Ageing, exercise and cardiovascular health: good and bad news

Ageing is associated with increased oxidative stress, and oxidative stress contributes to several ageing-related changes, among them endothelial dysfunction with reduced NO release and bioavailability. NO not only regulates vascular tone, but also inhibits platelet aggregation, leukocyte adhesion to the endothelial surface, and vascular smooth muscle proliferation, which are essential to maintain long term vascular health. Studies in the early 1990s showed that age and hypercholesterolaemia are independent predictors of reduced endothelium-dependent vasorelaxation to acetylcholine in human coronary resistance vessels and forearm resistance vessels. This impaired endothelial function occurs even in healthy humans without signs of atherosclerosis, diabetes, hypercholesterolaemia, or hypertension and affects most vascular beds. It was suggested that the reduction in endothelial function is mediated by a progressive reduction of NO bioavailability with ageing, based on the reduced vasoconstricting effect of NG-monomethyl-l-arginine (l-NMMA), attenuated flow-mediated vasodilatation (NO dependent) and reduced vasodilator response to acetylcholine infusion in the presence of nitric oxide synthase (NOS) inhibition (Taddei et al. 2001; Eskurza et al. 2004). This contrasts with a preserved endothelium-independent vasodilatation response in the elderly (Taddei et al. 2001), i.e. the response of the smooth muscle cells to NO is not altered. Based on the fact that antioxidant infusion restores immediately endothelium-dependent vasodilatation in the forearm vasculature combined with the known NO-scavenging properties of free radicals, it was postulated that the main mechanism by which ageing reduces endothelium function is by reducing NO bioavailability. However, direct evidence was lacking. In this issue of The Journal of Physiology, Nyberg et al. (2012) have shown by measuring NO metabolites in the circulation and muscle interstitium, combined with the assessment of NOS protein content in the musculature, that NO bioavailability is reduced in the systemic circulation and muscle interstitial space of sedentary aged humans. The good news is that these changes are not observed in lifelong physically active men. However, 24 weeks of aerobic training, increasing by 15%, failed to significantly increase venous NO metabolites and forearm flow mediated vasodilatation in older men and women (Brinkley et al. 2009). Despite leg training, in the study of Brinkley et al. (2009), forearm flow mediated vasodilatation should have been improved (Green et al. 2004). In fact, Hambrecht et al. (1998) found increased acetylcholine-induced blood flow in the femoral artery after 24 weeks of aerobic training in chronic heart failure patients (mean age = 56 years). In contrast, immobilization increases oxidative stress and impairs endothelial function (Zhang et al. 2009). The role played by NO in exercise hyperaemia has been the subject of some debate. Increasing NO availability has been reported to enhance forearm blood flow during exercise (Crecelius et al. 2010). In their article Nyberg et al. (2012) provide robust evidence for a secondary role, if any, of NO in exercise-induced hyperaemia during leg exercise, in agreement with others (Radegran & Hellsten, 2000). Increasing NO bioavailability had no influence on femoral arterial blood flow in any of the experimental groups; this was supported by an unchanged oxygen extraction across the exercising leg, a variable that is very sensitive to changes in blood flow. Thus, these results should be reconciled with the reported increased forearm blood flow during exercise with ascorbate (Eskurza et al. 2004; Kirby et al. 2009; Crecelius et al. 2010). Regional differences in the regulation of vascular tone or functional sympatholysis could explain this apparent discrepancy between forearm and leg muscles in humans. Increased NO bioavailability could facilitate functional sympatholysis, and maybe it does in the forearm. Since sympatholysis is impaired with sedentary ageing, increased NO bioavailability should have increased blood flow at least in the sedentary older people, but this was not the case. Thus, the study by Nyberg et al. (2012) does not give support for endothelial-released NO as playing a role in functional sympatholysis. Nyberg et al. (2012) also report that during submaximal leg extension exercise at 12 W, oxygen uptake was lower, and lactate release greater, in sedentary older men than in their active counterparts. Since lactate is produced at equimolar rates with H+, a greater amount of H+ should have been produced by the older sedentary subjects. Increase acidification during exercise is associated with higher oxidative stress (Morales-Alamo et al. 2012), and thus increased free radical production during low intensity exercise may be an additional contributing factor to the reduction of NO bioavailability with ageing, which deserves further research. In summary, the study of Nyberg et al. (2012) provides strong evidence for regular exercise as a mechanism to preserve endothelial function in the leg muscles, to increase systemic NO bioavailability and to enhance the endothelial cell capacity to produce NO. However, this does not restore the reduced hyperaemic response to exercise associated to ageing. Increasing NO bioavailability does not seem to influence O2 offloading from the haemoglobin in older humans with endothelial dysfunction. New studies should also focus on central haemodynamic factors and endothelial cell reactivity to potential NO-releasing mechanisms. One possibility is that advanced glycosylation end products, which increase with age, may contribute to decreased endothelium-dependent vasodilatation by inducing NO resistance (Soro-Paavonen et al. 2010).