The Circulating Milieu Mediates Arterial Dysfunction with Aging: Protection by Habitual Aerobic Exercise

Abstract

Age-related arterial dysfunction (aortic stiffening and endothelial dysfunction) is the key antecedent to cardiovascular diseases. Habitual aerobic exercise largely mitigates arterial dysfunction in mid-life/older (ML/O) adults; however, the mechanisms by which this occurs remain to be fully elucidated. The circulating milieu (bioactive factors in the bloodstream) shifts towards a pro-inflammatory/oxidative state with advancing age but is preserved with habitual aerobic exercise. However, it is unclear if the circulating milieu directly contributes to age-related arterial dysfunction and if habitual aerobic exercise preserves arterial function with aging, in part, by favorably modulating the circulating milieu. PURPOSE: To determine the influence of aging and habitual aerobic exercise on circulating milieu-mediated aortic stiffening and endothelial function. METHODS: Human serum was collected from healthy young (18-29 yr) and ML/O (50+ yr) men and women. Aerobic exercise status was determined by leisure-time physical activity (>60 h/wk). Aortic rings (~1 mm) and common carotid arteries were obtained from young adult (3-4 mo), intervention naïve male and female C57BL/6N mice to assess aortic stiffness and endothelial function, respectively. Arteries were exposed ex vivofor 24-48 hours to 5% sex-matched human serum from one of the following groups: young sedentary (n=9; 4F), ML/O sedentary (n=14; 7F) or ML/O habitually aerobic exercise trained (n=8; 4F). Aortic stiffness was measured as elastic modulus (a measure of intrinsic mechanical wall stiffness). Endothelial function was assessed as endothelium-dependent dilation (EDD) and endothelium-independent dilation (EID) as peak response to acetylcholine and the nitric oxide (NO) donor sodium nitroprusside, respectively. Differences were determined via one-way ANOVA. RESULTS: Aortic Stiffness. Aortic elastic modulus was higher in aorta rings incubated with ML/O sedentary serum compared to young sedentary serum (ML/O sedentary, 4912 ± 588 v. Young sedentary, 3019 ± 522 kPa; p=0.020). Compared with ML/O sedentary serum, aorta rings incubated with ML/O trained serum had lower elastic modulus (2237 ± 426 kPa, p=0.002) which was not different to aorta rings incubated with young sedentary serum (p=0.369). Endothelial Function. Peak EDD was lower in carotid arteries incubated with ML/O sedentary v. young sedentary serum (79 ± 3% v. 92 ± 2%, p=0.001). Compared with ML/O sedentary serum, incubation with ML/O trained serum evoked higher peak EDD (93 ± 1%; p=0.001) that was similar to that produced by Young sedentary serum (p=0.866). There were no group differences in peak EID (p=0.228) suggesting that circulating milieu-induced differences were endothelium-specific and were not attributable to changes in smooth muscle sensitivity to NO. CONCLUSION: These findings suggest that the circulating milieu is a key mechanism by which aging induces arterial dysfunction and by which habitual aerobic exercise training preserves arterial function with aging.

F31 HL165885, R21 AG078408, K99 HL159241, K99/R00 HL151818.