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...

Long- and short-term voluntary physical exercise up-regulates cardiac telomere-stabilizing proteins and thereby induces antisenescent and protective effects, for example, to prevent doxorubicin-induced cardiomyopathy. These beneficial cardiac effects are mediated by TERT, eNOS, and IGF-1.

Ambivalent effects of interleukin-6 on the pathogenesis of ischaemic stroke have been reported. However, to date, the long-term actions of interleukin-6 after stroke have not been investigated. Here, we subjected interleukin-6 knockout (IL-6(-/-)) and wild-type control mice to mild brain ischaemia by 30-min filamentous middle cerebral artery occlusion/reperfusion. While ischaemic tissue damage was comparable at early time points, IL-6(-/-) mice showed significantly increased chronic lesion volumes as well as worse long-term functional outcome. In particular, IL-6(-/-) mice displayed an impaired angiogenic response to brain ischaemia with reduced numbers of newly generated endothelial cells and decreased density of perfused microvessels along with lower absolute regional cerebral blood flow and reduced vessel responsivity in ischaemic striatum at 4 weeks. Similarly, the early genomic activation of angiogenesis-related gene networks was strongly reduced and the ischaemia-induced signal transducer and activator of transcription 3 activation observed in wild-type mice was almost absent in IL-6(-/-) mice. In addition, systemic neoangiogenesis was impaired in IL-6(-/-) mice. Transplantation of interleukin-6 competent bone marrow into IL-6(-/-) mice (IL-6(chi)) did not rescue interleukin-6 messenger RNA expression or the early transcriptional activation of angiogenesis after stroke. Accordingly, chronic stroke outcome in IL-6(chi) mice recapitulated the major effects of interleukin-6 deficiency on post-stroke regeneration with significantly enhanced lesion volumes and reduced vessel densities. Additional in vitro experiments yielded complementary evidence, which showed that after stroke resident brain cells serve as the major source of interleukin-6 in a self-amplifying network. Treatment of primary cortical neurons, mixed glial cultures or immortalized brain endothelia with interleukin 6-induced robust interleukin-6 messenger RNA transcription in each case, whereas oxygen-glucose deprivation did not. However, oxygen-glucose deprivation of organotypic brain slices resulted in strong upregulation of interleukin-6 messenger RNA along with increased transcription of key angiogenesis-associated genes. In conclusion, interleukin-6 produced locally by resident brain cells promotes post-stroke angiogenesis and thereby affords long-term histological and functional protection.

OBJECTIVE-Peroxisome proliferator-activated receptor-␥ (PPAR␥) agonists (thiazolidinediones [TZDs]) are used for the treatment of diabetes. Bone marrow-derived endothelial progenitor cells (EPCs) improve vascular function and predict cardiovascular risk. The effect of pioglitazone therapy on EPCs was examined. RESEARCH DESIGN AND METHODS AND RESULTS-Weperformed a prospective, randomized, double-blind study on patients with documented stable coronary artery disease and normal glucose tolerance. Of 54 patients with normal fasting glucose levels, 18 showed impaired glucose tolerance and 36 patients with normal glucose tolerance were randomized to 30-day treatment with pioglitazone (45 mg) or placebo in addition to optimal medical therapy. All patients in the TZD group showed an increase of adiponectin levels as an indicator of compliance (11.4 Ϯ 1.1 to 36.8 Ϯ 2.1 g/ml; P Ͻ 0.001). TZD, but not placebo, decreased mean high-sensitivity C-reactive protein to 43 Ϯ 19% (P Ͻ 0.05). Pioglitazone increased CD34 ϩ /kinase insert domain receptor ϩ EPCs to 142 Ϯ 9% and cultured 1,1Ј-dioctadecyl-3,3,3Ј,3Ј-tetramethylindocarbocyanine-labeled acetylated LDL ϩ / lectin ϩ EPCs to 180 Ϯ 3% (P Ͻ 0.05). EPC numbers were not changed in the placebo group. TZD increased the SDF-1-induced migratory capacity to 146 Ϯ 9% per EPC number (P Ͻ 0.05) and upregulated the clonogenic potential of EPCs, increasing the colony-forming units to 172 Ϯ 12% (P Ͻ 0.001). In cultured human EPCs, TZD increased EPC numbers and migration and reduced NADPH-oxidase activity. The TZD effect was reversed by the PPAR␥ antagonist GW9662 and mimicked by treatment with adiponectin.CONCLUSIONS-The PPAR␥ agonist pioglitazone increases the number and function of EPCs in patients with coronary artery disease. The effect represents a potential regenerative mechanism in atherosclerosis and is observed in normoglycemic individuals with stable coronary artery disease.

AimsIt is unknown whether different training modalities exert differential cellular effects. Telomeres and telomere-associated proteins play a major role in cellular aging with implications for global health. This prospective training study examines the effects of endurance training, interval training (IT), and resistance training (RT) on telomerase activity and telomere length (TL).Methods and resultsOne hundred and twenty-four healthy previously inactive individuals completed the 6 months study. Participants were randomized to three different interventions or the control condition (no change in lifestyle): aerobic endurance training (AET, continuous running), high-intensive IT (4 × 4 method), or RT (circle training on 8 devices), each intervention consisting of three 45 min training sessions per week. Maximum oxygen uptake (VO2max) was increased by all three training modalities. Telomerase activity in blood mononuclear cells was up-regulated by two- to three-fold in both endurance exercise groups (AET, IT), but not with RT. In parallel, lymphocyte, granulocyte, and leucocyte TL increased in the endurance-trained groups but not in the RT group. Magnet-activated cell sorting with telomerase repeat-ampliflication protocol (MACS-TRAP) assays revealed that a single bout of endurance training—but not RT—acutely increased telomerase activity in CD14+ and in CD34+ leucocytes.Conclusion This randomized controlled trial shows that endurance training, IT, and RT protocols induce specific cellular pathways in circulating leucocytes. Endurance training and IT, but not RT, increased telomerase activity and TL which are important for cellular senescence, regenerative capacity, and thus, healthy aging.

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Supplementation with dietary fiber from psyllium or gum arabic was associated with a decrease in the percentage of incontinent stools and an improvement of stool consistency. Improvements in fecal incontinence or stool consistency did not appear to be related to unfermented dietary fiber.

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