Reduced oxidant stress, increased NO-dependent vasodilatation, and improved endothelial function with voluntary exercise in old mice: another excuse for long walks on the beach.

The study by Durrant and coworkers (2009) in this issue of The Journal of Physiology investigates the effect of aerobic exercise on endothelium-dependent (vaso)dilatation (EDD) in B6D2F1 mice, a model of age-associated endothelial dysfunction (Lesniewski et al. 2009). The authors note that increasing age is a major risk factor for cardiovascular disease (Lakatta & Levy, 2003) that is likely to be mediated via increased oxidative stress and reduced NO levels (Cai & Harrison, 2000; Taddei et al. 2001). Current evidence indicates that habitual aerobic exercise improves EDD in older humans by reducing oxidative stress and increasing NO availability (Seals et al. 2008). The multiple beneficial effects of exercise that the authors report in the older mice are consistent with existing studies in humans, but provide more detailed insight into the potential mechanisms by which habitual aerobic exercise may improve EDD with age and potentially reduce age-associated risks of cardiovascular disease. The study evaluates multiple indices of EDD from the whole animal level to the vascular and enzymatic level in young and old mice with and without access to an exercise wheel for voluntary running. The authors report that voluntary exercise ameliorates the decreased whole body sensitivity to systemic infusion of acetylcholine in conscious older mice. The improvement in whole body acetylcholine sensitivity in older mice was accompanied by a restoration of both the maximum capacity for EDD and the NO-dependent component of EDD in the carotid artery, increased eNOS expression and activation (Ser1177 phosphorylation) in the aorta, and reduced nitrotyrosine levels in the aorta. The beneficial effects of voluntary exercise in the older mice are mediated via effects on both pro-oxidant and antioxidant mechanisms. For example, exercise not only increased total SOD activity, MnSOD activity, and Cu/Zn SOD + ecSOD activity in aortas of the older mice, but also ameliorated the increased expression of the p67 subunit of NADPH oxidase and the increased NADPH oxidase activity in aortas of the older mice. An important and striking observation in this study was that the beneficial effects of voluntary exercise in the older mice occurred even though their exercise levels were only about 10% of those in the younger mice. The importance of endothelial dysfunction and vascular oxidant stress in contributing to cardiovascular morbidity and mortality in humans was strongly emphasized in a recent review (Widlansky et al. 2003) citing 10 different studies showing that the presence of endothelial dysfunction is predictive of future adverse cardiovascular events (including death), and suggesting that evaluation of endothelial function in peripheral arteries may be beneficial in guiding the diagnosis and treatment of cardiovascular disease. In this regard, the results of the present study raise the possibility that voluntary exercise might not only reduce the risk of cardiovascular disease in older asymptomatic humans (see Lakatta and Levy, 2003), but also be beneficial in ameliorating more serious conditions such as peripheral artery disease, which increases with age and is associated with increased cardiovascular morbidity and mortality (McDermott et al. 2008; Sakamoto et al. 2009). The latter possibility is supported by studies showing that antioxidant treatment with glutathione infusion increases pain free walking distance and improves several indicators of microcirculatory and whole bed blood flow in humans with peripheral artery disease (Arosio et al. 2002) and that peripheral artery disease patients completing a supervised exercise training programme show reduced cardiovascular morbidity and mortality (Sakamoto et al. 2009).