Physical Exercise Prevents Cellular Senescence in Circulating Leukocytes and in the Vessel Wall

Abstract

Background-The underlying molecular mechanisms of the vasculoprotective effects of physical exercise are incompletely understood. Telomere erosion is a central component of aging, and telomere-associated proteins regulate cellular senescence and survival. This study examines the effects of exercising on vascular telomere biology and endothelial apoptosis in mice and the effects of long-term endurance training on telomere biology in humans. Methods and Results-C57/Bl6 mice were randomized to voluntary running or no running wheel conditions for 3 weeks.Exercise upregulated telomerase activity in the thoracic aorta and in circulating mononuclear cells compared with sedentary controls, increased vascular expression of telomere repeat-binding factor 2 and Ku70, and reduced the expression of vascular apoptosis regulators such as cell-cycle-checkpoint kinase 2, p16, and p53. Mice preconditioned by voluntary running exhibited a marked reduction in lipopolysaccharide-induced aortic endothelial apoptosis. Transgenic mouse studies showed that endothelial nitric oxide synthase and telomerase reverse transcriptase synergize to confer endothelial stress resistance after physical activity. To test the significance of these data in humans, telomere biology in circulating leukocytes of young and middle-aged track and field athletes was analyzed. Peripheral blood leukocytes isolated from endurance athletes showed increased telomerase activity, expression of telomere-stabilizing proteins, and downregulation of cell-cycle inhibitors compared with untrained individuals. Long-term endurance training was associated with reduced leukocyte telomere erosion compared with untrained controls. Conclusions-Physical activity regulates telomere-stabilizing proteins in mice and in humans and thereby protects from stress-induced vascular apoptosis. (Circulation. 2009;120:2438-2447.)Key Words: aging Ⅲ exercise Ⅲ nitric oxide synthase Ⅲ prevention Ⅲ telomeres P hysical training is associated with improvements in exercise capacity, blood pressure regulation, insulin sensitivity, abdominal fat reduction, lipid profile, and psychosocial, hemodynamic, and inflammatory parameters. These effects contribute to an augmentation of endothelial function, delayed atherosclerotic lesion progression, and enhanced vascular collateralization in patients with diabetes mellitus, coronary artery disease, and chronic heart failure. However, despite the wealth of evidence, our understanding of the underlying molecular mechanisms, especially with regard to cellular survival and senescence, is limited. Clinical Perspective on p 2447Aging is a predominant and independent risk factor for the development of atherosclerotic diseases. Vascular aging is characterized by impaired endothelial function and arterial stiffening. 1 On the cellular level, telomere biology is a central regulator of the aging process. Telomeres and their regulatory proteins compose t-loop structures at both ends of eukaryotic chromosomes and protect the genome from degradation during repetitive cellul...

Moderate and intense exercise lifestyles attenuate the effects of aging on telomere length and the survival and composition of T cell subpopulations

“…Comparisons among these studies are limited by differences in study design, including the immunological parameters assessed and the cohorts analyzed, which differed not only in age and gender but also in the type, intensity, and regularity of physical activity. Our results are consistent with those of Werner et al who elegantly showed that middle-aged track-and-field athletes had reduced telomere erosion compared with non-athletes and that the probable mechanism involved exerciseassociated increases in both the expression of telomere-stabilizing proteins and the activity of telomerase (Werner et al 2009). We hypothesize that the longer TL of the TCD8 + compartment in our trained elderly involved similar mechanisms.…”

Human aging and CD31+T-cell number, migration, apoptotic susceptibility, and telomere length

“…Shortened telomere length and blunted telomerase activity are deleterious age-related modifications that lower a cell's ability to resist physiological stressors due to activation of cell senescence and apoptotic programs (34,41). For example, Werner et al (37) demonstrated that genetic ablation of telomerase activity in mice significantly increased aortic endothelial cell susceptibility to LPS-induced apoptosis. Reduced telomere length and telomerase activity may precede and predispose to cellular dysfunction with age (18).…”

Physical exercise attenuates age‐associated reduction in endothelium‐reparative capacity of endothelial progenitor cells by increasing CXCR4/JAK‐2 signaling in healthy men

“…In addition to favorably modifying traditional risk factors, physical exercise has been shown to prevent and restore age-associated loss in endothelial function in humans (DeSouza et al, 2000;Werner et al, 2009). Recent data also suggest that the beneficial effect of exercise on endothelial protection is, at least in part, related to the exercise-induced upregulation of EPC function and number (Laufs et al, 2004;Yang et al, 2007;Van Craenenbroeck et al, 2010;Witkowski et al, 2010).…”