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Prevention of age-related endothelial dysfunction by habitual aerobic exercise in healthy humans: possible role of nuclear factor ?B.

ABSTRACT: Habitual aerobic exercise prevents age-related impairments in endothelium-dependent dilation (EDD). We have hypothesized that the pro-inflammatory transcription factor nuclear factor ?B (NF-?B) impairs EDD with sedentary aging, and habitual aerobic exercise prevents this age-related suppression of EDD by NF-?B. To test this hypothesis, we have inhibited NF-?B signalling via oral salsalate administration in healthy older aerobic exercise-trained adults (OT, n=14, 58 ± 2 years), older non-exercising adults (ON, n=16, 61 ± 1 years) and young non-exercising controls (YN, n=8, 23 ± 1 years). Salsalate reduced endothelial cell expression of NF-?B p65 by ~25% in ON (P<0.05) but did not significantly change expression in OT or YN (P>0.05). EDD, assessed by brachial artery flow-mediated dilation (FMD), was improved by salsalate in ON (4.0 ± 0.7% compared with 6.8 ± 0.7%, placebo compared with salsalate, P<0.001) but did not change with salsalate in OT or YN (OT: 7.2 ± 0.7% compared with 7.7 ± 0.6%; YN: 7.6 ± 0.9% compared with 8.1 ± 0.8%; placebo compared with salsalate, P>0.05). Endothelium-independent dilation was not affected by salsalate in any group (P>0.05). In ON, vitamin C infusion improved FMD by ~30% during placebo (P<0.001) but had no affect during salsalate (P>0.05). In OT and YN, vitamin C infusion did not affect FMD during either placebo or salsalate (P>0.05). Salsalate reduced endothelial cell nitrotyrosine content by ~25% and NADPH oxidase p47phox expression by ~30% in ON (P<0.05) but had no effect in OT or YN (P>0.05). Our results suggest that endothelial NF-?B signalling is associated with oxidative stress-related impairment of EDD in healthy non-exercising but not aerobically exercising older adults. This may be a key mechanism by which regular aerobic exercise preserves endothelial function and reduces cardiovascular risk with aging.

SUBMITTER: Walker AE

PROVIDER: S-EPMC4408779 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Prevention of age-related endothelial dysfunction by habitual aerobic exercise in healthy humans: possible role of nuclear factor κB.

Walker Ashley E AE Kaplon Rachelle E RE Pierce Gary L GL Nowlan Molly J MJ Seals Douglas R DR

Clinical science (London, England : 1979) 20141201 11

Habitual aerobic exercise prevents age-related impairments in endothelium-dependent dilation (EDD). We have hypothesized that the pro-inflammatory transcription factor nuclear factor κB (NF-κB) impairs EDD with sedentary aging, and habitual aerobic exercise prevents this age-related suppression of EDD by NF-κB. To test this hypothesis, we have inhibited NF-κB signalling via oral salsalate administration in healthy older aerobic exercise-trained adults (OT, n=14, 58 ± 2 years), older non-exercisi ...[more]

PMID: 24947434

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Project description:Cellular senescence is emerging as a key mechanism of age-related vascular endothelial dysfunction, but evidence in healthy humans is lacking. Moreover, the influence of lifestyle factors such as habitual exercise on endothelial cell (EC) senescence is unknown. We tested the hypothesis that EC senescence increases with sedentary, but not physically active, aging and is associated with vascular endothelial dysfunction. Protein expression (quantitative immunofluorescence) of p53, a transcription factor related to increased cellular senescence, and the cyclin-dependent kinase inhibitors p21 and p16 were 116%, 119%, and 128% greater (all P < 0.05), respectively, in ECs obtained from antecubital veins of older sedentary (60 ± 1 yr, n = 12) versus young sedentary (22 ± 1 yr, n = 9) adults. These age-related differences were not present (all P > 0.05) in venous ECs from older exercising adults (57 ± 1 yr, n = 13). Furthermore, venous EC protein levels of p53 (r = -0.49, P = 0.003), p21 (r = -0.38, P = 0.03), and p16 (r = -0.58, P = 0.002) were inversely associated with vascular endothelial function (brachial artery flow-mediated dilation). Similarly, protein expression of p53 and p21 was 26% and 23% higher (both P < 0.05), respectively, in ECs sampled from brachial arteries of healthy older sedentary (63 ± 1 yr, n = 18) versus young sedentary (25 ± 1 yr, n = 9) adults; age-related changes in arterial EC p53 and p21 expression were not observed (P > 0.05) in older habitually exercising adults (59 ± 1 yr, n = 14). These data indicate that EC senescence is associated with sedentary aging and is linked to endothelial dysfunction. Moreover, these data suggest that prevention of EC senescence may be one mechanism by which aerobic exercise protects against endothelial dysfunction with age.NEW & NOTEWORTHY Our study provides novel evidence in humans of increased endothelial cell senescence with sedentary aging, which is associated with impaired vascular endothelial function. Furthermore, our data suggest an absence of age-related increases in endothelial cell senescence in older exercising adults, which is linked with preserved vascular endothelial function.

Project description:Habitual aerobic exercise enhances physiological function and reduces risk of morbidity and mortality throughout life, but the underlying molecular mechanisms are largely unknown. The circulating proteome reflects the intricate network of physiological processes maintaining homeostasis and may provide insight into the molecular transducers of the health benefits of physical activity. In this exploratory study, we assessed the plasma proteome (SOMAscan proteomic assay; 1,129 proteins) of healthy sedentary or aerobic exercise-trained young women and young and older men ( n = 47). Using weighted correlation network analysis to identify clusters of highly co-expressed proteins, we characterized 10 distinct plasma proteomic modules (patterns). In healthy young (24 ± 1 yr) men and women, 4 modules were associated with aerobic exercise status and 1 with participant sex. In healthy young and older (64 ± 2 yr) men, 5 modules differed with age, but 2 of these were partially preserved at young adult levels in older men who exercised; among all men, 4 modules were associated with exercise status, including 3 of the 4 identified in young adults. Exercise-linked proteomic patterns were related to pathways involved in wound healing, regulation of apoptosis, glucose-insulin and cellular stress signaling, and inflammation/immune responses. Importantly, several of the exercise-related modules were associated with physiological and clinical indicators of healthspan, including diastolic blood pressure, insulin resistance, maximal aerobic capacity, and vascular endothelial function. Overall, these findings provide initial insight into circulating proteomic patterns modulated by habitual aerobic exercise in healthy young and older adults, the biological processes involved, and their relation to indicators of healthspan. NEW & NOTEWORTHY This is the first study to assess the relation between plasma proteomic patterns and aerobic exercise status in healthy adults. Weighted correlation network analysis identified 10 distinct proteomic modules, including 5 patterns specific for exercise status. Additionally, 5 modules differed with aging in men, two of which were preserved in older exercising men. Exercise-associated modules included proteins related to inflammation, stress pathways, and immune function and correlated with clinical and physiological indicators of healthspan.

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Prevention of age-related endothelial dysfunction by habitual aerobic exercise in healthy humans: possible role of nuclear factor ?B.

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Prevention of age-related endothelial dysfunction by habitual aerobic exercise in healthy humans: possible role of nuclear factor κB.

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