Edward F. Adolph Distinguished Lecture: The remarkable anti-aging effects of aerobic exercise on systemic arteries

Abstract

Cardiovascular diseases (CVD) remain the leading cause of morbidity and mortality in modern societies, and advancing age is the major risk factor for CVD. Arterial dysfunction, characterized by large elastic artery stiffening and endothelial dysfunction, is the key event leading to age-associated CVD. Our work shows that regular aerobic exercise inhibits large elastic artery stiffening with aging (optimizes arterial compliance) and preserves endothelial function. Importantly, among previously sedentary late middle-aged and older adults, aerobic exercise improves arterial stiffness and enhances endothelial function in most groups and, therefore, also can be considered a treatment for age-associated arterial dysfunction. The mechanisms by which regular aerobic exercise destiffens large elastic arteries are incompletely understood, but existing evidence suggests that reductions in oxidative stress associated with decreases in both adventitial collagen (fibrosis) and advanced glycation end-products (structural protein cross-linking molecules), play a key role. Aerobic exercise preserves endothelial function with aging by maintaining nitric oxide bioavailability via suppression of excessive superoxide-associated oxidative stress, and by inhibiting the development of chronic low-grade vascular inflammation. Recent work from our laboratory supports the novel hypothesis that aerobic exercise may exert these beneficial effects by directly inducing protection to aging arteries against multiple adverse factors to which they are chronically exposed. Regular aerobic exercise should be viewed as a "first line" strategy for prevention and treatment of arterial aging and a vital component of a contemporary public health approach for reducing the projected increase in population CVD burden.

Keywords: arterial stiffness; endothelial dysfunction; inflammation; oxidative stress.

Copyright © 2014 the American Physiological Society.

Figures

Fig. 1.

Aging, vascular dysfunction, and cardiovascular disease (CVD) risk. Aging causes increased risk of developing CVDs in large part through the development of arterial dysfunction, characterized in part by vascular endothelial dysfunction and stiffening of large elastic arteries (aorta and carotid arteries). As such, evidence-based lifestyle, pharmaceutical, and nutraceutical strategies that either delay/minimize/prevent arterial aging, or, in late middle-aged/older adults who already demonstrate features of vascular aging, improve arterial function and reduce the risk of CVD, are of high biomedical research priority.

Fig. 2.

Aging, aortic pulse wave velocity, and regular aerobic exercise. Aortic (femoral to carotid artery) pulse wave velocity, a measure of aortic stiffness, is greater in healthy postmenopausal compared with premenopausal sedentary women, but not significantly different in premenopausal and postmenopausal endurance exercise-trained women. These and other findings support the concept that regular aerobic lessens/prevents aortic stiffing with aging in healthy adult humans. *P < 0.05 vs. other groups. Data are from Tanaka et al. (75).

Fig. 3.

Aging, carotid artery compliance, and regular aerobic exercise. A: carotid artery compliance is lower in healthy older men and women compared with young controls. However, the age-associated difference in carotid compliance in aerobically exercising (Ex) adults is only ∼50% as great as that observed in their nonexercising (non-Ex) peers. *P < 0.05 vs. young. **P < 0.05 vs. older non-Ex. B: carotid artery compliance is increased by ∼30% after 12 wk of moderate-intensity aerobic exercise (brisk walking) in previously sedentary late middle-aged/older men and women. *P < 0.05 vs. preexercise training. Data are from Moreau et al. (51) and Tanaka et al. (76).

Fig. 4.

Aging, types of aerobic exercise, and large elastic artery stiffness. Differences in carotid artery compliance (CC) are compared with late middle-aged/older healthy untrained (non-Ex) controls in age-matched groups of (left to right) solely resistance Ex adults, runners, swimmers, and rowers. Groups performing some type of aerobic exercise all have greater carotid compliance than non-Ex controls, whereas solely resistance exercise-trained adults have lower compliance. Data are from DeVan and Seals (14), based on data from Refs. , , .

Fig. 5.

Aging, aerobic exercise, and large elastic artery collagen. Carotid artery collagen I expression is greater in old control (non-Ex) compared with young controls due to greater collagen in the adventitial layer. Voluntary wheel running (VR) for 10–14 wk in old mice reverses carotid artery collagen I to levels at or below those of young controls. *P < 0.05 vs. young. Data are from Fleenor et al. (22).

Fig. 6.

Aging, aerobic exercise, and microvascular endothelial function. A: forearm blood flow (FBF) responses to acetylcholine (ACh) are impaired in older vs. young Non-Ex healthy men. B: FBF to ACh does not differ in older vs. young endurance exercise-trained men. C: FBF to ACh is improved by 12 wk of aerobic exercise in older previously Non-Ex men. D: mean peak FBF to ACh is lower in healthy Non-Ex older men (Older Before) vs. combined young Non-Ex and trained men (Young), older trained men (Older Trained), and older Non-Ex men after aerobic exercise training (Older After) (left). Group differences in mean peak FBF to ACh are abolished under conditions of nitric oxide inhibition using NG monomethyl-l-arginine (l-NMMA) (right). *P < 0.05 vs. other group(s) or condition(s). FAV, forearm tissue volume. Data are from DeSouza et al. (12) and Taddei et al. (74).

Fig. 7.

Aging, aerobic exercise, and macrovascular endothelial function. A: brachial artery flow-mediated dilation (FMD) is impaired in older vs. young Non-Ex healthy men, but is preserved in older aerobically Ex men. B: brachial artery FMD is improved by 8 wk of aerobic exercise in older previously Non-Ex men. *P < 0.05 vs. other group(s) or condition. Δ, Change. Data are from Eskurza et al. (20) and Pierce et al. (59).

Fig. 8.

Aging, aerobic exercise, estrogen status, and endothelial function. In estrogen-deficient postmenopausal women, 12 wk of aerobic exercise did not improve brachial artery FMD, unless preceded by estrogen replacement treatment (ET) using oral or transdermal (Trans) estradiol (E2). These results suggest that estrogen sufficiency may be required to induce improvements in endothelial function in at least some postmenopausal women. *P < 0.05 vs. baseline. **P < 0.05 vs. estrogen or placebo. Data are from Moreau et al. (53).

Fig. 9.

Mechanisms of aging and aerobic exercise on endothelial function. Aging induces endothelial dysfunction via vascular oxidative stress and inflammation involving excessive superoxide (O2·−) production as modulated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, superoxide dismutase (SOD), uncoupling of endothelial nitric oxide synthase (eNOS), and other mechanisms (e.g., dysfunctional mitochondria). Excessive superoxide causes peroxynitrite formation (ONOO−) and protein oxidation (nitrotyrosine), as well as activation of nuclear factor-κB (NF-κB) and induction of inflammatory cytokines.

Fig. 10.

Aging, aerobic exercise, and arterial oxidative stress. A: nitrotyrosine, a cellular marker of oxidative stress, is markedly increased with sedentary aging in whole aorta of mice (left) and endothelial cells sampled from the brachial artery of healthy men (right); this age-associated increase in nitrotyrosine is reversed by 10–14 wk of voluntary wheel (Vol) running in old mice and is not observed in older men who regularly perform aerobic Ex. B: similarly, expression of the oxidant enzyme NADPH oxidase is increased with sedentary aging, but reversed/prevented by voluntary aerobic exercise in both mice (left) and humans (right). *P < 0.05 vs. the other groups. AU, arbitrary units. Data are from Durrant et al. (17) and Pierce et al. (58).

Fig. 11.

Aging, aerobic exercise, and arterial SOD enzyme defenses. A: total activity of the antioxidant enzyme SOD and the activities of the manganese (Mn; mitochondrial) and copper-zinc + extracellular (CuZn/ec) SOD isoforms are increased in old mice that engage in VR for 10–14 wk. B and C: MnSOD expression in endothelial cells obtained from the brachial artery and the activity of circulating ecSOD of healthy men are decreased in older sedentary (Non-Ex), but not older Ex subjects. *P < 0.05 vs. the other groups. Data are from Durrant et al. (17) and Pierce et al. (58).

Fig. 12.

Aging, aerobic exercise, and arterial inflammation. Aortic expression of the inflammatory cytokines interleukin-6 (IL-6), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) increases with sedentary aging in mice, but this effect is reversed by 10–14 wk of voluntary (Vol) running in old animals. *P < 0.05 vs. the other groups. Data are from Lesniewski et al. (41).

Fig. 13.

Aging, aerobic exercise, and inflammatory suppression of endothelial function. Brachial artery FMD is improved in sedentary, but not aerobically Ex, older healthy adults in response to short-term inhibition of NF-κB activity with oral salsalate treatment. This suggests that the enhanced baseline brachial artery FMD of older Ex adults is associated with an absence of the tonic NF-kB-related inhibition of endothelial function seen with sedentary aging. *P < 0.05 vs. placebo. Data are from Walker et al. (82).

Fig. 14.

Aging, aerobic exercise, and oxidative/inflammatory gene expression. Expression of genes associated with oxidative stress and inflammation, including receptor for advanced glycation end-products (RAGE), NADPH oxidase (p47 subunit) and monocyte chemoattractant protein-1 (MCP-1), are increased with sedentary aging in peripheral blood mononuclear cells (PBMCs) of healthy adults; these increases are reversed in older subjects by ∼8 wk of regular aerobic exercise (EX). *P < 0.05 vs. young. **P < 0.05 vs. before exercise training. Data are from Gano et al. (26).

Fig. 15.

Aging, aerobic exercise, and “resistance” to cardiovascular risk factors. Brachial artery FMD is reduced with sedentary (Sed) aging in healthy adults with normal fasting blood glucose (NFG; P < 0.05 vs. young. **P < 0.05 vs. old NFG. Data are from DeVan et al. (13).