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 < 0.05), respectively, in ECs obtained from antecubital veins of older sedentary (60 ± 1 yr, = 12) versus young sedentary (22 ± 1 yr, = 9) adults. These age-related differences were not present (all > 0.05) in venous ECs from older exercising adults (57 ± 1 yr, = 13). Furthermore, venous EC protein levels of p53 ( = -0.49, = 0.003), p21 ( = -0.38, = 0.03), and p16 ( = -0.58, = 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 < 0.05), respectively, in ECs sampled from brachial arteries of healthy older sedentary (63 ± 1 yr, = 18) versus young sedentary (25 ± 1 yr, = 9) adults; age-related changes in arterial EC p53 and p21 expression were not observed ( > 0.05) in older habitually exercising adults (59 ± 1 yr, = 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. 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.

The role of senescence, telomere dysfunction and shelterin in vascular aging

“…More recently, we have demonstrated that arteries from older healthy adults and hypertensive patients have greater expression of p21, a marker of senescence, as well as the SASP pro‐inflammatory phenotype . Likewise, endothelial cells sampled from healthy older adults have greater expression of the senescence markers p21 and p16, both of which are correlated with blunted endothelial function . In contrast, older adults that perform habitual exercise (a vasoprotective lifestyle) have normalized endothelial senescent markers and endothelial function .…”

“…22 In contrast, older adults that perform habitual exercise (a vasoprotective lifestyle) have normalized endothelial senescent markers and endothelial function. 22 Lastly, in preclinical rodent models, drugs that remove senescent cells, known as senolytics, improve arterial function in older mice (3 months of treatment starting at 24 months). 23 Therefore, senescent cells are a viable candidate for explaining the upregulation and maintenance of both inflammation and oxidative stress that are seen in aged vessels ( Figure 1).…”

Calorie Restriction Curbs Proinflammation That Accompanies Arterial Aging, Preserving a Youthful Phenotype

“…The rate of arterial biological aging or systemic aging can be modulated by changes in lifestyle, for example, food consumption, cessation of smoking, and physical exercise 11, 12, 13, 14, 15. Calorie restriction (CR) effectively reduces the morbidity and mortality of Fischer 344 rats, which is related to a retardation of arterial stiffening, an improvement of arterial distensibility, and an eventual prolongation of the life span 16.…”

Inflammation as a mediator of arterial ageing

“…Habitually exercising older adults exhibit lower PWV compared with their sedentary counterparts, and improvements in PWV induced by inhibition of NFκB occur only in sedentary older adults (Jablonski et al., ), suggesting that NFκB activity is restrained by chronic exercise. Habitually exercising older adults also exhibit blunted endothelial senescence and production of SASP components compared with their sedentary counterparts (Rossman et al., ). In a cross‐sectional study, exercise‐trained postmenopausal women exhibited lower CRP when compared with sedentary postmenopausal women; however, the exercise‐trained women did not exhibit improved EDD in either the macro‐ or microvasculature of the forearm (Santos‐Parker et al., ).…”

“…Building on the base of correlational evidence, two seminal studies directly demonstrate the upregulation of NF B in both venous and arterial endothelial cells of older humans (Donato et al, 2007;Donato, Black, Jablonski, Gano, & Seals, 2008). Furthermore, venous endothelial cells from older adults exhibit increased IL-6, TNF-and the pro-inflammatory chemokine CCL2 (Morgan et al, 2013;Rossman et al, 2017). The upregulation of these endothelial inflammatory factors that are components of the SASP might be attributable to increased age-associated arterial cell senescence (Morgan et al, 2013;Rossman et al, 2017).…”