52] and improves the blood lipid profile [53]. A review of randomized, controlled trials by Leon and Sanchez examined the effect of 12 weeks or more of exercise on hyperlipidemia. They found that programs consisting of moderate to vigorous intensity levels 3–5 days/week for at least 30 min/session resulted in an increase in high-density lipoprotein cholesterol levels in half of the studies [54].
INFLAMMATION Research aimed at understanding the pathophysiology of many common chronic diseases has shifted in recent decades from a focus on serum lipids and the proliferation of smooth muscle cells to the role of inflammation in chronic conditions such as T2DM, metabolic
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syndrome, and atherosclerosis. Low-grade systemic inflammation can be detected by an elevation in a variety of circulating inflammatory biomarkers including CRP and cytokines such as tumor necrosis factor (TNF-α) and interleukin-6 (IL-6). CRP is produced in the liver and regulated principally by the inflammatory cytokines IL-6 and TNF-α. Research has revealed a significant increase in CRP in individuals with atherosclerotic disease and metabolic syndrome [55,56]. Cytokines are small polypeptides produced by cells that regulate the body’s response to disease, trauma, and infection. Cytokines deemed “proinflammatory” act to accentuate disease processes, while anti-inflammatory cytokines serve to reduce inflammation and promote healing. Research since 2000 into exercise’s role in reducing low-grade systemic inflammation points to two potential mechanisms: a decrease in visceral adipose tissue and the release of anti-inflammatory cytokines from working skeletal muscle. In low-grade systemic inflammation, the cytokine TNF-α is released (mainly by adipose tissue) and stimulates the production of IL-6 in adipocytes and in mononuclear cells in the blood. IL-6, in turn, stimulates increased levels of plasma IL-1 receptor antagonist (IL-1ra), TNF receptor (TNFR), IL-10, and CRP by the liver [57]. The link between low-level chronic inflammation and illness related to atherosclerosis, obesity, metabolic syndrome, and diabetes appears to lie with TNF-α. Patients with T2DM possess high levels of TNF-α in skeletal muscle [58] and in the bloodstream [59–61], and research points to adipose tissue as the primary source of the elevated levels of TNF-α [62,23]. In these patients, studies suggest that TNF-α may have direct inhibitory effects on insulin signaling [64–66]. In patients with metabolic syndrome, high levels of TNF-α and IL-6 have been associated with abdominal obesity, and it is theorized that increases in TNF-α released by adipose tissue is responsible for the observed increase in s ystemic levels of IL-6. TNF-α is prevalent in atherosclerotic lesions, and elevated levels of TNF-α in the blood are predictive of a risk of myocardial infarction, the severity of peripheral arterial disease, and the degree of carotid artery atherosclerosis in healthy middle-aged men [67]. Chronic low-grade systemic inflammation is associated with advancing age, with circulating proinflammatory cytokines such as TNF-α, IL-6, and CRP typically measured at levels two to four times that of young adults, even in the absence of chronic disease [68]. Although age-related chronic disease plays a significant role in the low-grade inflammation observed in the elderly, the natural decline in immune function with age that promotes an inflammatory state is also believed to contribute as well [69]. In recent years, a direct association between physical activity and exercise and the release of cytokines with anti-inflammatory properties was revealed, which
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supports the benefit of regular physical activity in protecting individuals against certain chronic diseases [57]. During a bout of exercise, there is a transient increase in anti-inflammatory cytokines, a response that is markedly different from that seen with low-level inflammation or in response to disease or trauma: with exercise, muscle fiber production of IL-6 increases plasma levels of IL-6 by up to 100-fold [70–73], followed by an increase in anti-inflammatory cytokines and cytokine inhibitors such as IL-1ra, IL-10, and soluble TNFR (sTNFR) [74,45]. The plasma increase in IL-6 is related to exercise intensity, duration, and muscle mass recruited [70–72] and has the added benefit of inhibiting the production of the proinflammatory cytokine TNF-α [57]. The long-term effect of regular exercise is, thus, a reduction in basal levels of proinflammatory cytokines [76]. Although weight loss has been associated with a reduction in lowgrade inflammation due to a decrease in adiposity, studies also support a decrease in low-grade inflammation with exercise and/or diet, independent of weight loss [77], reflecting an anti-inflammatory effect of exercise itself.
REVIEW OF THE EVIDENCE ON THE EFFECT OF EXERCISE ON INFLAMMATORY MARKERS Recent studies that examine the effect of exercise and daily activity levels on inflammation can be categorized into observational and random control studies. In reviewing the literature of observational studies, most examined healthy subjects and relied on self-reported exercise and/or activity levels over the duration of the study [78–81]. Mora et al. followed a group of healthy women who were health professionals, ages 45 years and older, having them complete surveys and provide blood samples for CRP and fibrinogen. These women completed activity diaries for four separate weeks over the course of a year, estimating the amount of time spent in a variety of recreational activities and the number of flights of stairs climbed daily. A mean follow up of 10.9 ± 1.6 years found that women with an active lifestyle had lower risk factors for cardiovascular disease, including CRP and fibrinogen. The risk of cardiovascular disease showed a linear decrease with increasing levels of physical activity [78]. Mora et al. also investigated BMI and physical activity in the same group of women. BMI positively correlated with the inflammatory markers, CRP and fibrinogen, while physical activity negatively correlated with these biomarkers [79]. A group of 177 men, aged 40–75 years of age with BMIs between 25 and 35 kg/m2 who were being treated for hypertension, were randomly selected from the Hypertension High Risk Management Trial. They were asked
about the frequency and duration of all physical activities related to work, hobbies, home, leisure, transportation, regular exercise, and sedentary activities engaged in during the previous week. All participants were deemed sedentary, defined as performing regular exercise for < 1 hour/week. A fitness test was conducted for each subject using a bicycle and testing “time to exhaustion” as per the Borg Scale. This study revealed an inverse relationship between CRP and fitness, but no significant relationship was found between CRP and the level of physical activity in this population. The authors concluded that an increased level of physical fitness is beneficial in slowing the progression of cardiovascular disease in a sedentary population of drug-treated hypertensive men [80]. Kadoglou et al. studied 60 overweight subjects with T2DM, randomly assigning 30 participants to an exercise group and 30 to a control group. The exercise group completed aerobic exercise sessions four times/week for 45–60 min/session. At the end of the 6-month training period, the exercise group had large decreases in CRP and IL-18 plasma levels and small decreases in TNF-α compared to both the control group and baseline levels. These changes were attained without significant changes in body weight [81]. Exercise can be divided into two categories: endurance training and resistance training (RT). Many studies look at endurance exercise, while few focus on RT. RT, also referred to as strength training, is defined as exercise in which movement is performed against an external force. Single bouts of resistance exercise have shown a temporary increase in CRP levels, as well as an increase in IL-6, with long-term effects demonstrating a decrease in proinflammatory markers [82]. Calle and Fernandez followed a group of women performing an RT program twice weekly over the course of a year. The first 16 weeks were supervised and the remaining sessions were selfreported. At the end of the year, there was a decrease in CRP levels, but no change in IL-6 levels. The authors concluded that a decrease in CRP levels may be due to multiple factors and suggested that there may be a relationship between an individual’s level of training and their response to RT [83]. Phillips et al. utilized a randomized control design to examine a group of postmenopausal women over a 12-week period. The women, with an average age of 65.6 years, were split into two groups: one performed an RT program three times/week, involving three sets of 8–12 repetitions for 10 muscle groups, while the other group attended a program twice/week for stretching, knitting, and health information lectures. At the end of 12 weeks, the RT group had a decrease in CRP, leptin, and TNF-α plasma levels, with no change in body composition observed [84]. The results of the observational studies discussed above show a positive effect of exercise and physical activity on inflammatory markers in healthy subjects.
Review of the Evidence on the Effect of Exercise on Inflammatory Markers
In contrast, the results of randomized controlled studies that examined the impact of exercise on inflammation are mixed. These studies have often utilized subjects with various chronic conditions. Kohut et al. studied a group of 87 adults aged 64–87 years during a 10-month training program of either cardiovascular exercise or strength, balance, and flexibility exercises. The cardiovascular exercise program was performed three times/week, and consisted of a warmup, stretching, and 25–30 min of aerobic exercise on equipment, and finished with a cooldown consisting of stretching and balance exercises. The strength, flexibility, and balance training consisted of a 10-min warm up, stretching exercises targeting large muscle groups, and a 25–30-min exercise class including components of yoga, tai chi, weights, and stability balls, with a transition to weight machines for the second 5 months of the study. The session ended with a 10-min cooldown similar to that of the cardiovascular exercise group. At the end of the study, the cardiovascular exercise group had significant decreases in CRP, IL-6, and IL-18 levels, whereas the strength training group did not show these changes. Both groups had a reduction in TNF-α levels [85]. Walther et al. followed 101 men with coronary artery disease over 2 years, randomly assigning them into two groups: a group that performed 20 min of daily aerobic exercise and a group that underwent percutaneous coronary intervention (PCI) with stent placement. After 2 years, a significant decrease in CRP and IL-6 levels was observed in the exercise group, with no change noted in the PCI group. In addition, 78% of the group that p erformed regular exercise suffered no additional cardiac events, compared to 62% of subjects in the PCI group [86]. Nicklas et al. conducted a randomized controlled trial that looked at CRP and IL-6 levels over 12 months in 424 sedentary subjects, aged 70–89, assigned to either a physical activity group or a health education group. The successful aging health education group met weekly initially and then monthly for education on topics such as preventive health care, nutrition, medication, and foot care. Each session also included 5–10 min of upper extremity stretching. The physical activity group started with a supervised exercise program three times/week, decreased to two sessions/week after 2 months, and then, for the last 6 months, the participants exercised at home. The physical activity group focused on walking, with a goal of completing at least 150 min/week, and also completed lower extremity strengthening and stretching exercises. In addition, this group attended weekly behavioral counseling sessions for the first 10 weeks to encourage participation in the physical activity program. At the start of the program, the baseline measures of CRP and IL-6 were the same. After 12 months, the group that exercised had lower
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IL-6 concentrations, with no change noted in CRP concentration [87]. Martins et al. examined the effect of different types of exercise on an elderly adult population over the age of 64. The subjects were ambulatory and received medical clearance from their physicians. Some of the subjects had hypertension (47%), T2DM (16%), and angina pectoris (15%). They assigned the subjects into three groups: an aerobic training group (AT), a strength training group (ST), and a control group. The AT group undertook 16 weeks of supervised exercise, 45 min in duration, progressing from 40–50% of heart rate reserve to 71–85% heart rate reserve. The ST group performed eight supervised exercises, including calisthenics and resistance exercises with elastic bands, progressing from one set of 8 repeats to three sets of 15 repeats, three times/week. A significant decrease in CRP levels was observed in both groups, with a greater decrease noted in the AT group [88]. Recent randomized control studies have also examined the effect of exercise on inflammatory markers such as CRP, IL-6, or TNF-α and found no positive effect of exercise [89–92]. These studies were conducted on generally healthy subjects, as well as those with diagnoses such as breast cancer, chronic arthritis, and impaired insulin sensitivity. Whereas the benefits of exercise in improving health and fitness and in preventing cardiovascular disease are clear, research into the anti-inflammatory effects of exercise remains in its early stages. Due to a lack of consistent findings in the literature, more studies need to be conducted to determine the type and intensity of exercise that is most beneficial in increasing serum levels of inflammatory markers associated with atherosclerosis and chronic disease. In addition, research is needed to determine the benefits of exercise in positively influencing inflammatory markers in subjects with different health conditions and of different ages. Further research is also needed to better define the role of specific systemic markers of inflammation in the development of cardiovascular disease, so that these markers can be utilized more effectively in the prevention of chronic disease.
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