Rossman Matthew J, Kaplon Rachelle E, Hill Sierra D, McNamara Molly N, Santos-Parker Jessica R, Pierce Gary L, Seals Douglas R, Donato Anthony J
Integrative Physiology, University of Colorado Boulder, Boulder, Colorado;
Integrative Physiology, University of Colorado Boulder, Boulder, Colorado.
Am J Physiol Heart Circ Physiol. 2017 Nov 1;313(5):H890-H895. doi: 10.1152/ajpheart.00416.2017. Epub 2017 Sep 29.
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.
细胞衰老正逐渐成为与年龄相关的血管内皮功能障碍的关键机制，但在健康人群中的证据尚缺。此外，诸如习惯性运动等生活方式因素对内皮细胞（EC）衰老的影响尚不清楚。我们检验了以下假设：EC衰老随久坐不动而非积极运动的衰老过程而增加，且与血管内皮功能障碍相关。在从老年久坐不动的成年人（60±1岁，n = 12）与年轻久坐不动的成年人（22±1岁，n = 9）肘前静脉获取的EC中，与细胞衰老增加相关的转录因子p53以及细胞周期蛋白依赖性激酶抑制剂p21和p16的蛋白表达（定量免疫荧光法）分别高出116%、119%和128%（均P<0.05）。在老年运动成年人（57±1岁，n = 13）的静脉EC中未出现这些与年龄相关的差异（均P>0.05）。此外，静脉EC中p53（r = -0.49，P = 0.003）、p21（r = -0.38，P = 0.03）和p16（r = -0.58，P = 0.002）的蛋白水平与血管内皮功能（肱动脉血流介导的扩张）呈负相关。同样，在从健康老年久坐不动的成年人（63±1岁，n = 18）与年轻久坐不动的成年人（25±1岁，n = 9）肱动脉采集的EC中，p53和p21的蛋白表达分别高出26%和23%（均P<0.05）；在老年习惯性运动的成年人（59±1岁，n = 14）中未观察到动脉EC中p53和p21表达的与年龄相关变化（P>0.05）。这些数据表明，EC衰老与久坐衰老相关，并与内皮功能障碍有关。此外，这些数据表明，预防EC衰老可能是有氧运动预防随年龄增长出现的内皮功能障碍的一种机制。我们的研究在人类中提供了新的证据，表明久坐衰老会导致内皮细胞衰老增加，这与血管内皮功能受损有关。此外，我们的数据表明，老年运动成年人中内皮细胞衰老没有与年龄相关的增加，这与保留的血管内皮功能有关。
