Lifelong voluntary aerobic exercise prevents age- and Western diet-induced vascular dysfunction, mitochondrial oxidative stress, and inflammation in mice.

KEY POINTS Overall, the results of the present study: Establish the temporal pattern of age-related vascular dysfunction across the adult lifespan in sedentary mice consuming a non-Western diet, and the underlying mechanisms; Demonstrate that consuming a Western diet accelerates and exacerbates vascular aging across the lifespan in sedentary mice; Show that lifelong voluntary aerobic exercise has remarkable protective effects on vascular function throughout the lifespan, in the setting of aging alone, as well as aging compounded by Western diet consumption; Indicate that amelioration of mitochondrial oxidative stress and inflammation are key mechanisms underlying the voluntary aerobic exercise-associated preservation of vascular function across the lifespan in both the presence and absence of a Western dietary pattern. ABSTRACT Advancing age is the major risk factor for cardiovascular diseases, driven largely by vascular endothelial dysfunction (impaired endothelium-dependent dilation, EDD) and aortic stiffening (increased aortic pulse wave velocity, aPWV). In humans, vascular aging occurs in the presence of differences in diet and physical activity, but the interactive effects of these factors are unknown. We assessed carotid artery EDD and aPWV across the lifespan in mice consuming standard (normal) low-fat chow (NC) or a high-fat/high-sucrose Western diet (WD) in the absence (sedentary, SED) or presence (voluntary wheel running, VWR) of aerobic exercise. Aging impaired nitric oxide-mediated EDD (peak EDD 88±12% 6 mo. P = 0.003 vs. 59±9% 27 mo. NC-SED), which was accelerated by WD (60±18% 6 mo. WD-SED). In NC mice, aPWV increased 32% with age (423±13 cm/sec 24 mo. P < 0.001 vs. 321±12 cm/sec 6 mo.) and absolute values were an additional ∼10 % higher at any age in WD mice (P = 0.042 vs. NC-SED). Increases in aPWV with age in NC and WD mice were associated with 30-65% increases in aortic intrinsic wall stiffness (6 vs. 19-27 mo., P = 0.007). Lifelong aerobic exercise prevented age- and WD- related vascular dysfunction across the lifespan, and this protection appeared to be mediated by mitigation of vascular mitochondrial oxidative stress and inflammation. Our results depict the temporal impairment of vascular function over the lifespan in mice, acceleration and exacerbation of that dysfunction with WD consumption, the remarkable protective effects of voluntary aerobic exercise, and the underlying mechanisms. This article is protected by copyright. All rights reserved.