Effect of Exercise on Oxidative Stress: A 12-month Randomized, Controlled Trial

From Medicine and Science in Sports and Exercise®

Peter T. Campbell; Myron D. Gross; John D. Potter; Kathryn H. Schmitz; Catherine Duggan; Anne Mctiernan; Cornelia M. Ulrich

Posted: 08/23/2010; Medicine and Science in Sports and Exercise®. 2010;42(8):1448-1453. © 2010 American College of Sports Medicine

Abstract

Purpose: This study examined the effect of a yearlong exercise intervention on F2-isoprostane, a specific marker of lipid peroxidation and a general marker of oxidative stress.

Methods: In a randomized, controlled trial, 173 overweight or obese, postmenopausal, sedentary women were randomized either to an aerobic exercise intervention (60%–75% observed maximal HR) for ≥45 min·d−1, 5 d·wk−1 (n = 87), or to a stretching control group (n = 86), on an intent-to-treat basis. Baseline and 12-month measures included urinary F2-isoprostane, maximal O2 uptake, body weight, body fat percentage, waist circumference, and intra-abdominal fat surface area. Urine samples were available from 172 and 168 women at baseline and 12 months, respectively.
Results: During the 12-month study, controls minimally changed maximal O2 uptake (+0.2%) and body weight (+0.1 kg), whereas exercisers increased maximal O2 uptake (+13.6%; P < 0.0001 vs controls) and decreased body weight (−1.3 kg; P = 0.007 vs controls). F2-isoprostane increased slightly among controls (+3.3%) and decreased in exercisers (−6.2%), although the effect was not statistically significant (P = 0.26). In planned subgroup analyses, F2-isoprostane decreased linearly with gain in maximal O2 uptake (P trend = 0.005) relative to controls; exercisers who increased maximal O2 uptake by >15% decreased F2-isoprostane by 14.1% (P = 0.005 vs controls). A borderline statistically significant trend was observed between decreased waist circumference and F2-isoprostane (P = 0.06). Similar subgroup analyses by 12-month changes in body fat percentage, weight, and intra-abdominal fat were not statistically significant.

Conclusions: These findings suggest that aerobic exercise, when accompanied by relatively marked gains in aerobic fitness, decreases oxidative stress among previously sedentary older women and that these effects occur with minimal change in mass or body composition.

Introduction

Oxidative stress occurs when the production of reactive species, derived largely from oxygen and nitrogen, exceeds degradation by the antioxidant defense system.
The ensuing damage to DNA, protein, and lipid has been implicated in cardiovascular and pulmonary diseases, diabetes, neurodegenerative disorders, and some cancers.
Thus, intervention strategies to reduce oxidative stress, especially among overweight/obese persons who generally have high oxidative stress levels,have widespread appeal. Such efforts with human study subjects have been hindered by difficulties in the measurement of oxidative damage. Recently, however, sensitive and stable methods have become available to measure F2-isoprostanes
F2-isoprostanes are a family of isomeric F2-prostaglandin-like compounds, derived from free radical-catalyzed peroxidation of arachidonic acid, independent of the cyclooxygenase enzyme. A recent multi-institutional study concluded that F2-isoprostane was the most accurate method to assess oxidative stress in vivo from urine or plasma samples.[9]

Reduced oxidative stress, probably achieved through improved antioxidant defenses and/or reduced reactive species formation, may be one mechanism that links physical activity to reduced risk of chronic disease.[3,19] Noncontrolled exercise intervention studies among premenopausal women have noted 25%[6] and 34%[18] decreased F2-isoprostane concentrations after 12–15 wk of exercise training; however, no intervention effects were observed in an 8-wk controlled exercise trial among older patients with type 2 diabetes.[15] Given the lack of data on this topic, we investigated the effect of a yearlong aerobic exercise intervention compared with a stretching control program on F2-isoprostane concentrations in postmenopausal women. We hypothesized that the 12-month exercise intervention would decrease F2-isoprostane and that this effect would be mediated by changes in maximal O2 uptake and by measures of body size/fat distribution.

This work was conducted with ancillary funding, using previously collected urine specimens and data from the Physical Activity for Total Health study (ClinicalTrials.gov Identifier: NCT00668174). The main objective of the parent trial was to examine the effects of exercise on steroid hormones among 173 postmenopausal, previously sedentary, overweight/obese women, as described previously.[11–13] A subgroup of participants (n = 115) from the parent trial, who met additional inclusion criteria, were included in separately funded studies of the effects of exercise on immune function[5] and inflammation.[4]

Discussion
We examined the effect of a yearlong aerobic exercise intervention compared with a stretching control program on urinary F2-isoprostane, a marker of systemic oxidative stress, among previously sedentary, overweight/obese, postmenopausal women. Overall, exercisers decreased F2-isoprostane concentrations, as predicted by our primary hypothesis, but the effect was not statistically significant, except in planned analyses by strata of gain in aerobic fitness.

Few previous studies have examined the effects of exercise alone on F2-isoprostane concentrations,[6,15,18] and no earlier studies, to our knowledge, were conducted exclusively among postmenopausal women. These studies suggest that exercise may reduce quite strongly F2-isoprostanes among relatively younger women,[6,18] whereas this beneficial effect may be attenuated among older study subjects, as observed currently and previously.[15] The three earlier studies and the current study noted similarly decreased body mass and increased aerobic fitness after exercise intervention, despite the wide range of intervention periods and age groups studied. Thus, these data suggest a potential age effect for the capacity of exercise to reduce oxidative stress. The mechanisms to explain such an effect are discussed in detail elsewhere[2] and are largely on the basis of experiments with laboratory animals: essentially, older animals have been observed to experience damage to cardiac and skeletal muscle after short-term exercise training if it is not initiated before a certain age, indicative of a physiologic age threshold. Alternatively, if exercise is initiated before this age, older animals experience the same health benefits as younger exercising animals. However, it is important to note that the older adults in the current study, and the participants in the previous study,[15] marginally decreased oxidative stress levels, although the effects were not statistically significant, suggesting that the laboratory animal data are not entirely generalizable to humans.

We observed an inverse linear association between aerobic fitness and oxidative stress, suggesting a hormetic effect of exercise training.[10] This finding for aerobic fitness and oxidative stress complements recent results from a subset of participants in this trial (n = 115) where we reported that the effect of exercise on inflammation (C-reactive protein and serum amyloid A) was restricted to participants who were obese (BMI ≥ 30 kg·m−2 or waist circumference > 88 cm) at baseline.[4] In contrast, baseline obesity status did not modify the influence of exercise on F2-isoprostane in the current study (data not shown). For our study participants, in particular, these results suggest that gains in aerobic fitness improve oxidative stress levels, probably because of exercise-induced adaptations of the antioxidant defense system,[3,8,16] and this effect occurs independent of general or abdominal obesity status. Although our subgroup analyses among exercisers by strata of weight/fat loss were largely not statistically significant, it is worth noting that this trial was not designed to elicit much weight loss, and our exercise participants only reduced body weight by approximately 1.3 kg, on average. Therefore, we could not assess the effects of much weight/fat loss on oxidative stress, a limitation that future studies should address.

Particular strengths of this study include the following: the selection of a sensitive and stable biomarker for oxidative stress;[9] the long period of exercise intervention, with high participant retention; the good participant adherence to the exercise protocol; the bona fide effects of the aerobic exercise intervention, quantified by direct measures of maximal O2 uptake; and the gold standard randomized, controlled trial design. Limitations of this study include the highly homogeneous study sample that limits comparisons to other groups and the fact that we studied only one biomarker of oxidative stress, F2-isoprostane; future studies should consider other measures of lipid peroxidation, such as TBARS, and biomarkers that additionally reflect oxidative damage to protein and DNA.

In conclusion, in a randomized, controlled trial with excellent retention and good adherence to the aerobic exercise intervention, conducted among 173 previously sedentary, overweight/obese, postmenopausal women, we observed a modest reduction in F2-isoprostane overall that was not statistically significant. When exercisers were stratified by gain in aerobic fitness, as measured by maximal O2 uptake, an inverse and linear association was observed between aerobic fitness and F2-isoprostane, suggesting a training effect on oxidative stress.