New Investigator Award
Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of β-blockers, BMI, and psychosocial factors in older adults

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Abstract

Increased serum levels of inflammatory mediators have been associated with numerous disease states including atherosclerosis, Type II diabetes, hypertension, depression, and overall mortality. We hypothesized that a long-term exercise intervention among older adults would reduce serum inflammatory cytokines, and this reduction would be mediated, in part, by improvements in psychosocial factors and/or by β-adrenergic receptor mechanisms. Adults ⩾age 64 were randomly assigned to either an aerobic exercise treatment (CARDIO) or a flexibility/strength exercise treatment (FLEX) 3 days/week, 45 min/day for 10 months. A subgroup of subjects treated with non-selective β1β2 adrenergic antagonists were included to evaluate the potential role of β-adrenergic receptor adaptations as mediators of an exercise-induced change in inflammation. The inflammatory mediators [C-reactive protein (CRP), IL-6, tumor necrosis factor (TNF)-α, and IL-18] and the psychosocial factors (depression, perceived stress, optimism, sense of coherence, and social support) were measured pre- and post-intervention. The CARDIO treatment resulted in significant reductions in serum CRP, IL-6, and IL-18 compared to the FLEX treatment (significant treatment × time interaction, p < .05), whereas TNFα declined in both groups (main effect of time, p = .001). However, several psychosocial factors (depression, optimism, and sense of coherence) improved in both groups suggesting that the reduction of CRP, IL-6, and IL-18 in the CARDIO group was not mediated by improvements in psychosocial scores. With respect to the potential role of β-adrenergic receptors, both CARDIO subjects treated with β-adrenergic antagonists and those who were not treated with those medications demonstrated similar reductions in serum CRP, IL-6, IL-18, and TNFα. In summary, we have observed that an aerobic exercise intervention can significantly reduce serum inflammatory mediators, but β-adrenergic receptors and psychosocial factors do not appear to be involved.

Introduction

Elevated levels of inflammatory mediators have been associated with an increased risk and/or severity of chronic disease. Atherosclerosis and coronary artery disease are associated with greater levels of C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α (Larsson et al., 2005, Ridker et al., 2003, Schwartz et al., 2003, Tzoulaki et al., 2005). Elevated blood pressure and congestive heart failure are associated with elevated serum CRP, IL-6, TNFα, and IL-1β (Barbieri et al., 2003, Blake et al., 2003, Torre-Amione, 2005, Vasan et al., 2003). Patients with metabolic disorders including Type II diabetes, metabolic syndrome, and obesity also have increased IL-6 and CRP (Das, 2001, Fernandez-Real and Ricart, 2003, Pradhan et al., 2001, Ridker et al., 2003). IL-18 is a pleiotropic inflammatory cytokine that is elevated in the serum of Type II diabetics and is a predictor of cardiovascular death and future coronary heart disease (Blankenberg et al., 2002, Blankenberg et al., 2003, Moriwaki et al., 2003). Aging is also considered to be an inflammatory state, and levels of inflammatory markers are predictors of mortality and disability (Kritchevsky et al., 2005).

Physical activity has been inversely associated with elevated inflammatory markers (Church et al., 2002) and this relationship has been demonstrated in older adults (Colbert et al., 2004, Geffken et al., 2001). Several studies in middle-aged adults reported that exercise and diet interventions resulting in weight loss reduced serum CRP, IL-6, and IL-18, whereas exercise training alone reduced serum CRP, IL-6, and blood mononuclear cell production of TNFα and IL-1α in patients at risk for heart disease (Esposito et al., 2003, Goldhammer et al., 2005, Smith et al., 1999, You et al., 2004). However, the findings from one exercise intervention study with older adult subjects showed no significant reduction in serum CRP (Hammett et al., 2004). Therefore, it is not clear whether an exercise intervention in older adults can significantly reduce CRP, IL-6, or IL-18. It is also not known what type of exercise may be most effective, as currently published trials have used primarily aerobic exercise. In addition, the mechanism(s) by which exercise may reduce inflammatory mediators have not been addressed, although changes in body fat or body mass index (BMI) have been suggested to play a role.

β-Adrenergic receptor activation may be one mechanism that mediates exercise-induced alteration of inflammatory mediators. β-Adrenergic receptor activation of adipocytes increases pro-inflammatory cytokine secretion, and β-adrenergic receptor density and activity may change with exercise training (Nieto et al., 1996). An association between β-blocker treatment and reduced CRP has also been reported (Jenkins et al., 2002). Another mechanism by which exercise may reduce inflammatory mediators involves alterations of psychosocial factors. Major depressive disorder, stress, and anxiety are associated with elevated inflammatory cytokines, and exercise has been shown to reduce clinical depression and anxiety (Black and Garbutt, 2002, Blumenthal et al., 1999, Dantzer et al., 1999, Kiecolt-Glaser and Glaser, 2002, King et al., 1993, Pitsavos et al., 2005, Suarez, 2004). Thus, more than one mechanism (psychosocial and physiological) may mediate the exercise-induced reduction of inflammatory factors.

There are two goals of this study: (1) determine the type(s) of exercise that may result in a reduction of serum inflammatory markers in older adults and (2) establish the extent to which β-adrenergic receptors and psychosocial factors mediate exercise-induced change in inflammatory markers. We hypothesize that aerobic exercise will be more effective than flexibility/resistance exercise in reducing serum inflammatory factors, and that both psychosocial factors and β-adrenergic receptor activation will mediate, in part, the reduction of inflammatory factors. Clearly, there are important clinical benefits to be obtained by understanding what type of exercise is most effective in reducing inflammation among older adults. In addition, an understanding of how exercise modulates inflammation could lead to the development of additional effective therapies.

Section snippets

Participant screening and randomization

Older adults were recruited from two different central Iowa communities through the placement of advertisements, by press releases in local newspapers, visits to senior citizen meal sites, churches and church groups, senior community service organizations, independent living housing facilities, and by friend referral. All procedures involving human subjects were approved by the Institutional Review Board for Human Subjects at Iowa State University and Des Moines University of Osteopathic

Health and fitness measures

Baseline characteristics of participants are shown in Table 1. Health/disease status was similar between groups, and there were no significant differences between the CARDIO and FLEX groups on the baseline health or fitness variables (see Table 1, Table 2). Use of statins was not different between groups, but there were a greater number of subjects in the cardio treated with daily aspirin therapy. When medications (statins and aspirin) were included as a covariate in subsequent analyses of

Discussion

To our knowledge, the findings from this study are the first to suggest that the type of exercise performed may impact the extent to which serum inflammatory mediators may be altered. Cardiovascular exercise reduced serum levels of IL-6, IL-18, and CRP whereas flexibility/moderate strength training did not have the same positive effect. We did, however, observe a reduction in TNFα in both groups, suggesting that flexibility/strength exercise may have some benefits. The change in plasma volume

Acknowledgments

This work was supported in part by a grant from NIAID, number R01 AI49956. David Senchina and Wanglok Lee also contributed to the experimental assays.

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