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Physical activity, exercise, and low-grade systemic inflammation

This is an excerpt from Physical Activity Epidemiology-3rd Edition by Rodney K. Dishman,Gregory W. Heath,Michael D. Schmidt & I-Min Lee.

Production of C-reactive protein in the liver is part of an acute-phase response to infection that is stimulated by cytokines such as IL-6, IL-1, and TNF-α. All those inflammatory markers can be elevated in people who are obese or have any of several other chronic health conditions, such as diabetes, cystic fibrosis, chronic obstructive pulmonary disease (COPD), MS, cancer (including cancer cachexia—i.e., wasting syndrome), and immunosenescence associated with old age. Increased physical activity could plausibly counter low-grade systemic inflammation by secreting anti-inflammatory cytokines during muscle contraction (Pedersen 2006; Lira et al. 2009; Senchina and Kohut 2007). Physical activity can also contribute to fat loss and thus reduce inflammation indirectly by reducing inflammatory adipokines and macrophages that reside in adipose tissue (Woods, Vieira, and Keylock 2009).

An early review of published studies of exercise and C-reactive protein concluded that strenuous exercise (e.g., marathons, road races, triathlons) induced a transitory, acute-phase inflammatory response but that exercise training seemed to result in a persistent anti-inflammatory adaptation. With just a handful of exceptions, nearly 20 cross-sectional studies showed that endurance athletes or physically active men and women of varying ages had lower levels of C-reactive protein measured at rest compared to less active or sedentary people. Also, two of three small exercise trials reported a reduction in C-reactive protein after endurance exercise training (Kasapis and Thompson 2005). Although a number of exercise studies adjusted for body mass index (BMI), most studies have not demonstrated that the association between physical activity and inflammatory markers is independent of fatness, which is a risk factor for low-grade inflammation (Wärnberg et al. 2010). Additionally, most of the investigations showing physical activity to be associated with lower levels of inflammation are cross-sectional studies. Thus, it is unclear whether physical activity leads to decreased inflammation or whether a reduced state of inflammation serves as a marker for healthier persons who may be more able and likely to be physically active. Subsequent evaluations of randomized controlled trials concluded that exercise training sufficient to increase fitness in people who are overweight or obese does not reliably lower C-reactive protein unless there is substantial weight loss (Kelley and Kelley 2006; Stewart et al. 2010).

A meta-analysis of 83 randomized and nonrandomized trials of exercise training and C-reactive protein (CRP) yielded 143 outcomes from more than 3700 people. There was, on average, a small drop in CRP of 0.26 standard deviations (SD). Concurrent decreases in BMI or percent body fat explained 11% or nearly 7% of the decrease in CRP. Nonetheless, regardless of loss in weight or fat, exercise training led to a favorable, though small, decrease in CRP (0.19 SD) (Fedewa, Hathaway, and Ward-Ritacco 2017).

A meta-analysis of 11 randomized controlled trials including 1250 middle-aged and older adults concluded that, on average, aerobic exercise training reduced CRP by 0.50 SD across seven studies, as well as tumor necrosis factor-alpha (TNF-α) (five studies) and interleukin 6 (IL-6) (six studies) each by 0.75 SD. Two studies reported no effect of exercise on IL-4 (Zheng et al. 2019).

The INFLAME Study

This was a randomized controlled trial of the effects of four months of supervised aerobic exercise training (16 kcal/kg body weight per week) at a vigorous intensity on elevated C-reactive protein concentrations (≥2.0 mg/L; median = 4.0 mg/L) in 162 initially sedentary, obese women and men who were mostly between ages 40 and 60 years (Thompson et al. 2008). There was no effect of exercise on C-reactive protein levels regardless of gender or baseline body weight. However, change in weight was associated with change in C-reactive protein. Only women who lost an average of about 6.5 lb (2.9 kg) or more (≥3%) had a significant reduction in C-reactive protein (about 1 mg/L) (Church et al. 2010).

The Dose Response to Exercise in Women Study

More than 400 sedentary, overweight, or obese postmenopausal women were randomized into one of four groups: a nonexercise control or one of three aerobic exercise groups. The exercise groups expended an exercise energy of 4, 8, or 12 kcal · kg⁻¹ · week⁻¹ for six months at a training intensity of 50% of peak V.O₂ (Stewart et al. 2010). Median levels of C-reactive protein ranged from 3.4 to 4.9. There was no effect of exercise on blood levels of C-reactive protein or on IL-6 and TNF-α or adiponectin (Arsenault et al. 2009) regardless of energy expenditure. Even though increases in peak V.O₂ were dose related, the decreases in waist circumference were similar in all the exercise groups. Only women who lost about 5.75 lb (2.6 kg) or more (≥3%) had a reduction in C-reactive protein (about 1 mg/L), regardless of control or exercise group.

Seattle, Washington

A similar 12-month randomized controlled trial of exercise in sedentary, overweight men and women, only some of whom had elevated initial levels, also found no effect on C-reactive protein levels despite a 2% reduction in body fat (Campbell et al. 2008). However, in a subsequent analysis of results from postmenopausal women who were obese, abdominally obese, or both, exercise reduced C-reactive protein by more than 10%, even though weight loss was modest and IL-6 was not affected by the exercise (Campbell et al. 2009).

The Lifestyle Interventions and Independence for Elders Trial

This was a long-term intervention that examined the effect of exercise on biomarkers of inflammation (C-reactive protein and IL-6) in 424 elderly (aged 70-89), nondisabled, community-dwelling men and women at risk for physical disability. Participants were randomly assigned to a 12-month, moderate-intensity physical activity intervention or a successful aging health education intervention at sites in Dallas, Texas; Stanford, California; Pittsburgh, Pennsylvania; and Winston-Salem, North Carolina (Nicklas et al. 2008). After adjustment for baseline IL-6, sex, clinic site, and diabetes, the exercise group had 8.5% lower IL-6 levels than the heath education group, but exercise did not affect C-reactive protein. An ancillary analysis of 368 participants showed no effects of exercise on blood levels of adiponectin, TNF-α, or IL-15 or on receptors for IL-1, IL-1 inhibitor, IL-2, IL-6, and TNF. IL-8 levels were 10% lower after exercise training, but that could have been a chance finding (Beavers et al. 2010). Overall, there was no evidence of an anti-inflammatory effect of exercise training.

Youths

The few studies of physical activity and inflammatory markers in adolescents have yielded results similar to those found in adults (Rubin and Hackney 2010). Several cross-sectional comparisons of physically active boys and girls and a few exercise training studies lasting two to three months showed 25% to 35% higher levels of adiponectin, 25% to 50% lower levels of IL-6, 30% reductions in C-reactive protein, and lower or unchanged TNF-α than in less active or sedentary boys and girls. However, body fatness was not well controlled in most of those studies, and randomized controlled trials with obese youths suggest that the effects of exercise on adipokines and inflammatory cytokines in obese youths, as in adults, depend on weight loss (Balagopal et al. 2005; Kelly et al. 2007).

Interactions of the immune system can also influence the balance of probiotic and pathogenic bacteria (microbiota) in the gut to influence vulnerability to inflammatory diseases. Emerging evidence has shown that different types of exercise training have different effects on the severity of intestinal inflammation during an inflammatory insult (for example, ulcerative colitis or Crohn disease) and may be related to immune cell homeostasis and microbiota-immune interactions in the gut (Cook et al. 2016).

More Excerpts From Physical Activity Epidemiology 3rd Edition

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