Journal of Geriatric Physical Therapy:
Special Interest Papers
Inflammation, Aging, and Adiposity: Implications for Physical Therapists
Addison, Odessa DPT1; LaStayo, Paul C. PT, PhD1,2,3; Dibble, Leland E. PT, PhD1,2; Marcus, Robin L. PT, PhD1,2
1Department of Physical Therapy, University of Utah, Salt Lake City.
2Department of Exercise and Sport Science, University of Utah, Salt Lake City.
3Department of Orthopedics, University of Utah, Salt Lake City.
Address correspondence to: Odessa Addison, DPT; Robin L. Marcus, PT, PhD, Department of Physical Therapy, University of Utah, 520 Wakara Way, Salt Lake City, UT 84108 (firstname.lastname@example.org; email@example.com).
The authors declare no conflicts of interest.
Background: Physical therapists treat older individuals, characterized as both a needy and expanding population. Frailty, a predisability condition with links to chronic inflammatory conditions, is estimated to affect 7% of individuals older than 60 years and 40% of people older than 80 years. Chronic inflammation is one of the most important physiologic correlates of the frailty syndrome and high levels of proinflammatory cytokines, related to both aging and increasing adiposity in older individuals are related to an increased risk of mortality, sarcopenia, reduced muscle strength and decreased mobility.
Purpose: The purpose of this narrative review is to inform the physical therapist of the effects of aging and increasing adiposity on chronic inflammation and the association of inflammation with muscle loss, strength, and mobility impairments in older adults; and to review the current evidence to provide clinical recommendations on physical activity and exercise regimes that may mitigate chronic inflammation in older adults.
Discussion: As physical therapists help manage and treat an increasingly older population, understanding how the inflammatory milieu changes with aging and increasing adiposity and how these changes can be impacted by physical therapists via exercise and physical activity is critical.
Conclusion: Exercise is a potent preventive intervention strategy and countermeasure for chronic inflammation and adiposity. Exercise can also benefit the frail older individual by combating the negative effects of chronic inflammation and optimally balancing the production of pro and anti-inflammatory cytokines. In addition to providing an anti-inflammatory environment within muscle to mitigate the effects of chronic inflammation, exercise has the added benefit of improving muscle mass and function and decreasing adiposity in older adults.
Physical therapists are increasingly treating an older population. By the year 2030 it is expected that 1 in 5 Americans will be older than 65 years and over the next decade there will be a 15% increase in the number of Americans older than 85 years.1 Frailty, a predisability condition with links to chronic inflammatory conditions, is estimated to affect 7% of individuals older than 60 years and 40% of people older than 80 years.2 Frailty is marked by dysfunction and decline across multiple physiologic systems including the neuromuscular, neuroendocrine, and immune system,3 and can result in significant health consequences such as frequent falls,4,5 fractures,4,5 and an increased risk of mortality.6,7 Chronic inflammation is one of the most important physiologic correlates of the frailty syndrome8,9 and high levels of proinflammatory cytokines in older individuals are related to an increased risk of mortality,10 sarcopenia,11,12 reduced muscle strength,13 and decreased mobility.14,15 Physical therapists help manage and treat an increasingly older population; therefore, understanding how the inflammatory milieu changes with aging and how it can be impacted by physical therapists via exercise and physical activity is important.
Chronically elevated systemic levels of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and c-reactive protein (CRP) play a central role in the etiology of numerous chronic diseases commonly seen in rehabilitation settings including type 2 diabetes,16 cardiovascular17–19 and cerebrovascular disease,20 dementia,21 and sarcopenia.22–24 Cytokines are hormone like proteins that are involved in cell-to-cell communication that regulate the intensity and duration of the immune response. Transient increases in the proinflammatory cytokine cascade associated with injury and illness are part of the normal healing process and assist the immune system in promoting tissue repair and regeneration by activation of the complement system and increased phagocytosis. Long-term elevation of proinflammatory cytokines, however, are detrimental leading ultimately to tissue damage,23,24 muscle loss,13 and even death.10
When tissue is injured due to trauma or illness macrophages are activated to assist in tissue repair and regeneration (Figure 1). Activated macrophages secrete various cytokines that have autocrine, paracrine, and endocrine function. The first actions of these cytokines are to influence the cells that produced them and then go on to affect surrounding cells as well. Eventually the production of these cytokines results in a spill over from the tissue in which they are produced to increases in circulating levels in serum which allow these cytokines to act in an endocrine function. Among the first cytokines released by macrophages are TNF-α and interluekin-1 (IL-1). Both are powerful proinflammatory cytokines that result in production of further cytokines such as IL-6 as well as the recruitment of additional macrophages and an induction of acute phase protein synthesis.
Interleukin-6 has been classified as both a “pro” and an “anti” inflammatory cytokine. When produced in response to TNF-α production from macrophages IL-6 results in T-cell differentiation and assists T-cells in resisting apoptosis. Interleukin-6 production also results in the production of CRP by hepatocytes and activation of the complement system resulting in increased phagocytic activity of immune cells. Besides these proinflammatory effects, IL-6 also has several powerful anti-inflammatory properties. The release of IL-6 also results in an increase in the production of IL-10, tumor necrosis factor soluble receptor, and IL-1 receptor agonist, all of which assist in decreasing the production of TNF-α and IL-1 and limit the proinflammatory cascade. More recent work has also demonstrated that IL-6 can be produced by muscle in a TNF-α independent manner. Repetitive muscle contraction results in the production of IL-6 without an increase in TNF-α (Figure 2). In fact, production of IL-6 via the TNF-α independent pathway actually suppresses the production of TNF-α resulting in a powerful anti-inflammatory pathway with exercise. The contradictory effects of IL-6 are most likely due to the environment in which it is produced and the presence or absence of TNF-α.
Systemically elevated inflammation in older adults is particularly troublesome as it is one of the most important physiological correlates of the frailty syndrome.8,9 Older adults with chronic increases in proinflammatory cytokines are more likely to suffer from a loss of lean tissue13 and strength,13 and to experience mobility limitations and disability22 than those with lower levels of inflammation. Moreover, several studies have demonstrated that older adults with chronically elevated levels of inflammation are at an increased risk of mortality.6,10,25 In a large study of nondisabled older adults, Harris et al10 found that those older individuals in the highest quartile for IL-6 serum markers of inflammation were twice as likely to die in the next 4 years than those individuals in the lowest quartile of inflammation. Although increased levels of inflammatory cytokines are associated with increasing age, chronic inflammation may not be an obligatory manifestation of aging per se. Evidence suggests that older individuals with higher activity levels consistently show lower levels of both systemic26–28 (as measured in the blood) and regional29 (as measured in the muscle) inflammation. In addition, several studies have demonstrated that aerobic training30–40 and strength training41,42 can diminish chronic inflammation in older adults. Because the positive inflammatory impact resulting from increased physical activity and exercise are integral components of physical therapy management in older adults, an awareness of how chronic inflammation is impacted by these variables is important.
The purpose of this narrative review is 3-fold. First, to inform the physical therapist of the effects of aging and increasing adiposity on chronic inflammation and the association of inflammation with muscle loss, strength, and mobility impairments in older adults; and second, to review the current evidence on the impact of physical activity levels and exercise on chronic inflammation in this population. Finally, we will provide evidence-based clinical recommendations for physical activity and exercise regimes with the aim of mitigating chronic inflammation in older adults. Literature targeted for this narrative review included peer reviewed cross-sectional, longitudinal, epidemiologic, and clinical studies in humans and animals that were related to aging, adiposity, inflammation, mobility, strength, physical activity, and exercise.
AGING AND INFLAMMATION
The relationship of systemic inflammation with increasing age is currently a hotly debated topic. Some have reported consistent positive correlations between aging and inflammation,43–49 though not all studies have found this to be the case.50–53 It has been suggested that aging-related increases in proinflammatory cytokines may be due to the presence of multiple comorbidities,45,50 dysregulation of the immune system,54–56 or an increase in adipose tissue.57 Multiple studies have demonstrated an age-related increase in the proinflammatory markers of IL-6, and CRP.43–49 Wei et al49, McKane et al47, and Hager et al46 have independently reported significant positive correlations between serum IL-6 and age; this relationship also exists in nonhumans.44 The caveat of most of these studies is that few took into consideration the influence of disease state, comorbidities, and adipose tissue on the relationship between aging and the specific inflammatory cytokines studied. Cartier et al and Ferrucci et al both found an initial positive relationship between aging and inflammation; however, further statistical analysis established that this relationship was greatly blunted after accounting for the amount of visceral adipose tissue43 or cardiovascular risk factors45, thus exposing the possibility that it is comorbid disease conditions or increases in adipose tissue rather than age itself that drives these relationships. That is, the increase in proinflammatory cytokines seen with aging may in fact be attributed to underlying comorbidities such as cardiovascular disease or increases in adipose tissue.
Further support for this assertion is found in both clinical50 and epidemiologic45 evidence. Beharka et al50 screened 20 young and 26 older males for chronic disease or illness prior to admission to their study and found no differences in circulating serum IL-6 between the young and old subjects. Because of the detailed screening process that was used in this study and not reported by previous authors, these findings suggest the possibility that previously reported associations between age and chronic inflammation may be at least in part attributed to the presence of underlying disease. Ferrucci et al45 examined the relationship of proinflammatory cytokines with age in more than 1000 adults aged 20 to 102 years. In both men and women, older age was associated with increased circulating levels of IL-6 and CRP; however, when these results were adjusted for the presence of cardiovascular risk factors and of subclinical cardiovascular disease, the relationships between IL-6 and CRP with age, though still present, were much less robust.45 Collectively, these results suggest that although the contribution of comorbid disease conditions to chronic inflammation in older adults should not be ignored, there does seem to be a degree of immune system dysregulation that occurs with advancing age.
Dysregulation of the immune system in older adults has been explored in multiple in vitro and in vivo studies. In vitro studies of cytokine production have been equivocal, as increased,58–63 unaltered,48,64 and decreased50,65,66 cytokine production in older adults have been reported. Possible reasons for these differences include the time points at which cytokine production are measured, the types of cells studied, and the sex and health status of the participants. Fewer studies have examined the effects of aging on dysregulation of the immune system in vivo. When both young (20–27 years old) and older adults (61–69 years old) are given an endotoxin injection of Escherichia coli, the older adults consistently demonstrate a larger increase in body temperature and serum levels of TNF-α56 when compared to younger individuals. Furthermore when examining both young and older adults who have been diagnosed with an acute pneumococcal infection older adults demonstrate an increased and prolonged immune response with higher levels of TNF-α and IL-6 than young infected and healthy age matched controls up to 7 days postinfection,54,55 indicating a prolonged inflammatory response and possible dysregulation of the immune system. It has also been noted that older adults with gastric cancer have higher levels of IL-6 postsurgery and that these levels fell more slowly than younger patients with gastric cancer undergoing similar surgeries. Finally, Marik et al noted that the oldest patients (those older than 85 years) admitted to the intensive care unit for septic shock had the highest levels TNF-α on admission.67 That older adults, both in the presence of and in the absence of disease, appear to have some level of immune system dysregulation is well supported in the literature, though the mechanism of this dysregulation is currently not well established. Possible reasons theorized for the apparent dysregulation include decreased production of sex steroids,68 the presences of undiagnosed comorbidities such as atherosclerosis,45 and higher amounts of adipose tissue.57
The increase in adipose tissue leading to immune system dysregulation is an attractive hypothesis as excessive adiposity has also been mentioned as a potential mechanism involved in age-related chronic inflammation.43,68 Excessive fat mass and obesity are directly linked to increased levels of the circulating proinflammatory cytokines TNF-α, IL-6, and CRP in both the young69 and old.57,70 Studies have also demonstrated a decrease in these same cytokines with weight loss.69,70 Currently, it is thought that as adipocytes increase in size with weight gain some adipocytes become dysfunctional due to the increased presence of lipids in the cell and local hypoxia within the adiopocyte.71 This combination of dysfunction and hypoxia leads to death of the adipocyte. As adipocytes die macrophages are needed to assist in clearing the dead cells. This increased presence of macrophages leads to an increase of proinflammatory cytokines and in a feed forward manner recruits additional macrophages to the tissue, thus precipitating the increase in proinflammatory cytokines, leading to chronic inflammation (Figure 3).71 Cesari et al have reported that both CRP and IL-6 serum levels are positively associated both with body mass index and with total fat mass in older individuals.57 Taken together, this literature suggests that age-related immune system dysregulation may stem from increased body fat, a factor that has also been linked to chronic systemic inflammation in older adults.
Although the precise mechanisms behind age-related chronic inflammation are not fully understood, it does appear that the rise in proinflammatory cytokines observed with increasing age may result from of a combination of inherent immune system dysregulation, the presence of comorbid disease conditions, decreased physical activity, and increased fat mass as individuals age. Regardless of the cause, the relationships between chronic inflammation and many of the negative consequences of aging cannot be ignored. These consequences include but are not limited to increased risk for a loss of muscle mass and strength,13 decreased mobility,25 and ultimately an increased risk of frailty22,72 and mortality.6,10,25
MUSCLE MASS, STRENGTH, AND INFLAMMATION
Although normal aging is accompanied by a progressive loss of muscle mass and force producing ability,73 large epidemiological studies have suggested that relative to those with lower TNF-α and IL-6 levels, older adults with higher levels are at increased risk of muscle impairments. In a study of more than 3000 adults aged 70 to 79 years, Visser et al13 reported that older adults with high levels of TNF-α or IL-6 (defined as levels above the population median) had smaller muscle area, lower appendicular muscle mass, and decreased grip and knee extensor strength. These findings were present even after statistically controlling for potential confounding factors such as age, height, total body fat, physical activity, health status, the use of anti-inflammatory medications, and smoking. The results were even more robust when looking at individuals who had increased levels of both IL-6 and TNF-α. Using this same population of individuals from the Health ABC study Schaap et al12 used a multiple linear regression model to examine the effects of increased IL-6 and TNF-α on thigh muscle cross-sectional area as well as grip strength. Even after controlling for multiple covariates those individuals with the highest levels of these proinflammatory cytokines experienced a decrease in muscle cross-sectional area as well as grip strength over a 5-year time period.12 Though the decrease in muscle cross-sectional area was attenuated when accounting for weight changes over the 5 years, a subanalysis of weight stable individuals revealed that higher TNF-α was again associated with decreased thigh muscle area and grip strength. Levinger et al74 recently reported that 19 older patients with knee osteoarthritis had elevated levels in various inflammatory cytokines including IL-6 within the quadriceps when compared to age and body mass index–matched individuals without osteoarthritis. Though they did not report the association between IL-6 and muscle strength, they did observe a significant negative correlation (r = −0.37) between strength and Monocyte chemotactic protein-1 (MCP-1), an inflammatory protein, whose expression is increased by the presence of TNF-α and IL-6.74
Chronic inflammation may be mechanistically linked to muscle loss through the direct catabolic effects of TNF-α, originally known as cachectin, due to its direct contribution to catabolic muscle wasting in numerous inflammatory conditions such as chronic obstructive pulmonary disease,75 chronic heart failure,76 human immunodeficiency virus,77 and cancer.78 Animal models, through injection and infusion of TNF-α have revealed the direct catabolic effects of increased levels of this proinflammatory cytokine. Mice, rat, and canine models have all demonstrated a loss of muscle mass directly related to the increased presence of TNF-α.23,79,80 The loss of muscle mass that occurs in the presence of elevated TNF-α is most likely due to the multifactorial effect TNF-α has on muscle tissue. High levels of TNF-α result in cell apopotosis,81 a decreased rate of protein synthesis, and an inhibition of myoblast differentiation82 ultimately resulting in an impaired ability to increase muscle mass. In a small study of 8 older frail adults, Greiwe et al41 demonstrated that the rate of muscle protein synthesis after 3 months of resistance training was inversely related (r = −0.53) to TNF-α protein levels in the muscle. Tumor necrosis factor-α may also inhibit muscle repair via apoptosis of muscle satellite cells83 resulting in a slow but progressive loss of muscle mass over time as the muscle is unable to repair itself from micro-injuries resulting in an overall decline in muscle mass as one ages.
Solely attributing overall declines in muscle strength to loss of muscle mass in older adults is inaccurate as the aging-related loss of muscle mass explains as little as 5% of the accompanying loss of muscle strength.84 Compounding muscle atrophy in older adults is a decrease in the specific force production of a muscle, defined as force produced per cross-sectional area of the muscle fiber.85 Various factors may contribute to this decrease in specific force production including the slowing of muscle contractile properties and rate of force development, reduced rate of cross-bridge cycling, alterations in excitation-contraction coupling, and changes in the muscle architectural properties. Although age-related force production decline likely results from multiple factors including diminished physical activity, the impact of chronic inflammation should not be ignored. The presence of elevated levels of proinflammatory cytokines in older adults may help to explain some of the diminished force producing capability observed in this population.
Evidence supporting this assertion is found in animal models that have revealed decreased muscle specific force production only hours after a TNF-α injection.86 Of note, this strength loss occurs prior to any loss of muscle mass, indicating that an inflammatory milieu contributes to impaired muscle force production in the absence of muscle atrophy. Furthermore, a 12-week resistance training study of frail elders with elevated baseline levels of TNF-α receptors (another measure of TNF-α activity), reported that the number of TNF-α receptors is inversely correlated with muscle strength gains.87 Those with the highest levels of TNF-α receptors experienced the lowest strength gains with training, indicating that the gain in muscle strength may be negatively influenced by the presence of high TNF-α levels.87
Strength decreases in the presence of increased levels of TNF-α may be due to an interruption in the excitation-contraction coupling process.88–92 Where exactly this disruption takes place is still under debate. The loss of strength may also be due to the removal of actin and myosin proteins resulting in an inhibition of the development of force even prior to a loss of muscle mass.86,89 High levels of TNF-α also decrease the resting membrane potential of the sarcolemma and the cells ability to regulate calcium release from the sarcoplasmic reticulum, both contributing to decreased force production independent of any protein loss.88,91
Smaller clinical studies as well as larger epidemiological studies support the hypothesis that chronic increases in proinflammatory cytokines impair both strength and muscle mass in older individuals. Although the mechanism behind muscle mass and strength loss in the presence of increased proinflammatory cytokines is still not clearly understood, it does appear that increased levels of TNF-α in particular are troublesome for older adults and may contribute to muscle impairments in this population.
MOBILITY AND INFLAMMATION
The loss of muscle mass and strength in the presence of high levels of proinflammatory cytokines may also partially explain why increased levels of inflammation have consistently been tied to decreased function and mobility in older adults. Increased levels of TNF-α, IL-6, and CRP have been linked to lower walking speed,25 poor physical function,93 a decreased ability to perform activities of daily living,22 and ultimately increased levels of disability and frailty.22,72
Large epidemiologic studies reveal that high levels of proinflammatory cytokines increase the risk for developing disability over 2 to 5 years.22,94,95 Ferrucci et al96 have reported that individuals with the highest baseline levels of IL-6 were also at the highest risk for the progression of disability and this could be at least partially explained by the loss of muscle strength also associated with high levels of IL-6. These study findings were confirmed by Penninx et al94 in a study of almost 3000 adults aged 70 to 79 years. In this investigation, those with the highest levels of TNF-α, IL-6, and CRP at baseline were at the highest risk of developing mobility limitations and disability over the next 30 months.
This relationship is consistent across comorbidities common in an aging population and across the aging spectrum. Brinkley et al93 examined several separate populations including those with chronic obstructive pulmonary disease (COPD), congestive heart failure, self-reported disability, and those at high risk for a cardiovascular event. They found that across all disease conditions and comorbidities that increased levels of serum CRP and IL-6 were associated with longer times to complete the 4-m walk and lower short physical performance battery scores.93 As well, across the aging spectrum multiple studies of individuals aged 50 to more then 90 years have reported that increased levels of proinflammatory cytokines are related to decreased physical performance and ability to perform activities of daily living.97 Tiainen et al97 demonstrated that in nearly 200 adults aged 90 years and older increased serum levels of IL-6 and CRP were associated with a worse Barthel Index score, a 10-item measure of ability to perform activities of daily living independently.
Though we cannot assign cause and effect, the literature clearly identifies relationships between inflammation and decreased muscle mass and strength, between inflammation and impaired mobility and between decreased muscle mass and impaired mobility in older individuals98 (Figure 4). Although speculative, it is intuitive that impaired mobility would lead to sedentary behavior in turn creating the environment for a self-perpetuating cycle of inflammation. In this theoretical cycle, inflammation, decreased muscle size and strength, and impaired mobility combine to create a sedentary lifestyle that further compounds the proinflammatory adverse responses in a feed-forward fashion. In summary, this underscores the important role of the physical therapist in minimizing mobility limitations in older adults with interventions aimed at interrupting this detrimental inflammatory cycle.
PHYSICAL ACTIVITY, EXERCISE, AND INFLAMMATION
Physical activity may be a powerful countermeasure to combat chronic inflammation and its deleterious effects in older adults. Physical activity includes any body movement produced by skeletal muscle that results in energy expenditure above resting basal levels and includes leisure time, recreational, occupational, and transport activities.99 In contrast, exercise is a subset of physical activity that is planned repetitive movement with the object of improving or maintaining fitness.99 Multiple epidemiological and cross-sectional studies have demonstrated a strong inverse relationship between levels of physical activity and markers of chronic inflammation across ages, body mass indexes, and comorbidities.26–28,100,101 These relationships are observed whether considering levels of proinflammatory cytokines in the serum26–28,100,101 or in the muscle.29
Though these studies have consistently revealed an inverse association between physical activity and chronic inflammation, exercise intervention studies aimed at reducing proinflammatory cytokine levels in older adults are more variable. Although a majority of studies that employ aerobic training,30–36,38–40 resistance training,41,42 or some combination of the two37,102 suggest that exercise decreases proinflammatory cytokines, some studies have not found this to be the case.86,103–107 Of the resistance training studies86,103 that reported no statistical difference in proinflammatory cytokines both reveal a trend for decreased IL-6 postintervention, thus, suggesting a lack of statistical power. Alternatively, the inconsistent findings between studies may be explained by the populations studied, and the time between the final exercise bout and the postintervention measures. Most studies that found no effect postexercise intervention do not report how long postexercise intervention blood draws for serum inflammatory markers were conducted37,87,104,106 and in at least one study blood draws were conducted as long as 2 weeks after the completion of the intervention.107 Thompson et al39 demonstrated that while it takes 12 weeks to see significant changes in serum markers of inflammation with exercise, it only takes 2 weeks of detraining to see returns on almost baseline levels.39 A prolonged time period between exercise intervention and blood draws contributes to additional variability in these investigations. Finally, study outcomes may differ based on pretraining cytokine levels as individuals with the highest levels of preexercise inflammatory markers usually benefit the most from exercise.39
Consistent with the cross-sectional and epidemiologic studies,26–28,100,101 those intervention studies reporting no change in proinflammatory cytokines with exercise86,103–107 have employed serum markers. Two studies have demonstrated that even in the presence of minimal change in serum markers of inflammation with exercise, there may be a very large change in the proinflammatory cytokines within the muscle postexercise intervention.30,32 Gielen et al32 examined serum and muscle markers of inflammation in 20 males with congestive heart failure pre- and post-6 months of an aerobic exercise intervention. Patients in this study exercised 20 minutes a day every day and additionally participated in 1 hour a week of supervised group aerobic training. Despite a significant decrease of more than 30% in muscle-specific IL-6 and TNF-α, these authors reported no change in serum inflammatory markers postexercise training. Lambert et al108 reported similar findings in a group of obese frail older adults. After 12 weeks of exercise (90 minutes, 3 times per week of combined aerobic and resistance exercise) the authors noted no decrease in serum IL-6 or TNF-α. However, muscle biopsies showed a 50% decrease in levels of IL-6 and TNF-α within the muscle tissue.108 Bruun et al30 also examined the combined effects of 15 weeks of aerobic activity with a hypocaloric diet in 27 severely obese individuals. The aerobic intervention consisted of 2 to 3 hours of moderate activity 5 days/week. At the end of 15 weeks, the authors noted a significant decrease in serum measures of IL-6 and CRP but not in TNF-α. However, when examining the muscle specific markers for IL-6 and TNF-α, large decreases that exceeded those seen in serum were noted to be more than 50% for IL-6 and 25% for TNF-α.
Decreased muscular expression of IL-6 in the absence of serum level changes with exercise may be explained by the influence of muscle contraction on the release of IL-6. As noted previously, contracting muscle is able to produce IL-6 in a TNF-α independent pathway. The IL-6 produced by contracting muscle is a powerful anti-inflammatory and, in fact, can suppress the release of TNF-α. Three hours of cycling can produce enough IL-6 in the muscle to suppress the release of TNF-α even when an individual is injected with an endotoxin.109 Repeated bouts of exercise such as those employed by Gielen et al and Lambert et al would lead to repeated release of IL-6 from the contracting muscle. This “myokine” would then provide a powerful anti-inflammatory environment within the muscle leading to overall decreases in the release of proinflammatory cytokines within the muscle tissue itself. (For a comprehensive review of this concept the reader is encouraged to see reviews on this topic by Pedersen et al110,111 for further details.) Overall exercise-induced fat mass reduction provides another potential hypothesis to explain proinflammatory cytokine decreases observed with exercise. Several studies have suggested that exercise, diet, or a combination of the 2 reduces adipose tissue, an effect that may contribute to an overall reduction in the proinflammatory cytokines that are released from inflamed adipocytes.70,105,112 Although this may be an attractive hypothesis, the observation that at least 1 study has failed to report decreased proinflammatory cytokines when only weight loss is used independent of exercise,108 raises further questions about fat mass as a potential mechanistic link between exercise and chronic inflammation.
Regardless of the precise cause, there appears to be strong evidence that both formal exercise30–42,102,105 and simply increased levels of physical activity100 can have a positive influence on chronic inflammation in older adults. Furthermore, it is likely that the anti-inflammatory effects of exercise are present in muscle even if no change is seen in serum markers of inflammation.41,108 These findings provide yet another clear indication of the beneficial effects of exercise and increased daily physical activity in this vulnerable population.
Chronic increases in proinflammatory cytokines are associated with a myriad of impairments and dysfunction in older adults. Exercise is a potent preventive and intervention strategy for chronic inflammation and appears to be beneficial even in frail older adults.41 Exercise dosage that has proven effective in decreasing proinflammatory cytokines have ranged from a frequency of 2 to 5 days a week and in daily duration from 20 minutes to 3 hours. Exercise modes have included home walking programs, treadmill walking, cycling, and resistance training using machines and free weights. Aerobic exercise intensity has varied between moderate walking and vigorous aerobic activity at 80% of age–predicted maximum heart rate. Resistance training has been reported effective utilizing 8 to 10 exercises with 8 to 10 repetitions to target all major muscle groups done 2 to 3 times per week at an intensity of 65% to 80% of a one repetition maximum.41,42,102
Though exercise of any mode and duration may positively impact chronic inflammation, there is currently limited literature to provide specific guidelines as to the most effective mode and dose of exercise to decrease chronic inflammation. Although further research is needed for the most effective exercise prescription to target chronic inflammation, the current American College of Sports Medicine (ACSM) guidelines provide a reasonable initial approach with the aim of reducing chronic inflammation and improving physical function in older adults. Exercise to combat not only the proinflammatory cytokines but also the deleterious effects that stem from them should include a combination of aerobic and whole body resistance training a minimum of 3 days a week for 30 to 60 minutes and the initial training program should last at least 12 weeks.37,39,102,113 Thompson et al39 demonstrated that it takes at least 12 weeks to see changes in the serum levels of IL-6 but only 2 weeks of detraining to return to baseline. In addition, one long-term study examining the effects of 12 months of aerobic exercise on serum levels of IL-6 found that there was an additional decrease of serum IL-6 at 12 months compared with 6 months.37 These studies underscore the importance of regular physical activity in this population as positive changes in proinflammatory cytokines may continue to take place weeks and months after the initiation of exercise but may disappear in as little as 2 weeks after cessation of exercise.
Activation of large amounts of muscle mass are critical to the muscular release of IL-6 from the TNF-α independent pathway, activities that engage large amounts of muscle are most effective at producing IL-6 in this manner.111 Activities such as walking, running, biking, or using an elliptical trainer would be advised. The addition of resistance exercises 2 to 3 days a week targeting all major muscle groups would also be beneficial to both decreasing the proinflammatory cytokines41,42 as well as increasing muscle protein synthesis.41
As physical therapists see a larger proportion of older adults who suffer the functional consequences of frailty, there is an increasing interest in how best to address the treatment and prevention of this debilitating syndrome. Chronic inflammation is one of the strongest correlates of the frailty syndrome and can lead to a myriad of problems including muscle and strength loss and mobility limitations. Physical activity is a powerful anti-inflammatory tool that physical therapists can use not only to combat the effects of chronic inflammation but also to combat the production of proinflammatory cytokines. Exercise and increased physical activity can provide an anti-inflammatory environment within the muscle that may mitigate many of the effects of chronic inflammation on muscle. Future research should focus on the causes of chronic inflammation as well as the most effective treatments and exercise regimes to decrease inflammation.
2. Wilhelm-Leen ER, Hall YN, Deboer IH, Chertow GM Vitamin D deficiency and frailty in older Americans. J Intern Med. 2010;268:171–180.
3. Fried LP, Xue Q-L, Cappola AR, et al. Nonlinear multisystem physiological Dysregulation associated with frailty in older women: implications for etiology and treatment. J Gerontol A Biol Sci Med Sci. 2009;64A:1049–1057.
4. Ensrud KE, Ewing SK, Taylor BC, et al. Comparison of 2 frailty indexes for prediction of falls, disability, fractures, and death in older women. Arch Intern Med. 2008;168:382–389.
5. Ensrud KE, Ewing SK, Taylor BC, et al. Frailty and risk of falls, fracture, and mortality in older women: the study of osteoporotic fractures. J Gerontol A Biol Sci Med Sci. 2007;62:744–751.
6. Cawthon PM, Marshall LM, Michael Y, et al. Frailty in older men: prevalence, progression, and relationship with mortality. J Am Geriatr Soc. 2007;55:1216–1223.
7. Rockwood K, Mitnitski A, Song X, Steen B, Skoog I Long-term risks of death and institutionalization of elderly people in relation to deficit accumulation at age 70. J Am Geriatr Soc. 2006;54:975–979.
8. Ershler WB, Keller ET Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med. 2000;51:245–270.
9. Kanapuru B, Ershler WB Inflammation, coagulation, and the pathway to frailty. Am J Med. 2009;122:605–613.
10. Harris TB, Ferrucci L, Tracy RP, et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med. 1999;106:506–512.
11. Degens H The role of systemic inflammation in age-related muscle weakness and wasting. Scand J Med Sci Sports. 2009;20:28–38.
12. Schaap LA, Pluijm SM, Deeg DJ, et al. Higher inflammatory marker levels in older persons: associations with 5-year change in muscle mass and muscle strength. J Gerontol A Biol Sci Med Sci. 2009;64:1183–1189.
13. Visser M, Pahor M, Taaffe DR, et al. Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women: the Health ABC Study. J Gerontol A Biol Sci Med Sci. 2002;57:M326–M332.
14. Cesari M, Penninx BW, Pahor M, et al. Inflammatory markers and physical performance in older persons: the InCHIANTI study. J Gerontol A Biol Sci Med Sci. 2004;5:242–248.
15. Taaffe DR, Harris TB, Ferrucci L, Rowe J, Seeman TE Cross-sectional and prospective relationships of interleukin-6 and C-reactive protein with physical performance in elderly persons: MacArthur studies of successful aging. J Gerontol A Biol Sci Med Sci. 2000;55:M709–M715.
16. Pickup JC, Chusney GD, Thomas SM, Burt D Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes. Life Sci. 2000;67:291–300.
17. Kuller LH, Tracy RP, Shaten J, Meilahn EN Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1996;144:537–547.
18. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–979.
19. Vasan RS, Sullivan LM, Roubenoff R, et al. Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation. 2003;107:1486–1491.
20. Vila N, Castillo J, Davalos A, Chamorro A Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke. 2000;31:2325–2329.
21. Wyss-Coray T Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med. 2006;12:1005–1015.
22. Ferrucci L, Harris TB, Guralnik JM, et al. Serum IL-6 level and the development of disability in older persons. J Am Geriatr Soc. 1999;47:639–646.
23. Goodman MN Tumor necrosis factor induces skeletal muscle protein breakdown in rats. Am J Physiol. 1991;260:E727–E730.
24. Goodman MN Interleukin-6 induces skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med. 1994;205:182–185.
25. Cappola AR, Xue QL, Ferrucci L, Guralnik JM, Volpato S, Fried LP Insulin-like growth factor I and interleukin-6 contribute synergistically to disability and mortality in older women. J Clin Endocrinol Metab. 2003;88:2019–2025.
26. Autenrieth C, Schneider A, Doring A, et al. Association between different domains of physical activity and markers of inflammation. Med Sci Sports Exerc. 2009;41:1706–1713.
27. Fischer CP, Berntsen A, Perstrup LB, Eskildsen P, Pedersen BK Plasma levels of interleukin-6 and C-reactive protein are associated with physical inactivity independent of obesity. Scand J Med Sci Sports. 2007;17:580–587.
28. Ford ES Does exercise reduce inflammation? Physical activity and C-reactive protein among U.S. adults. Epidemiology. 2002;13:561–568.
29. Safdar A, Hamadeh MJ, Kaczor JJ, Raha S, Debeer J, Tarnopolsky MA Aberrant mitochondrial homeostasis in the skeletal muscle of sedentary older adults. PLoS One. 2010;5:e10778.
30. Bruun JM, Helge JW, Richelsen B, Stallknecht B Diet and exercise reduce low-grade inflammation and macrophage infiltration in adipose tissue but not in skeletal muscle in severely obese subjects. Am J Physiol Endocrinol Metab. 2006;290:E961–E967.
31. Giannopoulou I, Fernhall B, Carhart R, et al. Effects of diet and/or exercise on the adipocytokine and inflammatory cytokine levels of postmenopausal women with type 2 diabetes. Metabolism. 2005;54:866–875.
32. Gielen S, Adams V, Mobius-Winkler S, et al. Anti-inflammatory effects of exercise training in the skeletal muscle of patients with chronic heart failure. J Am Coll Cardiol. 2003;42:861–868.
33. Goldhammer E, Tanchilevitch A, Maor I, Beniamini Y, Rosenschein U, Sagiv M Exercise training modulates cytokines activity in coronary heart disease patients. Int J Cardiol. 2005;100:93–99.
34. Huffman KM, Samsa GP, Slentz CA, et al. Response of high-sensitivity C-reactive protein to exercise training in an at-risk population. Am Heart J. 2006;152:793–800.
35. Kohut ML, McCann DA, Russell DW, et al. Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of beta-blockers, BMI, and psychosocial factors in older adults. Brain Behav Immun. 2006;20:201–209.
36. Larsen AI, Aukrust P, Aarsland T, Dickstein K Effect of aerobic exercise training on plasma levels of tumor necrosis factor alpha in patients with heart failure. Am J Cardiol. 2001;88:805–808.
37. Nicklas BJ, Hsu FC, Brinkley TJ, et al. Exercise training and plasma C-reactive protein and interleukin-6 in elderly people. J Am Geriatr Soc. 2008;56:2045–2052.
38. Okita K, Nishijima H, Murakami T, et al. Can exercise training with weight loss lower serum C-reactive protein levels? Arterioscler Thromb Vasc Biol. 2004;24:1868–1873.
39. Thompson D, Markovitch D, Betts JA, Mazzatti D, Turner J, Tyrrell RM Time course of changes in inflammatory markers during a 6-mo exercise intervention in sedentary middle-aged men: a randomized-controlled trial. J Appl Physiol. 2010;108:769–779.
40. You T, Berman DM, Ryan AS, Nicklas BJ Effects of hypocaloric dietand exercise training on inflammation and adipocyte lipolysis in obese postmenopausal women. J Clin Endocrinol Metab. 2004;89:1739–1746.
41. Greiwe JS, Cheng B, Rubin DC, Yarasheski KE, Semenkovich CF Resistance exercise decreases skeletal muscle tumor necrosis factor alpha in frail elderly humans. FASEB J. 2001;15:475–482.
42. Prestes J, Shiguemoto G, Botero JP, et al. Effects of resistance training on resistin, leptin, cytokines, and muscle force in elderly post-menopausal women. J Sports Sci. 2009;27:1607–1615.
43. Cartier A, Cote M, Lemieux I, et al. Age-related differences in inflammatory markers in men: contribution of visceral adiposity. Metabolism. 2009;58:1452–1458.
44. Ershler WB, Sun WH, Binkley N, et al. Interleukin-6 and aging: blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction. Lymphokine Cytokine Res. 1993;12:225–230.
45. Ferrucci L, Corsi A, Lauretani F, et al. The origins of age-related proinflammatory state. Blood. 2005;105:2294–2299.
46. Hager K, Machein U, Krieger S, Platt D, Seefried G, Bauer J Interleukin-6 and selected plasma proteins in healthy persons of different ages. Neurobiol Aging 1994;15:771–772.
47. McKane WR, Khosla S, Peterson JM, Egan K, Riggs BL Circulating levels of cytokines that modulate bone resorption: effects of age and menopause in women. J Bone Miner Res. 1994;9:1313–1318.
48. Roubenoff R, Harris TB, Abad LW, Wilson PW, Dallal GE, Dinarello CA Monocyte cytokine production in an elderly population: effect of age and inflammation. J Gerontol A Biol Sci Med Sci. 1998;53:M20–M26.
49. Wei J, Xu H, Davies JL, Hemmings GP Increase of plasma IL-6 concentration with age in healthy subjects. Life Sci. 1992;51:1953–1956.
50. Beharka AA, Meydani M, Wu D, Leka LS, Meydani A, Meydani SN Interleukin-6 production does not increase with age. J Gerontol A Biol Sci Med Sci. 2001;56:B81–B88.
51. Caruso C, Candore G, Cigna D, et al. Cytokine production pathway in the elderly. Immunol Res. 1996;15:84–90.
52. Maes M, DeVos N, Wauters A, et al. Inflammatory markers in younger vs elderly normal volunteers and in patients with Alzheimer's disease. J Psychiatr Res. 1999;33:397–405.
53. Ahluwalia N, Mastro AM, Ball R, Miles MP, Rajendra R, Handte G Cytokine production by stimulated mononuclear cells did not change with aging in apparently healthy, well-nourished women. Mech Ageing Dev. 2001;122:1269–1279.
54. Bruunsgaard H, Pedersen M, Pedersen BK Aging and proinflammatory cytokines. Curr Opin Hematol. 2001;8:131–136.
55. Bruunsgaard H, Skinhoj P, Qvist J, Pedersen BK Elderly humans show prolonged in vivo inflammatory activity during pneumococcal infections. Journal of Infectious Diseases. 1999 1999;180:551–554.
56. Krabbe KS, Bruunsgaard H, Hansen CM, et al. Ageing is associated with a prolonged fever response in human endotoxemia. Clin Diagn Lab Immunol. Mar 2001;8:333–338.
57. Cesari M, Kritchevsky SB, Baumgartner RN, et al. Sarcopenia, obesity, and inflammation—-results from the Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors study. Am J Clin Nutr. 2005;82:428–434.
58. Fagiolo U, Cossarizza A, Scala E, et al. Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol. 1993;23:2375–2378.
59. McNerlan SE, Rea IM, Alexander HD A whole blood method for measurement of intracellular TNF-alpha, IFN-gamma and IL-2 expression in stimulated CD3+ lymphocytes: differences between young and elderly subjects. Exp Gerontol. 2002;37:227–234.
60. O'Mahony L, Holland J, Jackson J, Feighery C, Hennessy TP, Mealy K Quantitative intracellular cytokine measurement: age-related changes in proinflammatory cytokine production. Clin Exp Immunol. 1998;11:213–219.
61. Sandmand M, Bruunsgaard H, Kemp K, Andersen-Ranberg K, Schroll M, Jeune B High circulating levels of tumor necrosis factor-alpha in centenarians are not associated with increased production in T lymphocytes. Gerontology. 2003;49:155–160.
62. Born J, Uthgenannt D, Dodt C, et al. Cytokine production and lymphocyte subpopulations in aged humans. An assessment during nocturnal sleep. Mech Ageing Dev. 1995;84:113–126.
63. Riancho JA, Zarrabeitia MT, Amado JA, Olmos JM, Gonzalez-Macias J Age-related differences in cytokine secretion. Gerontology. 1994;40:8–12.
64. Rudd AG, Banerjee DK Interleukin-1 production by human monocytes in ageing and disease. Age Ageing. 1989;18:43–46.
65. Gon Y, Hashimoto S, Hayashi S, Koura T, Matsumoto K, Horie T Lower serum concentrations of cytokines in elderly patients with pneumonia and the impaired production of cytokines by peripheral blood monocytes in the elderly. Clin Exp Immunol. 1996;106:120–126.
66. McLachlan JA, Serkin CD, Morrey KM, Bakouche O Antitumoral properties of aged human monocytes. J Immunol. 1995;154:832–843.
67. Marik PE, Zaloga GP The effect of aging on circulating levels of proinflammatory cytokines during septic shock. Norasept II Study Investigators. J Am Geriatr Soc. Jan 2001;49(1):5–9.
68. Krabbe KS, Pedersen M, Bruunsgaard H Inflammatory mediators in the elderly. Exp Gerontol. 2004;39:687–699.
69. Moschen AR, Molnar C, Geiger S, et al. Anti-inflammatory effects of excessive weight loss: potent suppression of adipose interleukin 6 and tumour necrosis factor alpha expression. Gut. 2010;59:1259–1264.
70. Ryan AS, Nicklas BJ Reductions in plasma cytokine levels with weight loss improve insulin sensitivity in overweight and obese postmenopausal women. Diabetes Care. 2004;27:1699–1705.
71. Schenk S, Saberi M, Olefsky JM Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest. 2008;118:2992–3002.
72. Leng SX, Xue QL, Tian J, Walston JD, Fried LP Inflammation and frailty in older women. J Am Geriatr Soc. 2007;55:864–871.
73. Frontera WR, Hughes VA, Fielding RA, Fiatarone MA, Evans WJ, Roubenoff R Aging of skeletal muscle: a 12-yr longitudinal study. J Appl Physiol. 2000;88:1321–1326.
74. Levinger I, Levinger P, Trenerry MK, et al. Increased inflammatory cytokine expression in the vastus lateralis of patients with knee osteoarthritis. Arthritis Rheum. 2011;63:1343–1348.
75. Wust RC, Degens H Factors contributing to muscle wasting and dysfunction in COPD patients. Int J Chron Obstruct Pulmon Dis. 2007;2:289–300.
76. Anker SD, Ponikowski PP, Clark AL, et al. Cytokines and neurohormones relating to body composition alterations in the wasting syndrome of chronic heart failure. Eur Heart J. 1999;20:683–693.
77. Moldawer LL, Sattler FR Human immunodeficiency virus-associated wasting and mechanisms of cachexia associated with inflammation. Semin Oncol. 1998;25:S73–S81.
78. Tisdale MJ Wasting in cancer. J Nutr. 1999;129:243S–246S.
79. Charters Y, Grimble RF Effect of recombinant human tumour necrosis factor alpha on protein synthesis in liver, skeletal muscle and skin of rats. Biochem J. 1989;258:493–497.
80. Wilcox PG, Wakai Y, Walley KR, Cooper DJ, Road J Tumor necrosis factor alpha decreases in vivo diaphragm contractility in dogs. Am J Respir Crit Care Med. 1994;150:1368–1373.
81. Li YP, Schwartz RJ, Waddell ID, Holloway BR, Reid MB Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-kappaB activation in response to tumor necrosis factor alpha. FASEB J. 1998;12:871–880.
82. Guttridge DC, Mayo MW, Madrid LV, Wang CY, Baldwin AS Jr NF-kappaB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science. 2000;289:2363–2366.
83. Thaloor D, Miller KJ, Gephart J, Mitchell PO, Pavlath GK Systemic administration of the NF-kappaB inhibitor curcumin stimulates muscle regeneration after traumatic injury. Am J Physiol. 1999;277:C320–C329.
84. Goodpaster BH, Park SW, Harris TB, et al. The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging, and body composition study. J Gerontol A Biol Sci Med Sci. 2006;61:1059–1064.
85. Morse CI, Thom JM, Reeves ND, Birch KM, Narici MV In vivo physiological cross-sectional area and specific force are reduced in the gastrocnemius of elderly men. J Appl Physiol. 2005;99:1050–1055.
86. Hardin BJ, Campbell KS, Smith JD, et al. TNF-alpha acts via TNFR1 and muscle-derived oxidants to depress myofibrillar force in murine skeletal muscle. J Appl Physiol. 2008;104:694–699.
87. Bruunsgaard H, Bjerregaard E, Schroll M, Pedersen BK Muscle strengthafter resistance training is inversely correlated with baseline levels of soluble tumor necrosis factor receptors in the oldest old. J Am Geriatr Soc. 2004;52:237–241.
88. Reid MB, Lannergren J, Westerblad H Respiratory and limb muscle weakness induced by tumor necrosis factor-alpha: involvement of muscle myofilaments. Am J Respir Crit Care Med. 2002;166:479–484.
89. Supinski GS, Callahan LA Caspase activation contributes to endotoxin-induced diaphragm weakness. J Appl Physiol. 2006;100:1770–1777.
90. Tracey KJ, Lowry SF, Beutler B, Cerami A, Albert JD, Shires GT Cachectin/tumor necrosis factor mediates changes of skeletal muscle plasma membrane potential. J Exp Med. 1986;164:1368–1373.
91. van Kann LN, Bakker AJ Effect of tumor necrosis factor alpha on electrically induced calcium transients elicited in C2C12 skeletal myotubes. Muscle Nerve. 2007;35:251–253.
92. Yokoyama T, Vaca L, Rossen RD, Durante W, Hazarika P, Mann DL Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. J Clin Invest. 1993;92:2303–2312.
93. Brinkley TE, Leng X, Miller ME, et al. Chronic inflammation is associated with low physical function in older adults across multiple comorbidities. J Gerontol A Biol Sci Med Sci. 2009;64:455–461.
94. Penninx BW, Kritchevsky SB, Newman AB, et al. Inflammatory markers and incident mobility limitation in the elderly. J Am Geriatr Soc. 2004;52:1105–1113.
95. Figaro MK, Kritchevsky SB, Resnick HE, et al. Diabetes, inflammation, and functional decline in older adults: findings from the Health, Aging and Body Composition (ABC) study. Diabetes Care. 2006;29:2039–2045.
96. Ferrucci L, Penninx BW, Volpato S, et al. Change in muscle strength explains accelerated decline of physical function in older women with high interleukin-6 serum levels. J Am Geriatr Soc. 2002;50:1947–1954.
97. Tiainen K, Hurme M, Hervonen A, Luukkaala T, Jylha M Inflammatory markers and physical performance among nonagenarians. J Gerontol A Biol Sci Med Sci. 2010;65:658–663.
98. Kidde J, Marcus R, Dibble L, Smith S, Lastayo P Regional muscle and whole-body composition factors related to mobility in older individuals: a review. Physiother Can. 2009;61:197–209.
99. Caspersen CJ, Powell KE, Christenson GM Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research. Public Health Rep. 1985;100:126–131.
100. Colbert LH, Visser M, Simonsick EM, et al. Physical activity, exercise, and inflammatory markers in older adults: findings from the Health, Aging and Body Composition Study. J Am Geriatr Soc. 2004;52:1098–1104.
101. Pitsavos C, Panagiotakos DB, Chrysohoou C, Kavouras S, Stefanadis C The associations between physical activity, inflammation, and coagulation markers, in people with metabolic syndrome: the ATTICA study. Eur J Cardiovasc Prev Rehabil. 2005;12:151–158.
102. Stewart LK, Flynn MG, Campbell WW, et al. The influence of exercise training on inflammatory cytokines and C-reactive protein. Med Sci Sports Exerc. 2007;39:1714–1719.
103. Bautmans I, Njemini R, Vasseur S, et al. Biochemical changes in response to intensive resistance exercise training in the elderly. Gerontology. 2005;51:253–265.
104. Marcell TJ, McAuley KA, Traustadottir T, Reaven PD Exercise training is not associated with improved levels of C-reactive protein or adiponectin. Metabolism. 2005;54:533–541.
105. Nicklas BJ, Ambrosius W, Messier SP, et al. Diet-induced weight loss, exercise, and chronic inflammation in older, obese adults: a randomized controlled clinical trial. Am J Clin Nutr. 2004;79:544–551.
106. Zoppini G, Targher G, Zamboni C, et al. Effects of moderate-intensity exercise training on plasma biomarkers of inflammation and endothelial dysfunction in older patients with type 2 diabetes. Nutr Metab Cardiovasc Dis. 2006;16:543–549.
107. Beavers KM, Hsu FC, Isom S, et al. Long-term physical activity and inflammatory biomarkers in older adults. Med Sci Sports Exerc. 2010;42:2189–2196.
108. Lambert CP, Wright NR, Finck BN, Villareal DT Exercise but not diet-induced weight loss decreases skeletal muscle inflammatory gene expression in frail obese elderly persons. J Appl Physiol. 2008;105:473–478.
109. Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 2003;17:884–886.
110. Pedersen BK The diseasome of physical inactivity–and the role of myokines in muscle–fat cross talk. J Physiol. 2009;587:5559–5568.
111. Pedersen BK, Febbraio MA Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev. 2008;88:1379–1406.
112. Clement K, Viguerie N, Poitou C, et al. Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J. 2004;18:1657–1669.
113. Chodzko-Zajko WJ, Proctor DN, Fiatarone Singh MA, et al. American College of Sports Medicine position stand. Exercise and physical activity for older adults. Med Sci Sports Exerc. 2009;41:1510–1530.
chronic inflammation; frailty; exercise; muscle
Copyright © 2012 the Section on Geriatrics of the American Physical Therapy Association
Highlight selected keywords in the article text.