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Endothelial cell senescence with aging in healthy humans: prevention by habitual exercise and relation to vascular endothelial function.

ABSTRACT: 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.

SUBMITTER: Rossman MJ

PROVIDER: S-EPMC5792201 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Endothelial cell senescence with aging in healthy humans: prevention by habitual exercise and relation to vascular endothelial function.

Rossman Matthew J MJ Kaplon Rachelle E RE Hill Sierra D SD McNamara Molly N MN Santos-Parker Jessica R JR Pierce Gary L GL Seals Douglas R DR Donato Anthony J AJ

American journal of physiology. Heart and circulatory physiology 20170929 5

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 f ...[more]

PMID: 28971843

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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.

Project description:Age-related vascular endothelial dysfunction is a major antecedent to cardiovascular diseases. We investigated whether increased circulating levels of the gut microbiome-generated metabolite trimethylamine-N-oxide induces endothelial dysfunction with aging. In healthy humans, plasma trimethylamine-N-oxide was higher in middle-aged/older (64±7 years) versus young (22±2 years) adults (6.5±0.7 versus 1.6±0.2 µmol/L) and inversely related to brachial artery flow-mediated dilation (r2=0.29, P<0.00001). In young mice, 6 months of dietary supplementation with trimethylamine-N-oxide induced an aging-like impairment in carotid artery endothelium-dependent dilation to acetylcholine versus control feeding (peak dilation: 79±3% versus 95±3%, P<0.01). This impairment was accompanied by increased vascular nitrotyrosine, a marker of oxidative stress, and reversed by the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl. Trimethylamine-N-oxide supplementation also reduced activation of endothelial nitric oxide synthase and impaired nitric oxide-mediated dilation, as assessed with the nitric oxide synthase inhibitor L-NAME (NG-nitro-L-arginine methyl ester). Acute incubation of carotid arteries with trimethylamine-N-oxide recapitulated these events. Next, treatment with 3,3-dimethyl-1-butanol for 8 to 10 weeks to suppress trimethylamine-N-oxide selectively improved endothelium-dependent dilation in old mice to young levels (peak: 90±2%) by normalizing vascular superoxide production, restoring nitric oxide-mediated dilation, and ameliorating superoxide-related suppression of endothelium-dependent dilation. Lastly, among healthy middle-aged/older adults, higher plasma trimethylamine-N-oxide was associated with greater nitrotyrosine abundance in biopsied endothelial cells, and infusion of the antioxidant ascorbic acid restored flow-mediated dilation to young levels, indicating tonic oxidative stress-related suppression of endothelial function with higher circulating trimethylamine-N-oxide. Using multiple experimental approaches in mice and humans, we demonstrate a clear role of trimethylamine-N-oxide in promoting age-related endothelial dysfunction via oxidative stress, which may have implications for prevention of cardiovascular diseases.

Dataset Information

Endothelial cell senescence with aging in healthy humans: prevention by habitual exercise and relation to vascular endothelial function.

Publications

Endothelial cell senescence with aging in healthy humans: prevention by habitual exercise and relation to vascular endothelial function.

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