These findings provide randomized controlled trial evidence that a one-year physical activity intervention results in reduced systemic concentrations of IL-6 in elderly individuals at risk for disability. However, the effect of the exercise intervention on IL-6 was driven by the subgroup of participants with a lower functional status (SPPB score ≤ 7), and those with a higher baseline IL-6, as there was no observed effect in persons with a higher SPPB or a lower baseline IL-6. There was no interaction of gender for the effects of physical activity on IL-6, so similar responses were observed between men and women. Thus, regular physical activity—even in the absence of weight loss—is an effective therapy for reducing systemic concentrations of IL-6, an important biological predictor of increased risk for disability and mortality.6–10
Further, this benefit of regular physical activity is most beneficial in those older individuals at the greatest risk for disability and subsequent loss of independence.
It is well-known that a single bout of strenuous exercise acutely increases systemic IL-6 levels, as well as concentrations of other cytokines and acute phase reactants.38
However, as our observation of a reduction in systemic IL-6 with long-term exercise training is consistent with some previously published data from smaller and uncontrolled studies of a shorter duration,28, 31, 34
it appears that chronic muscle contractions performed on a regular basis decrease systemic IL-6 concentrations. Additionally, our findings extend those of previous studies in several ways. First, our data provide evidence from a randomized, controlled design which causally links the observed decrease in IL-6 to the increased physical activity. In addition, the intervention was of sufficient length (12 months), but did not change body weight, indicating that exercise training does not need to result in weight loss to have an effect on IL-6. Finally, we found that the effect of the increased physical activity on IL-6 was much more pronounced in the subset of persons with higher baseline IL-6, and in those with worse physical function. Of note, there was a mean increase in IL-6 levels in the Successful Aging group, especially in those with lower function at baseline, suggesting that physical activity may result in lower IL-6 by preventing an age-related increase. As seen in other published studies,6, 14–16
concentrations of IL-6 were positively related to age at baseline in the individuals enrolled in this study.
The mechanism by which chronic exercise alter IL-6 concentrations in the circulation must be through either an inhibitory effect on IL-6 production or through a stimulatory effect on IL-6 clearance. Adipose tissue is a significant source of circulating IL-6 and individuals with more fat have higher levels of IL-6.39
In the present study, IL-6 was directly related to BMI at baseline, but the intervention did not cause weight loss—nor changes in body composition (measured in a subset of LIFE participants)—making it unlikely that the observed reduction in IL-6 could be solely attributed to a loss of body fat. In addition, although data are limited, it does not appear that exercise in the absence of fat loss influences production or release of IL-6 by adipose tissue per se.40, 41
On the other hand, data are beginning to show that chronic exercise may decrease pro-inflammatory cytokine production from peripheral mononuclear cells.42, 43
Although there was a trend for the PA intervention to lower CRP levels, we did not find a statistically significant treatment effect for CRP, either in the entire sample or in subgroups of individuals with higher CRP or with lower physical function at baseline. On average, the physical activity intervention reduced CRP by nearly 2.0 mg/L; however, this reduction was not different from the control group. Using this effect size, post-hoc power analyses indicate that statistical power with the present sample size was 27% and that, in order to reach 80% power with the same effect size, we would need to study 643 participants in each intervention group. Despite a large body of cross-sectional evidence showing that a higher volume of physical activity is associated with a lower CRP concentration,19–25
not all, prior intervention studies show an effect of increasing physical activity for reducing CRP.27, 30, 32, 34, 44, 45
However, these studies were conducted with smaller sample sizes (n=16–140) than the current study. Previously published intervention studies showing that exercise training reduced CRP either did not compare individuals randomized to exercise or a non-exercise control group,26, 28, 29, 46–48
or the intervention also resulted in slight to moderate decreases in body weight/fat.26, 33, 47–49
Thus, exercise training interventions that result in even a slight amount of weight reduction are beneficial for reducing CRP levels, whereas it appears that increasing physical activity alone has a small, often undetectable, effect on CRP.
While our findings indicate that increasing physical activity can be advocated as an effective therapy for reducing systemic IL-6, we did not test whether this reduction resulted in an improvement in risk factors for adverse health conditions associated with inflammation. An elevated blood concentration of IL-6 can be indicative of several aging-related diseases, but is an especially strong risk factor for subsequent cardiovascular disease1, 2
in older persons. While there is currently no established IL-6 cut-point used to identify an increase in disease or disability risk, one study suggested that the elevated risk of mobility-disability associated with IL-6 was nonlinear, with the risk rising rapidly beyond a concentration of 2.5 pg/ml—individuals above this level were approximately 62% more likely to develop disability over the next four years.7
The average baseline IL-6 in the individuals enrolled in the LIFE trial was 3.38 pg/ml, suggesting that, overall, they are at high risk for development of disability. Furthermore, the mean decrease in IL-6 in all individuals in the physical activity intervention group was 0.53 pg/ml (~16%), down to an average of 2.97 pg/ml. Unfortunately, there are no available data regarding whether this magnitude of decline in IL-6 is associated with a lowered risk of subsequent disability or other aging-related adverse health condition. Thus, longitudinal studies are needed to determine whether there is a delay in the onset of physical disability or a reduction in disease incidence associated with this reduction in IL-6 seen with regular exercise.
These findings should be interpreted in light of certain aspects of the study and potential limitations. First, the entire sample was older (>70 yrs) and the effects of the intervention may not directly translate to another age group, and they may not be observed in all older persons. Moreover, because the observed IL-6 response to physical activity was driven by the subset of individuals with lower physical function, this effect may have been underestimated as missing blood samples may have disproportionally come from these impaired individuals. In addition, the physical activity intervention in the LIFE study utilized a combination of aerobic (mainly walking) and light lower extremity resistance exercise. This intervention does not allow us to distinguish whether one type of training has greater anti-inflammatory effects over another, nor does it provide information regarding possible dose-response effects of increasing the exercise intensity or the overall caloric expenditure of physical activity. Despite these caveats, this study points to the benefit of regular physical activity—even in the absence of weight loss—as an effective therapy for reducing systemic concentrations of IL-6 in the elderly, especially in those with the greatest risk for disability.