Key points 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 The results demonstrate that consuming a Western diet accelerates and exacerbates vascular ageing across the lifespan in sedentary mice They also show that lifelong voluntary aerobic exercise has remarkable protective effects on vascular function throughout the lifespan, in the setting of ageing alone, as well as ageing compounded by Western diet consumption Overall, the results 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 dilatation, EDD) and aortic stiffening (increased aortic pulse wave velocity, aPWV). In humans, vascular ageing 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. Ageing impaired nitric oxide‐mediated EDD (peak EDD 88 ± 12% 6 months P = 0.003 vs. 59 ± 9% 27 months NC‐SED), which was accelerated by WD (60 ± 18% 6 months WD‐SED). In NC mice, aPWV increased 32% with age (423 ± 13 cm/s at 24 months P < 0.001 vs. 321 ± 12 cm/s at 6 months) 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 months, 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.

Aging is associated with stiffening of the large elastic arteries and consequent increases in systolic blood pressure (SBP), which together increase cardiovascular disease risk; however, the upstream mechanisms are incompletely understood. Using complementary translational approaches in mice and humans, we investigated the role of the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO) in age-related aortic stiffening and increased SBP. Aortic stiffness was measured using carotid-femoral or aortic pulse wave velocity (PWV) in humans and mice, respectively. Study 1: Plasma TMAO concentrations were elevated ( P <0.001) in healthy middle-aged to older (6.3±5.8 µmol/L) versus young (1.8±1.4 µmol/L) humans and positively related to carotid-femoral PWV ( r 2 =0.15, P <0.0001) and SBP ( r 2 =0.09, P <0.001), independent of traditional cardiovascular risk factors. Study 2: Dietary supplementation with TMAO increased aPWV in young mice and exacerbated the already elevated aPWV of old mice, accompanied by increases in SBP of ≈10 mm Hg in both groups. TMAO-supplemented versus control-fed mice also had higher intrinsic mechanical stiffness of the aorta (stress-strain testing) associated with higher aortic abundance of advanced glycation end-products, which form crosslinks between structural proteins to promote aortic stiffening. Study 3: Ex vivo incubation of aortic rings with TMAO increased intrinsic stiffness, which was attenuated by the advanced glycation end-products crosslink breaker alagebrium and prevented by inhibition of superoxide signaling. TMAO induces aortic stiffening and increases SBP via formation of advanced glycation end-products and superoxide-stimulated oxidative stress, which together increase intrinsic wall stiffness. Increases in circulating TMAO with aging represent a novel therapeutic target for reducing risk of aortic stiffening-related clinical disorders.

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We assessed the efficacy of oral supplementation with the flavanoid apigenin on arterial function during aging and identified critical mechanisms of action. Young (6 months) and old (27 months) C57BL/6N mice (model of arterial aging) consumed drinking water containing vehicle (0.2% carboxymethylcellulose; 10 young, 7 old) or apigenin (0.5 mg/ml in vehicle; 10 young, 9 old) for 6 weeks. In vehicle-treated animals, isolated carotid artery endothelium-dependent dilation (EDD), bioassay of endothelial function, was impaired in old vs young (70±9 vs 92±1 %, P<0.0001) due to reduced nitric oxide (NO) bioavailability. Old mice had greater arterial reactive oxygen species (ROS) production and oxidative stress (higher nitrotyrosine) associated with greater nicotinamide adenine dinucleotide phosphate oxidase (oxidant enzyme) and lower superoxide dismutase 1 and 2 (antioxidant enzymes); ex vivo administration of TEMPOL (antioxidant) restored EDD to young levels, indicating ROS-mediated suppression of EDD. Old animals also had greater aortic stiffness as indicated by higher aortic pulse wave velocity (PWV, 434±9 vs 346±5 cm/sec, P<0.0001) due to greater intrinsic aortic wall stiffness associated with lower elastin levels and higher collagen, advanced glycation end-products (AGEs) and pro-inflammatory cytokine abundance. In old mice, apigenin restored EDD (96±2%) by increasing NO bioavailability, normalized arterial ROS, oxidative stress and antioxidant expression, and abolished ROS inhibition of EDD. Moreover, apigenin prevented foam cell formation in vitro (initiating step in atherosclerosis) and mitigated age-associated aortic stiffening (PWV 373±5 cm/sec) by normalizing aortic intrinsic wall stiffness, collagen, elastin, AGEs, and inflammation. Thus, apigenin is a promising therapeutic for arterial aging.

Cardiovascular diseases (CVD) are the leading cause of death worldwide and aging is the primary risk factor for CVD. The development of vascular dysfunction, including endothelial dysfunction and stiffening of the large elastic arteries (i.e., the aorta and carotid arteries), contribute importantly to the age-related increase in CVD risk. Vascular aging is driven in large part by oxidative stress, which reduces bioavailability of nitric oxide and promotes alterations in the extracellular matrix. A key upstream driver of vascular oxidative stress is age-associated mitochondrial dysfunction. This review will focus on vascular mitochondria, mitochondrial dysregulation and mitochondrial reactive oxygen species (ROS) production and discuss current evidence for prevention and treatment of vascular aging via lifestyle and pharmacological strategies that improve mitochondrial health. We will also identify promising areas and important considerations (‘research gaps’) for future investigation.