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Journal of Diabetes Research
Volume 2013 (2013), Article ID 789607, 12 pages
Review Article

Exercise and the Aging Endothelium

Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada V6T 1Z3

Received 14 January 2013; Accepted 2 July 2013

Academic Editor: Cristina M. T. Sena

Copyright © 2013 Saeid Golbidi and Ismail Laher. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The endothelium plays a critical role in the maintenance of cardiovascular health by producing nitric oxide and other vasoactive materials. Aging is associated with a gradual decline in this functional aspect of endothelial regulation of cardiovascular homeostasis. Indeed, age is an independent risk factor for cardiovascular diseases and is in part an important factor in the increased exponential mortality rates from vascular disease such as myocardial infarction and stroke that occurs in the ageing population. There are a number of mechanisms suggested to explain age-related endothelial dysfunction. However, recent scientific studies have advanced the notion of oxidative stress and inflammation as the two major risk factors underlying aging and age-related diseases. Regular physical activity, known to have a favorable effect on cardiovascular health, can also improve the function of the ageing endothelium by modulating oxidative stress and inflammatory processes, as we discuss in this paper.

1. Introduction

The global population, especially those in developed countries, is getting older and this trend is predicted to continue in the coming decades [1, 2]. Some have defined aging as a decreased ability to resist cellular stresses or insults [3, 4], and in fact, aging is one of the most important cardiovascular risk factors for predisposing conditions such as diabetes, hypertension, and hypercholesterolemia. Accordingly, the incidence and prevalence of clinical and subclinical cardiovascular diseases increase dramatically with age [2], making cardiovascular disease the most common cause of death among the elderly.

The endothelium has a primary role in adjusting vascular function by the production of nitric oxide (NO) and other biologically active vasodilator materials [5] that decrease vascular resistance, inhibit platelet adhesion and aggregation, and decrease vascular smooth muscle cell proliferation. Alterations in the control of these processes, a feature of endothelial dysfunction, often leads to atherosclerosis and other vascular disorders [6] that are accompanied by a proinflammatory, proliferative, and procoagulatory state [7]. The endothelium is ideally placed to bear the brunt of hemodynamic stresses, oxidized lipids, and oxidative radicals, all of which increase their vulnerability to aging [8].

Chronic aerobic exercise improves cardiovascular function in humans. This is true not only in healthy subjects without underlying risk factors [9], but also in older people [10] and those with cardiovascular risk factors [11]. Indeed, those with cardiovascular risk factor/disease will benefit more. For instance, eight weeks of exercise significantly improve endothelial function, as measured by flow-mediated dilation, in diabetic patients [12] but not in healthy subjects [13].

Although there are clear health benefits of exercise in the elderly, a detailed understanding of the molecular basis underlying these improvements remains incomplete. In this minireview, we discuss some mechanisms thought to be involved in endothelial aging. We focus on the role of oxidative stress and subsequent inflammation and the role of exercise in boosting antioxidative and anti-inflammatory mechanisms.

2. Endothelial Function

The endothelial cells form a monolayer that lines blood vessels to form an interface between circulating blood and the smooth muscle layer. In addition to its barrier function, the endothelium modulates coagulation, growth, and inflammation throughout the circulatory system. It also contributes to adjusting tissue perfusion by secreting several vasoactive substances [14], which can be vasoconstrictors (endothelin-1, angiotensin II, thromboxane A2, etc.) or vasodilators (NO, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF), etc.) [15]. Among the many vasoactive agents released by the endothelium, NO has been characterized in greatest detail. It is released in response to a variety of chemical and physical stimuli to cause vasodilation, such that one of the most common methods for assessing endothelial health is by determining vascular capacity to produce NO [16]. NO is produced by the catalytic activity of NO synthase (NOS), which transforms L-arginine to L-citrulline. All isoforms of NOS require five cofactors/prosthetic groups: flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), heme, tetrahydrobiopterin (BH4), and Ca2+/calmodulin. Calcium is required for the activation of neuronal NOS (nNOS) and endothelial NOS (eNOS) but not for the activity of inducible NOS (iNOS) [17]. eNOS binds to caveolin-1 in endothelial cell caveolae, a subset of specialized lipid domains that form invaginations and so increase intracellular microdomains where organelles and anchoring proteins aggregate. Caveolin-1 inhibits eNOS activity, and this interaction is regulated by Ca2+/calmodulin [18]. Upon agonist activation, the increases in intracellular calcium results in Ca2+/calmodulin binding, which then displaces caveolin and reverses its inhibitory interaction with eNOS [19]. Mechanical stimuli such as shear stress and vascular smooth muscle stretch also raise intracellular calcium concentrations. Several chemical events such as interaction with Ca2+/calmodulin, heat shock protein 90, and subsequent association of Akt results in eNOS phosphorylation at Ser1177 are involved in NO production [19]. Released NO causes vasorelaxation, which in turn results in increased blood flow and reduced blood pressure, inhibition of platelet adhesion and aggregation, inhibition of leukocyte adhesion, reduction in smooth muscle proliferation, and retardation of atherogenesis [4].

3. Endothelial Dysfunction and Aging

Endothelial dysfunction is defined as functional alterations in endothelial physiology characterized by reduction of vasodilator substance output (in particular NO) and augmentation in endothelium-derived contracting factors [4]. This imbalance leads to a vasoconstrictive, hypercoagulative, proliferative, and proinflammatory state, so favoring atherosclerosis [7]. Over time, most humans are exposed to a variety of modifiable cardiovascular risk factors, such as hyperglycemia and insulin resistance, obesity, altered lipid profile, hypertension, and glomerulosclerosis. All these confounding factors get exacerbated with age-related decreases in physical activity. Even short periods of inactivity lead to insulin resistance and endothelial dysfunction [3537]. Bed rest of about 48 hours induces vascular dysfunction, which is then followed by insulin resistance, dyslipidemia, and increased blood pressure [38]. Thus, shortening of hospital stays and bed confinement periods are highly beneficial in the elderly. Bed rest also increases circulating endothelial cells [39], possibly due to increased endothelial cell apoptosis resulting from reduced shear stress during bed rest. These stresses activate endothelial repair systems. According to Thorin et al., as long as the damage is minimal or maintenance systems work properly as in young subjects, the functional capacity of the endothelium is preserved. In cases of severe damage, injured cells are omitted by a poorly described mechanism and replaced by dividing neighboring cells. Circulating progenitor endothelial cells also play a role in the repair mechanisms of injured endothelial cells. However, as part of the aging processes, the cumulative effects of stresses coupled with the inevitable metabolic changes that occur with time, there is a decline in the function and repair capacity of the endothelium. Since endothelial cells can only undergo a limited number of divisions, they eventually enter a state of senescence, which is an endogenous and hereditary process of biological aging, in which cells are still metabolically active, but express a pro-inflammatory, prooxidative, and proatherogenic phenotype [40]. The cumulative effects of these parameters strongly promote a decline in the functional capacity of endothelium. All forms of cardiovascular disease have an increased prevalence in the elderly, even in those free of cardiovascular risk factors [41]. Since there are no changes in endothelium-independent vasodilation in older humans and animals, it is reasonable to suggest that vascular age-dependent endothelial changes largely reflect the release NO [15], although there are also some changes in the production and release of other endothelial derived vasodilators such as prostacyclin and EDHF, along with increases in vasoconstrictor prostanoids [42]. There are also several age-related structural changes in endothelium such as increases in the expression of adhesion molecules, permeability, sensitivity to apoptotic stimuli, with decreases in angiogenic and regenerative capacities [43, 44].

4. Mechanisms of Endothelial Aging

There are a number of mechanisms proposed to explain age-related endothelial function. However, oxidative stress and inflammation appear critical to this process.

4.1. Oxidative Stress and Endothelial Dysfunction

Oxidative stress is an imbalance between production of oxidizing agents, such as free radicals, and opposing antioxidant systems which scavenge or metabolize those reactive agents. Free radicals are reactive chemical molecules having a single unpaired electron in an outer orbit. This unstable configuration provides energy which is released through reactions with adjacent molecules such as proteins, lipids, carbohydrates, and nucleic acids. The majority of free radicals that damage biological systems are oxygen-free radicals [45]. Oxygen-free radicals or, more generally, reactive oxygen species (ROS), as well as reactive nitrogen species (RNS), are products of normal cellular metabolism. Oxidative stress interferes with endothelial function in different ways, but the most prominent mechanism is via reduction of NO bioavailability, which is the net product of the rate of NO production and its degradation by superoxide [46].

In the case of NO generation, reduced vasoconstrictive responses to the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) in older patients [47] and reduced shear stress-induced NO release and vasodilation in older animals [48] suggest decreased production of NO in aged endothelium. In spite of these, direct measurements of eNOS in aged animals were inconclusive, as raised, fallen, or unchanged levels have been reported [4952].

The increased production of superoxide anions in the aging vascular wall rapidly inactivates NO [53, 54]. Cyclooxygenase (COX) and NADPH-oxidase have central roles in ROS production [47, 5558]. Removal of the endothelium or inhibition of NADPH-oxidase reduces vascular superoxide generation in the aorta of aged Wistar-Kyoto rats [55]. Superoxide rapidly reacts with NO to generate cytotoxic peroxynitrite (ONOO), a reaction with several consequences. First, ONOO alters the function of biomolecules by protein nitration as well as by causing lipid peroxidation [59]. For example, potassium channels, which hyperpolarize vascular cells and mediate regulate vasorelaxation, are inhibited by nitration [60, 61]. Second, ONOO causes single-strand DNA breakage, which in turn activates nuclear enzyme poly(ADP-ribose) polymerase (PARP) (a nuclear DNA-repair enzyme) [62]. Third, it decreases NO bioavailability causing impaired relaxation and inhibition of the antiproliferative effects of NO. Furthermore, ONOO oxidizes BH4, an important cofactor for NOS, leading to the uncoupling of eNOS and causing it to produce superoxide instead of NO. ROS-induced peroxidation of membrane lipids alters the structure and the fluidity of biological membranes, so having global detrimental effects on vascular function [53]. The role of oxidative stress in aged endothelial dysfunction is shown by the ability of vitamin C to restore the impaired vasodilatory response to acetylcholine only in subjects aged 60 years or older [47]. This indicates that oxidative stress is a critical mechanism for endothelial dysfunction only in older subjects. Administration of BH4 also improves flow-mediated dilatation (FMD) in older sedentary subjects, while having no beneficial effects in young or older trained people [63].

Antioxidant deficiency is another mechanism for oxidative stress in endothelial cells. All cells have evolved highly complex enzymatic and nonenzymatic antioxidant systems that act synergistically to defend the body from free radical-induced damage. The most efficient enzymatic antioxidants are glutathione peroxidase, catalase, superoxide dismutase, heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO-1), and thioredoxin. Nonenzymatic antioxidants include vitamins E and C, thiol antioxidants (glutathione, thioredoxin) [64]. Attenuation of antioxidant defense mechanisms during the aging process has been proposed in some studies. For instance, reduced concentration of plasma SOD, but not cellular SOD, occurs in rats [65]. Higher production of peroxynitrite causes antioxidant enzyme deactivation, as is the case for manganese SOD (MnSOD) in mitochondria [51]. Levels of protein expression and enzymatic activity of glutathione peroxidase 1 (GPX-1) are lower in proangiogenic endothelial progenitor cells (derived from cultured blood mononuclear cells) from older subjects [66].

4.2. Inflammation and Endothelial Dysfunction

Inflammation has a prominent role in the pathogenesis of several cardiovascular diseases. Atherosclerosis is an inflammatory disease that is mediated by monocyte-derived macrophages which accumulate in arterial plaques and become activated to release cytokines that cause tissue damage [67]. As evidence accumulates favoring the role of inflammation during the different phases of atherosclerosis, it is likely that markers of inflammation such as high sensitivity C-reactive protein (hs-CRP) could be increasingly used to provide additional insights on the biological status of atherosclerotic lesions. Elevations of CRP are considered independent predictors of cardiovascular events and of the outcome of acute coronary syndromes [68]. Besides their roles markers of systemic inflammation and as predictors of cardiovascular risk, CRP and other inflammatory cytokines also directly trigger vascular dysfunction [69], possibly by altering calcium channel expression and activity [70], upregulating of Rho-kinase expression and function [71], increasing ROS production [72], and/or enhancing COX expression [73]. In turn, COX-derived constrictor prostanoid(s) products cause vascular hypercontractility [74, 75] and increased formation of ROS [76]. Increases in COX-induced ROS production and the expression of proinflammatory mediators, such as IL-1B, IL-6, TNF-α, COX-2, and iNOS, occur during aging [77].

The NF-κB pathway is a critical component of inflammatory processes activated by oxidative stress [33, 78]. NF-κB is an ubiquitous transcription factor with multiple roles such as mediating inflammatory responses to a variety of signals, immune function, endothelial cell activation, and control of cell growth [7981]. NF-κB is normally located in the cytoplasm in an inactive form by virtue of binding to a family of inhibitory NF-κB (IκB) proteins. Upon cell stimulation by a wide variety of stimuli, signals responsive IKK-α and IKK-β (also known as IKK-1 and IKK-2) are activated, which results in the phosphorylation of IκB and its proteasomal degradation. IκB degradation liberates NF-κB, allowing it to translocate to the nucleus and induce gene expression of a number of proinflammatory cytokines, such as IL-1β, IL-6, TNF-α, COX-2, lipoxygenase, iNOS, and adhesion molecules (VCAM-1, ICAM-1, PCAM, E-selectin). Aging increases NF-κB levels due to activation of IKKα/β and degradation of IκB [82]. Under usual conditions, the activation of NF-κB during inflammation is temporary and limited. In aging, however, a chronic and self-perpetuating condition exists. Proteins such as TNF-α, IL-1, IL-6, and COX-2 that are NF-κB induced also activate NF-κB production, thus creating a vicious cycle [83]. Aging increases plasma levels of TNF-α, IL-6, IL-1β, CRP, and inflammatory blood cells [8486]. The plasma concentration of IL-6 correlates with senile neural atrophy [87] and inflammatory diseases, such as type 2 diabetes and atherosclerosis [88]. Plasma levels of TNF-α and IL-6 are also predictors of disability and mortality among elderly [89].

5. Role of Exercise in Improving Endothelial Function in Elderly

The significance of exercise as a modifiable risk factor for cardiovascular disease is widely acknowledged [90]. Physical inactivity and poor diet, preceded only by tobacco, are the leading causes of death [91]. The American College of Sports Medicine, defines exercise as “Any and all activity involving generation of force by the activated muscle(s) that results in disruption of a homeostatic state” [92]. Exercise can be classified by the type, intensity, and duration of activity. Endurance exercise is characterized by prolonged and continuous periods of contractile activity (high repetition) against low resistance. Resistance exercise (also termed strength training) involves short periods of contractile activity (low repetition) against a high opposing resistance. Sprint exercise consists of short periods of maximal (intense) repetitive contractile activity with a low interval and against a low resistance, for example, running 100 m sprint race. However, sprint training can also be performed against high resistance resulting in a combination of resistance and endurance modalities, for example, running with added weights [93].

Increased physical activity and fitness, of both men and women, reduce the relative risk of death by 20–35% [94, 95]. Some studies even suggest greater benefits (up to 50% risk reduction) for exercise in terms of all-cause mortality and death from cardiovascular disease [96]. Brown et al. in almost one decade follow-up study evaluated the relationship between physical activity and risk of all-cause mortality in a large number of elderly (7080 women aged 70–75 and 11668 men aged 65–83) [97]. They found an inverse dose-response relationship between exercise and all-cause mortality. Risk reductions were 30–50% higher in females than in males in every category of exercise intensity. This study clearly shows that there are clear health benefits from all levels of physical activity. Regular aerobic exercise can slow down the age-related losses in endothelial function [98] supposedly by restoration of NO availability consequent to prevention of ROS production [99]. Aging is associated with a limited capacity of the vasculature to release NO, as older subjects show reduced levels of plasma nitrite in response to exercise [100]. The difference in plasma nitrate/nitrite ratio between older and young sedentary subjects is reduced by exercise. Heat-stimulated hand and foot skin increased blood flow are higher in trained older subjects compared to sedentary matched controls and are correlated with nitrate/nitrite ratios, suggesting better endothelial function secondary to greater NO bioavailability [101]. Trained elderly subjects also exhibit higher flow-mediated brachial artery dilation compared to sedentary counterparts [100]. Table 1 summarizes the findings of recent clinical studies on the endothelial benefits of exercise in the elderly.

Table 1: Selected recent clinical trials (last 5 years) about the effects of exercise in elderly.
5.1. Effect of Exercise in Mitigating Oxidative Stress

Exercise training upregulates antioxidant defense mechanisms in several tissues, presumably due to increased levels of oxidative stress that occurs during exercise. Exercise-induced production of ROS is proposed to evoke specific adaptations such as increasing repair mechanisms for oxidative damage, increasing resistance to oxidative stress, and lowering levels of oxidative damage. On the other hand, excessive production of ROS can have detrimental effects. Boosting levels of intrinsic antioxidant potential and reduction in lipid peroxidation occur in healthy elderly men after habitual physical activity [102].

A critical role has recently been described for a transcription factor “nuclear factor (erythroid-derived 2)-like 2 (Nrf2)” against oxidative stress. Normally, Nrf2 is located in the cytoplasm and kept dormant by the cytoplasmic repressor Kelch-like ECH-associated protein 1 (Keap1). A variety of activators, including oxidative free radicals, release, and translocate Nrf2 into the nucleus where it regulates the expression of antioxidant enzymes such as NQO-1, glutathione-S-transferase, glutathione peroxidase, and HO-1 [64]. Diminished Nrf2 activity contributes to increased oxidative stress and mitochondrial dysfunction leading to endothelial dysfunction, insulin resistance, and abnormal angiogenesis as observed in diabetics [103]. HO-1, which is mainly induced through the Nrf2-Keap1 signaling pathway (also known as heat shock protein 32), is the inducible isoform of heme oxygenase that catalyzes NADPH-dependent decomposition of heme to carbon monoxide (CO), ferrous iron, and biliverdin [104]. Three isoforms of HO have been identified: both HO-2 and HO-3 are 33-kDa constitutively expressed isoforms [105]. An important role of HO-1 in the antioxidant defense system arises from an induction of ferritin synthesis that diminishes the cellular pool of free iron [106] and also from the enhancement of bilirubin levels, which are potent antioxidants [107]. Carbon monoxide activates soluble guanylate cyclase, a key enzyme in the cell signaling cascade leading to relaxation of smooth muscle, and thrombocyte disaggregation. Carbon monoxide also affects cellular metabolism and counteracts proinflammatory cytokine cascades [105]. HO-1 is a sensitive and reliable marker of oxidative stress [108] and cytoplasmic expression levels of HO-1 increase in leukocytes of endurance-trained male subjects after a half-marathon run [109]. There is a paradoxical increased expression of HO-1 in a control group of untrained men at rest, suggesting that the downregulation of the baseline expression of HO-1 in athletes reflects an adaptation mechanism to regular exercise training [109]. The direct effect of exercise on Nrf2 expression has received much less attention except for a report that exercise increases nuclear levels of Nrf2 in the proximal renal tubules of old rats [110].

The increased expression of eNOS after exercise both in animals and human beings [111114] also occurs in patients with stable coronary artery disease and chronic heart failure [115, 116]. Exercise-induced upregulation of vascular eNOS expression is closely related to the frequency and the intensity of physical forces within the vasculature, especially shear stress. Shear stress is the product of all the perpendicular and parallel flow-mediated forces on endothelial cells. The types of these hemodynamic forces, either laminar or oscillatory, greatly impact the function and properties of endothelial cells and also determine the signal transduction pathways that are activated. Laminar flow, which is augmented during moderate and intense physical activities, upregulates eNOS expression—while oscillatory forces, which are associated with hypertension, leads to increased NADPH-oxidase activity and augments oxidative stress [40]. The mechanotransduction mechanisms that sense physical forces to cause altered gene expression are not completely described. Some reports suggest that activation of inward rectifying K+ cannels, followed by stimulation of outwardly rectifying Cl- channels, plays a major role in this process. Membrane hyperpolarization, due to inward K+ currents, drives extracellular Ca2+ into the cells through two shear stress-dependent ion channels (P2X purinoceptors and transient receptor potential channels). Raised intracellular calcium levels lead to a dissociation of caveolae-bound eNOS and increased production of NO [117]. Other intracellular events are also thought to mediate increased NO production in response to shear stress; however, the relative importance of these mechanisms is not clear (Table 2). Increased NO synthesis secondary to amplified shear stress induces extracellular superoxide dismutase (SOD) expression in a positive feedback manner so as to inhibit the degradation of NO by ROS [34]. Another parallel mechanism that participates in this harmony is the upregulation of eNOS through exercise-induced ROS production, since exercise-induced increases in shear stress stimulates vascular production of ROS by an endothelium dependent pathway [118]. Endothelial NAD(P)H oxidase has a critical role in this process [119]. Superoxides are rapidly converted to H2O2 by SOD; hydrogen peroxide then diffuses through the vascular wall and increases the expression and activity of eNOS [120, 121]. Thus, increased expression of SOD1 and SOD3 (which facilitate the generation of H2O2 from superoxide) augments the effect of H2O2 on exercise-induced eNOS expression. On the other hand, eNOS expression is not increased in catalase overexpressing transgenic mice [112, 122]. Another putative mechanism is exercise-induced increases in arterial compliance which is mediated by reduction of plasma ET-1 concentration as well as the elimination of ET-1 mediated vascular tone. Twelve weeks of aerobic exercise training increase arterial compliance, while decreasing plasma ET-1 levels. Moreover, the increase in central arterial compliance observed with ET-receptor blockade before the exercise intervention was eliminated after exercise training [123]. These results indicate that endogenous ET-1 participates in the beneficial influence of regular aerobic exercise on central arterial compliance.

Table 2: Suggested shear stress sensing mechanisms by the endothelial cells and related intracellular signal transductions [33, 34].
5.2. Anti-Inflammatory Role of Exercise

Exercise produces a short-term inflammatory response that is accompanied by leukocytosis, increases in oxidative stress and plasma levels of CRP. This proinflammatory response is followed by a long-term anti-inflammatory adaptive response [124]. Regular exercise reduces CRP, IL-6, and TNF-α levels while increasing anti-inflammatory substances such as IL-4 and IL-10 [125, 126]. Controlling the release and activity of at least two cytokines, TNF-α and IL-6, could contribute to the natural protective effects of physical activity. Interleukine-6 (IL-6) is the first cytokine to be released into the circulation during exercise, and its levels increase in an exponential fashion in response to exercise [74]. Contracting skeletal muscles upregulate levels of IL-6 mRNA [127] and the transcriptional rate of the IL-6 gene is also markedly enhanced by exercise [128]. IL-6 acts as both a proinflammatory and anti-inflammatory cytokine: when secreted by T cells and macrophages, IL-6 stimulates the immune response and boosts inflammatory reactions, while muscle-produced IL-6 exerts anti-inflammatory effects through its inhibitory effects on TNF-α and IL-1β, and activation of interleukin-1 receptor antagonist (IL-1ra) and IL-10 [129]. IL-10 in turn reduces the production of several proinflammatory cytokines, such as TNF-α and IL-1β [130]. Exercise-induced increases in plasma IL-6 correlate with the muscle mass involved in exercise activity and the mode, duration, and intensity of exercise [131], and this is especially the case in older individuals [132]. Exercise also confers protection against TNF-induced insulin resistance [133]. In addition, Starkie et al. report that infusion of recombinant human IL-6 (rhIL-6) into human subjects simulated exercise induced an IL-6 response in the prevention of endotoxin-induced increase in plasma TNF-α [134]. Exercise also suppresses TNF-α production by an IL-6 independent pathway, as there are modest decreases in plasma TNF-α after exercise in IL-6 knockout mice [135]. Exercise-induced increases in epinephrine levels blunt the TNF-α response [136]. In addition, IL-6 enhances lipid turnover and stimulates lipolysis as well as fat oxidation via activation of AMP-activated protein kinase [137]. Mice deficient in IL-6 (IL6−/−) develop mature onset obesity and have disturbed carbohydrate and lipid metabolism that is partly reversed by IL-6 replacement. Other data indicate that centrally acting IL-6 exerts an antiobesity effect in rodents [138]. The lipolytic effect of IL-6 on fat metabolism was confirmed in two clinical studies of healthy and diabetic subjects [137, 139]. Visceral fat is potentially a cause of low-grade systemic inflammation, which in turn leads to insulin resistance, type 2 diabetes, and atherosclerosis [140]. During exercise, IL-6 also increases hepatic glucose production. Glucose ingestion during exercise reduces IL-6 production by muscles, suggesting that IL-6 is released by a reduction in glycogen levels during endurance exercise and the consequent adrenergic stimulation of IL-6 gene transcription via protein kinase A activation [141].

Physical activity also increases the expression of IL-15 in the skeletal muscles. This cytokine exerts anabolic effects in muscles by inducing protein synthesis and inhibiting protein degradation [130, 142]. In some animal studies, this cytokine prevents muscle wasting by attenuating apoptotic DNA fragmentation and downregulating TNF-driven apoptotic pathways [143]. In agreement with this, four weeks of exercise reduce the extent of TNF-triggered myocyte apoptosis in old rats [144, 145]

6. Summary

Aging is an important independent risk factor for the development of cardiovascular disease, which is manifest as endothelial dysfunction. A large body of evidence underlines the importance of oxidative stress and inflammation as prominent features of the aging process. Reduced NO bioavailability and decreased responsiveness to other endothelial-derived vasodilators promote a vasoconstrictive, hypercoagulative, and proliferative state which favors the development of atherosclerosis. Vascular oxidative stress is the product of increased reactive oxygen species, such as superoxides, and reduced antioxidant defense. Oxidative stress-induced damage promotes a chronic inflammatory state which perpetuates a vicious cycle of endothelial dysfunction. Exercise training prevents and restores age-related impairment of endothelial function, possibly by the restoration of NO availability consequent to prevention of oxidative stress and alleviating inflammatory processes.


  1. S. Yusuf, S. Reddy, S. Ôunpuu, and S. Anand, “Global burden of cardiovascular diseases—part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization,” Circulation, vol. 104, no. 22, pp. 2746–2753, 2001. View at Scopus
  2. National Centre for Health Statistics (US), http://www.cdc.gov./nchs/hus.htm.
  3. B. P. Yu, “Aging and oxidative stress: modulation by dietary restriction,” Free Radical Biology and Medicine, vol. 21, no. 5, pp. 651–668, 1996. View at Publisher · View at Google Scholar · View at Scopus
  4. K. B. Beckman and B. N. Ames, “The free radical theory of aging matures,” Physiological Reviews, vol. 78, no. 2, pp. 547–581, 1998. View at Scopus
  5. J. A. Vita, “Nitric oxide-dependent vasodilation in human subjects,” Methods in Enzymology, vol. 359, pp. 186–200, 2002. View at Publisher · View at Google Scholar · View at Scopus
  6. P. O. Bonetti, L. O. Lerman, and A. Lerman, “Endothelial dysfunction: a marker of atherosclerotic risk,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 23, no. 2, pp. 168–175, 2003. View at Publisher · View at Google Scholar · View at Scopus
  7. T. J. Anderson, “Assessment and treatment of endothelial dysfunction in humans,” Journal of the American College of Cardiology, vol. 34, no. 3, pp. 631–638, 1999. View at Publisher · View at Google Scholar · View at Scopus
  8. H. Y. Chung, H. J. Kim, J. W. Kim, and B. P. Yu, “The inflammation hypothesis of aging: molecular modulation by calorie restriction,” Annals of the New York Academy of Sciences, vol. 928, pp. 327–335, 2001. View at Scopus
  9. P. Clarkson, H. E. Montgomery, M. J. Mullen et al., “Exercise training enhances endothelial function in young men,” Journal of the American College of Cardiology, vol. 33, no. 5, pp. 1379–1385, 1999. View at Publisher · View at Google Scholar · View at Scopus
  10. E. J. Benjamin, M. G. Larson, M. J. Keyes et al., “Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham Heart Study,” Circulation, vol. 109, no. 5, pp. 613–619, 2004. View at Publisher · View at Google Scholar · View at Scopus
  11. R. Hambrecht, E. Fiehn, C. Weigl et al., “Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure,” Circulation, vol. 98, no. 24, pp. 2709–2715, 1998. View at Scopus
  12. A. Maiorana, G. O'Driscoll, C. Cheetham et al., “The effect of combined aerobic and resistance exercise training on vascular function in type 2 diabetes,” Journal of the American College of Cardiology, vol. 38, no. 3, pp. 860–866, 2001. View at Publisher · View at Google Scholar · View at Scopus
  13. A. Maiorana, G. O'Driscoll, L. Dembo, C. Goodman, R. Taylor, and D. Green, “Exercise training, vascular function, and functional capacity in middle-aged subjects,” Medicine and Science in Sports and Exercise, vol. 33, no. 12, pp. 2022–2028, 2001. View at Scopus
  14. S. Verma and T. J. Anderson, “Fundamentals of endothelial function for the clinical cardiologist,” Circulation, vol. 105, no. 5, pp. 546–549, 2002. View at Publisher · View at Google Scholar · View at Scopus
  15. F. Cosentino and E. Osto, “Aging and endothelial dysfunction,” Clinical Hemorheology and Microcirculation, vol. 37, pp. 143–147, 2007.
  16. J. Deanfield, A. Donald, C. Ferri et al., “Endothelial function and dysfunction—part I: methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension,” Journal of Hypertension, vol. 23, no. 1, pp. 7–17, 2005. View at Publisher · View at Google Scholar · View at Scopus
  17. S. Golbidi, A. Mesdaghinia, and I. Laher, “Exercise in the metabolic syndrome,” Oxidative Medicine and Cellular Longevity, vol. 2012, Article ID 349710, 13 pages, 2012. View at Publisher · View at Google Scholar
  18. J. B. Michel, O. Feron, D. Sacks, and T. Michel, “Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin,” Journal of Biological Chemistry, vol. 272, no. 25, pp. 15583–15586, 1997. View at Publisher · View at Google Scholar · View at Scopus
  19. C. Dessy, O. Feron, and J.-L. Balligand, “The regulation of endothelial nitric oxide synthase by caveolin: a paradigm validated in vivo and shared by the ‘endothelium-derived hyperpolarizing factor’,” Pflugers Archiv—European Journal of Physiology, vol. 459, no. 6, pp. 817–827, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. F. Bobeuf, M. Labonte, I. J. Dionne, and A. Khalil, “Combined effect of antioxidant supplementation and resistance training on oxidative stress markers, muscle and body composition in an elderly population,” Journal of Nutrition, Health and Aging, vol. 15, no. 10, pp. 883–889, 2011. View at Publisher · View at Google Scholar · View at Scopus
  21. S. D. Anton, T. M. Manini, V. A. Milsom et al., “Effects of a weight loss plus exercise program on physical function in overweight, older women: a randomized controlled trial,” Clinical Interventions in Aging, vol. 6, no. 1, pp. 141–149, 2011. View at Scopus
  22. L. B. Gano, A. J. Donato, G. L. Pierce et al., “Increased proinflammatory and oxidant gene expression in circulating mononuclear cells in older adults: amelioration by habitual exercise,” Physiological Genomics, vol. 43, no. 14, pp. 895–902, 2011. View at Publisher · View at Google Scholar · View at Scopus
  23. P. T. Campbell, M. D. Gross, J. D. Potter et al., “Effect of exercise on oxidative stress: a 12-month randomized, controlled trial,” Medicine and Science in Sports and Exercise, vol. 42, no. 8, pp. 1448–1453, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. D. W. Wray, A. Uberoi, L. Lawrenson, D. M. Bailey, and R. S. Richardson, “Oral antioxidants and cardiovascular health in the exercise-trained and untrained elderly: a radically different outcome,” Clinical Science, vol. 116, no. 5, pp. 433–441, 2009. View at Publisher · View at Google Scholar · View at Scopus
  25. S. Sixt, A. Rastan, S. Desch et al., “Exercise training but not rosiglitazone improves endothelial function in prediabetic patients with coronary disease,” European Journal of Cardiovascular Prevention and Rehabilitation, vol. 15, no. 4, pp. 473–478, 2008. View at Publisher · View at Google Scholar · View at Scopus
  26. J. U. Gonzales, J. R. Thistlethwaite, B. C. Thompson, and B. W. Scheuermann, “Exercise-induced shear stress is associated with changes in plasma von Willebrand factor in older humans,” European Journal of Applied Physiology, vol. 106, no. 5, pp. 779–784, 2009. View at Publisher · View at Google Scholar · View at Scopus
  27. W.-H. Xia, J. Li, C. Su et al., “Physical exercise attenuates age-associated reduction in endothelium-reparative capacity of endothelial progenitor cells by increasing CXCR4/JAK-2 signaling in healthy men,” Aging Cell, vol. 11, no. 1, pp. 111–119, 2012. View at Publisher · View at Google Scholar · View at Scopus
  28. G. L. Pierce, I. Eskurza, A. E. Walker, T. N. Fay, and D. R. Seals, “Sex-specific effects of habitual aerobic exercise on brachial artery flow-mediated dilation in middle-aged and older adults,” Clinical Science, vol. 120, no. 1, pp. 13–23, 2011. View at Publisher · View at Google Scholar · View at Scopus
  29. G. P. van Guilder, C. M. Westby, J. J. Greiner, B. L. Stauffer, and C. A. DeSouza, “Endothelin-1 vasoconstrictor tone increases with age in healthy men but can be reduced by regular aerobic exercise,” Hypertension, vol. 50, no. 2, pp. 403–409, 2007. View at Publisher · View at Google Scholar · View at Scopus
  30. C. A. da Silva, J. P. Ribeiro, J. C. A. U. Canto et al., “High-intensity aerobic training improves endothelium-dependent vasodilation in patients with metabolic syndrome and type 2 diabetes mellitus,” Diabetes Research and Clinical Practice, vol. 95, no. 2, pp. 237–245, 2012. View at Publisher · View at Google Scholar · View at Scopus
  31. S. Okada, A. Hiuge, H. Makino et al., “Effect of exercise intervention on endothelial function and incidence of cardiovascular disease in patients with type 2 diabetes,” Journal of Atherosclerosis and Thrombosis, vol. 17, no. 8, pp. 828–833, 2010. View at Scopus
  32. M. Vona, G. M. Codeluppi, T. Iannino, E. Ferrari, J. Bogousslavsky, and L. K. von Segesser, “Effects of different types of exercise training followed by detraining on endothelium-dependent dilation in patients with recent myocardial infarction,” Circulation, vol. 119, no. 12, pp. 1601–1608, 2009. View at Publisher · View at Google Scholar · View at Scopus
  33. K. Yamamoto and J. Ando, “New molecular mechanisms for cardiovascular disease: blood flow sensing mechanism in vascular endothelial cells,” Journal of Pharmacological Sciences, vol. 116, no. 4, pp. 323–331, 2011. View at Publisher · View at Google Scholar · View at Scopus
  34. S. Gielen, G. Schuler, and V. Adams, “Cardiovascular effects of exercise training: molecular mechanisms,” Circulation, vol. 122, no. 12, pp. 1221–1238, 2010. View at Publisher · View at Google Scholar · View at Scopus
  35. C. A. Stuart, R. E. Shangraw, M. J. Prince, E. J. Peters, and R. R. Wolfe, “Bed-rest-induced insulin resistance occurs primarily in muscle,” Metabolism, vol. 37, no. 8, pp. 802–806, 1988. View at Scopus
  36. P. J. Arciero, D. L. Smith, and J. Calles-Escandon, “Effects of short-term inactivity on glucose tolerance, energy expenditure, and blood flow in trained subjects,” Journal of Applied Physiology, vol. 84, no. 4, pp. 1365–1373, 1998. View at Scopus
  37. J. Smorawiński, H. Kaciuba-Uściłko, K. Nazar et al., “Effects of three-day bed rest on metabolic, hormonal and circulatory responses to an oral glucose load in endurance or strength trained athletes and untrained subjects,” Journal of Physiology and Pharmacology, vol. 51, no. 2, pp. 279–289, 2000. View at Scopus
  38. S. S. Thosar, B. D. Johnson, J. D. Johnston, and J. P. Wallace, “Sitting and endothelial dysfunction: the role of shear stress,” Medical Science Monitor, vol. 18, pp. RA173–RA180, 2012. View at Publisher · View at Google Scholar
  39. C. Demiot, F. Dignat-George, J.-O. Fortrat et al., “WISE 2005: chronic bed rest impairs microcirculatory endothelium in women,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 293, no. 5, pp. H3159–H3164, 2007. View at Publisher · View at Google Scholar · View at Scopus
  40. S. di Francescomarino, A. Sciartilli, V. di Valerio, A. di Baldassarre, and S. Gallina, “The effect of physical exercise on endothelial function,” Sports Medicine, vol. 39, no. 10, pp. 797–812, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. T. F. Luscher and G. Noll, “The endothelium in coronary vascular control,” Heart Disease, vol. 3, pp. 1–10, 1995.
  42. P. W. Vanhoutte, “Ageing and endothelial dysfunction,” European Heart Journal, vol. 4, pp. A8–A17, 2002. View at Publisher · View at Google Scholar
  43. E. G. Lakatta, “Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises—part III: cellular and molecular clues to heart and arterial aging,” Circulation, vol. 107, no. 3, pp. 490–497, 2003. View at Publisher · View at Google Scholar · View at Scopus
  44. R. P. Brandes, I. Fleming, and R. Busse, “Endothelial aging,” Cardiovascular Research, vol. 66, no. 2, pp. 286–294, 2005. View at Publisher · View at Google Scholar · View at Scopus
  45. K. Rahman, “Studies on free radicals, antioxidants, and co-factors,” Clinical Interventions in Aging, vol. 2, no. 2, pp. 219–236, 2007. View at Scopus
  46. H. Cai and D. G. Harrison, “Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress,” Circulation Research, vol. 87, no. 10, pp. 840–844, 2000. View at Scopus
  47. S. Taddei, A. Virdis, L. Ghiadoni et al., “Age-related reduction of NO availability and oxidative stress in humans,” Hypertension, vol. 38, no. 2, pp. 274–279, 2001. View at Scopus
  48. D. Sun, A. Huang, E. H. Yan et al., “Reduced release of nitric oxide to shear stress in mesenteric arteries of aged rats,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 286, no. 6, pp. H2249–H2256, 2004. View at Publisher · View at Google Scholar · View at Scopus
  49. T. Minamino, H. Miyauchi, T. Yoshida, Y. Ishida, H. Yoshida, and I. Komuro, “Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction,” Circulation, vol. 105, no. 13, pp. 1541–1544, 2002. View at Publisher · View at Google Scholar · View at Scopus
  50. J. R. Durrant, D. R. Seals, M. L. Connell et al., “Voluntary wheel running restores endothelial function in conduit arteries of old mice: direct evidence for reduced oxidative stress, increased superoxide dismutase activity and down-regulation of NADPH oxidase,” Journal of Physiology, vol. 587, no. 13, pp. 3271–3285, 2009. View at Publisher · View at Google Scholar · View at Scopus
  51. B. van der Loo, R. Labugger, J. N. Skepper et al., “Enhanced peroxynitrite formation is associated with vascular aging,” Journal of Experimental Medicine, vol. 192, no. 12, pp. 1731–1743, 2000. View at Publisher · View at Google Scholar · View at Scopus
  52. M. R. Cernadas, L. Sánchez de Miguel, M. García-Durán et al., “Expression of constitutive and inducible nitric oxide synthases in the vascular wall of young and aging rats,” Circulation Research, vol. 83, no. 3, pp. 279–286, 1998.
  53. S. Pennathur and J. W. Heinecke, “Oxidative stress and endothelial dysfunction in vascular disease,” Current Diabetes Reports, vol. 7, no. 4, pp. 257–264, 2007. View at Publisher · View at Google Scholar · View at Scopus
  54. D. Versari, E. Daghini, A. Virdis, L. Ghiadoni, and S. Taddei, “The ageing endothelium, cardiovascular risk and disease in man,” Experimental Physiology, vol. 94, no. 3, pp. 317–321, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. C. A. Hamilton, M. J. Brosnan, M. McIntyre, D. Graham, and A. F. Dominiczak, “Superoxide excess in hypertension and aging a common cause of endothelial dysfunction,” Hypertension, vol. 37, no. 2, pp. 529–534, 2001. View at Scopus
  56. A. Görlach, R. P. Brandes, K. Nguyen, M. Amidi, F. Dehghani, and R. Busse, “A gp91phox containing NADPH oxidase selectively expressed in endothelial cells is a major source of oxygen radical generation in the arterial wall,” Circulation Research, vol. 87, no. 1, pp. 26–32, 2000. View at Scopus
  57. O. Jung, J. G. Schreiber, H. Geiger, T. Pedrazzini, R. Busse, and R. P. Brandes, “gp91phox-containing NADPH oxidase mediates endothelial dysfunction in renovascular hypertension,” Circulation, vol. 109, no. 14, pp. 1795–1801, 2004. View at Publisher · View at Google Scholar · View at Scopus
  58. A. J. Donato, I. Eskurza, A. E. Silver et al., “Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-κB,” Circulation Research, vol. 100, no. 11, pp. 1659–1666, 2007. View at Publisher · View at Google Scholar · View at Scopus
  59. I. V. Turko, S. Marcondes, and F. Murad, “Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA:3-oxoacid CoA-transferase,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 281, no. 6, pp. H2289–H2294, 2001. View at Scopus
  60. Y. Liu and D. D. Gutterman, “The coronary circulation in diabetes: influence of reactive oxygen species on K+ channel-mediated vasodilation,” Vascular Pharmacology, vol. 38, no. 1, pp. 43–49, 2002. View at Publisher · View at Google Scholar · View at Scopus
  61. Y. Liu, K. Terata, Q. Chai, H. Li, L. H. Kleinman, and D. D. Gutterman, “Peroxynitrite inhibits Ca2+-activated K+ channel activity in smooth muscle of human coronary arterioles,” Circulation Research, vol. 91, no. 11, pp. 1070–1076, 2002. View at Publisher · View at Google Scholar · View at Scopus
  62. F. Soriano, L. Virág, and C. Szabó, “Diabetic endothelial dysfunction: role of reactive oxygen and nitrogen species production and poly(ADP-ribose) polymerase activation,” Journal of Molecular Medicine, vol. 79, no. 8, pp. 437–448, 2001. View at Publisher · View at Google Scholar · View at Scopus
  63. I. Eskurza, L. A. Myerburgh, Z. D. Kahn, and D. R. Seals, “Tetrahydrobiopterin augments endothelium-dependent dilatation in sedentary but not in habitually exercising older adults,” Journal of Physiology, vol. 568, no. 3, pp. 1057–1065, 2005. View at Publisher · View at Google Scholar · View at Scopus
  64. S. Lee, Y. Park, M. Y. Zuidema, M. Hannink, and C. Zhang, “Effects of interventions on oxidative stress and inflammation of cardiovascular diseases,” World Journal of Cardiology, vol. 3, pp. 18–24, 2011.
  65. M. Barton, F. Cosentino, R. P. Brandes, P. Moreau, S. Shaw, and T. F. Lüscher, “Anatomic heterogeneity of vascular aging: role of nitric oxide and endothelin,” Hypertension, vol. 30, no. 4, pp. 817–824, 1997. View at Scopus
  66. T. He, M. J. Joyner, and Z. S. Katusic, “Aging decreases expression and activity of glutathione peroxidase-1 in human endothelial progenitor cells,” Microvascular Research, vol. 78, no. 3, pp. 447–452, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. F. P. Leung, L. M. Yung, I. Laher, X. Yao, Z. Y. Chen, and Y. Huang, “Exercise, vascular wall and cardiovascular diseases: an update (part 1),” Sports Medicine, vol. 38, no. 12, pp. 1009–1024, 2008. View at Scopus
  68. S. Balducci, S. Zanuso, A. Nicolucci et al., “Anti-inflammatory effect of exercise training in subjects with type 2 diabetes and the metabolic syndrome is dependent on exercise modalities and independent of weight loss,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 20, no. 8, pp. 608–617, 2010. View at Publisher · View at Google Scholar · View at Scopus
  69. A. H. Sprague and R. A. Khalil, “Inflammatory cytokines in vascular dysfunction and vascular disease,” Biochemical Pharmacology, vol. 78, no. 6, pp. 539–552, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. S. Tiwari, Y. Zhang, J. Heller, D. R. Abernethy, and N. M. Soldatov, “Artherosclerosis-related molecular alteration of the human Ca V1.2 calcium channel α1C subunit,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 45, pp. 17024–17029, 2006. View at Publisher · View at Google Scholar · View at Scopus
  71. J. Hiroki, H. Shimokawa, M. Higashi et al., “Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells,” Journal of Molecular and Cellular Cardiology, vol. 37, no. 2, pp. 537–546, 2004. View at Publisher · View at Google Scholar · View at Scopus
  72. C. Zhang, Y. Park, A. Picchi, and B. J. Potter, “Maturation-induces endothelial dysfunction via vascular inflammation in diabetic mice,” Basic Research in Cardiology, vol. 103, no. 5, pp. 407–416, 2008. View at Publisher · View at Google Scholar · View at Scopus
  73. J. A. Mitchell, S. Larkin, and T. J. Williams, “Cyclooxygenase-2: regulation and relevance in inflammation,” Biochemical Pharmacology, vol. 50, no. 10, pp. 1535–1542, 1995. View at Publisher · View at Google Scholar · View at Scopus
  74. N. Erdei, Z. Bagi, I. Édes, G. Kaley, and A. Koller, “H2O2 increases production of constrictor prostaglandins in smooth muscle leading to enhanced arteriolar tone in type 2 diabetic mice,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 292, no. 1, pp. H649–H656, 2007. View at Publisher · View at Google Scholar · View at Scopus
  75. T. Matsumoto, M. Kakami, E. Noguchi, T. Kobayashi, and K. Kamata, “Imbalance between endothelium-derived relaxing and contracting factors in mesenteric arteries from aged OLETF rats, a model of type 2 diabetes,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 293, no. 3, pp. H1480–H1490, 2007. View at Publisher · View at Google Scholar · View at Scopus
  76. E. H. C. Tang, F. P. Leung, Y. Huang et al., “Calcium and reactive oxygen species increase in endothelial cells in response to releasers of endothelium-derived contracting factor,” British Journal of Pharmacology, vol. 151, no. 1, pp. 15–23, 2007. View at Publisher · View at Google Scholar · View at Scopus
  77. H. J. Kim, K. J. Jung, B. P. Yu, C. G. Cho, J. S. Choi, and H. Y. Chung, “Modulation of redox-sensitive transcription factors by calorie restriction during aging,” Mechanisms of Ageing and Development, vol. 123, no. 12, pp. 1589–1595, 2002. View at Publisher · View at Google Scholar · View at Scopus
  78. H. Y. Chung, B. Sung, K. J. Jung, Y. Zou, and B. P. Yu, “The molecular inflammatory process in aging,” Antioxidants and Redox Signaling, vol. 8, no. 3-4, pp. 572–581, 2006. View at Publisher · View at Google Scholar · View at Scopus
  79. A. S. Baldwin Jr., “The NF-kappa B and I kappa B proteins: new discoveries and insights,” The Annual Review of Immunology, vol. 14, pp. 649–683, 1996. View at Publisher · View at Google Scholar
  80. P. J. Barnes and M. Karin, “Nuclear factor-κB—a pivotal transcription factor in chronic inflammatory diseases,” The New England Journal of Medicine, vol. 336, no. 15, pp. 1066–1071, 1997. View at Publisher · View at Google Scholar · View at Scopus
  81. S. Ghosh, M. J. May, and E. B. Kopp, “NF-κB and rel proteins: evolutionarily conserved mediators of immune responses,” Annual Review of Immunology, vol. 16, pp. 225–260, 1998. View at Publisher · View at Google Scholar · View at Scopus
  82. H. J. Kim, K. W. Kim, B. P. Yu, and H. Y. Chung, “The effect of age on cyclooxygenase-2 gene expression: NF-kappaB activation and IkappaBalpha degradation,” Free Radical Biology and Medicine, vol. 28, pp. 683–692, 2000.
  83. H. Y. Chung, M. Cesari, S. Anton et al., “Molecular inflammation: underpinnings of aging and age-related diseases,” Ageing Research Reviews, vol. 8, no. 1, pp. 18–30, 2009. View at Publisher · View at Google Scholar · View at Scopus
  84. S. B. Kritchevsky, M. Cesari, and M. Pahor, “Inflammatory markers and cardiovascular health in older adults,” Cardiovascular Research, vol. 66, no. 2, pp. 265–275, 2005. View at Publisher · View at Google Scholar · View at Scopus
  85. A. Cartier, M. Côté, I. Lemieux et al., “Age-related differences in inflammatory markers in men: contribution of visceral adiposity,” Metabolism, vol. 58, no. 10, pp. 1452–1458, 2009. View at Publisher · View at Google Scholar · View at Scopus
  86. H. Bruunsgaard, K. Andersen-Ranberg, B. Jeune, A. N. Pedersen, P. Skinhøj, and B. K. Pedersen, “A high plasma concentration of TNF-alpha is associated with dementia in centenarians,” The Journal of Gerontology: Series A, vol. 54, no. 7, pp. M357–M364, 1999. View at Publisher · View at Google Scholar
  87. A. A. Willette, B. B. Bendlin, D. G. McLaren et al., “Age-related changes in neural volume and microstructure associated with interleukin-6 are ameliorated by a calorie-restricted diet in old rhesus monkeys,” NeuroImage, vol. 51, no. 3, pp. 987–994, 2010. View at Publisher · View at Google Scholar · View at Scopus
  88. B. Devaux, D. Scholz, A. Hirche, W. P. Klovekorn, and J. Schaper, “Upregulation of cell adhesion molecules and the presence of low grade inflammation in human chronic heart failure,” European Heart Journal, vol. 18, no. 3, pp. 470–479, 1997. View at Scopus
  89. M. Maggio, J. M. Guralnik, D. L. Longo, and L. Ferrucci, “Interleukin-6 in aging and chronic disease: a magnificent pathway,” Journals of Gerontology: Series A, vol. 61, no. 6, pp. 575–584, 2006. View at Scopus
  90. S. G. Wannamethee, A. G. Shaper, and P. H. Whincup, “Modifiable lifestyle factors and the metabolic syndrome in older men: effects of lifestyle changes,” Journal of the American Geriatrics Society, vol. 54, no. 12, pp. 1909–1914, 2006. View at Publisher · View at Google Scholar · View at Scopus
  91. A. H. Mokdad, J. S. Marks, D. F. Stroup, and J. L. Gerberding, “Actual causes of death in the United States, 2000,” Journal of the American Medical Association, vol. 291, no. 10, pp. 1238–1245, 2004. View at Publisher · View at Google Scholar · View at Scopus
  92. S. Golbidi and I. Laher, “Molecular mechanisms in exercise-induced cardioprotection,” Cardiology Research and Practice, vol. 2011, Article ID 972807, 15 pages, 2011. View at Publisher · View at Google Scholar
  93. S. Ghosh, S. Golbidi, I. Werner, B. C. Verchere, and I. Laher, “Selecting exercise regimens and strains to modify obesity and diabetes in rodents: an overview,” Clinical Science, vol. 119, no. 2, pp. 57–74, 2010. View at Publisher · View at Google Scholar · View at Scopus
  94. C. A. Macera, J. M. Hootman, and J. E. Sniezek, “Major public health benefits of physical activity,” Arthritis Care and Research, vol. 49, no. 1, pp. 122–128, 2003. View at Scopus
  95. C. A. Macera and K. E. Powell, “Population attributable risk: implications of physical activity dose,” Medicine and Science in Sports and Exercise, vol. 33, no. 6, pp. S635–S639, 2001. View at Scopus
  96. J. Myers, A. Kaykha, S. George et al., “Fitness versus physical activity patterns in predicting mortality in men,” American Journal of Medicine, vol. 117, no. 12, pp. 912–918, 2004. View at Publisher · View at Google Scholar · View at Scopus
  97. W. J. Brown, D. McLaughlin, J. Leung et al., “Physical activity and all-cause mortality in older women and men,” British Journal of Sports Medicine, vol. 46, pp. 664–668, 2012.
  98. C. A. DeSouza, L. F. Shapiro, C. M. Clevenger et al., “Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men,” Circulation, vol. 102, no. 12, pp. 1351–1357, 2000. View at Scopus
  99. S. Taddei, F. Galetta, A. Virdis et al., “Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes,” Circulation, vol. 101, no. 25, pp. 2896–2901, 2000. View at Scopus
  100. T. Lauer, C. Heiss, J. Balzer et al., “Age-dependent endothelial dysfunction is associated with failure to increase plasma nitrite in response to exercise,” Basic Research in Cardiology, vol. 103, no. 3, pp. 291–297, 2008. View at Publisher · View at Google Scholar · View at Scopus
  101. F. Franzoni, F. Galetta, C. Morizzo et al., “Effects of age and physical fitness on microcirculatory function,” Clinical Science, vol. 106, no. 3, pp. 329–335, 2004. View at Publisher · View at Google Scholar · View at Scopus
  102. J. Karolkiewicz, L. Szczêsniak, E. Deskur-Smielecka, A. Nowak, R. Stemplewski, and R. Szeklicki, “Oxidative stress and antioxidant defense system in healthy, elderly men: relationship to physical activity,” Aging Male, vol. 6, no. 2, pp. 100–105, 2003. View at Scopus
  103. X. Cheng, R. C. M. Siow, and G. E. Mann, “Impaired redox signaling and antioxidant gene expression in endothelial cells in diabetes: a role for mitochondria and the nuclear factor-E2-related factor 2-Kelch-like ECH-associated protein 1 defense pathway,” Antioxidants and Redox Signaling, vol. 14, no. 3, pp. 469–487, 2011. View at Publisher · View at Google Scholar · View at Scopus
  104. W. Bao, F. Song, X. Li et al., “Plasma heme oxygenase-1 concentration is elevated in individuals with type 2 diabetes mellitus,” PLoS One, vol. 5, no. 8, Article ID e12371, 2010. View at Publisher · View at Google Scholar · View at Scopus
  105. E. Babusikova, M. Jesenak, P. Durdik, D. Dobrota, and P. Banovcin, “Exhaled carbon monoxide as a new marker of respiratory diseases in children,” Journal of Physiology and Pharmacology, vol. 59, supplement 6, pp. 9–17, 2008. View at Scopus
  106. G. F. Vile and R. M. Tyrrell, “Oxidative stress resulting from ultraviolet A irradiation of human skin fibroblasts leads to a heme oxygenase-dependent increase in ferritin,” Journal of Biological Chemistry, vol. 268, no. 20, pp. 14678–14681, 1993. View at Scopus
  107. S. Bélanger, J.-C. Lavoie, and P. Chessex, “Influence of bilirubin on the antioxidant capacity of plasma in newborn infants,” Biology of the Neonate, vol. 71, no. 4, pp. 233–238, 1997. View at Scopus
  108. S. W. Ryter, J. Alam, and A. M. K. Choi, “Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications,” Physiological Reviews, vol. 86, no. 2, pp. 583–650, 2006. View at Publisher · View at Google Scholar · View at Scopus
  109. A. M. Niess, F. Passek, I. Lorenz et al., “Expression of the antioxidant stress protein heme oxygenase-1 (HO-1) in human leukocytes: acute and adaptational responses to endurance exercise,” Free Radical Biology and Medicine, vol. 26, no. 1-2, pp. 184–192, 1999. View at Publisher · View at Google Scholar · View at Scopus
  110. M. Asghar, L. George, and M. F. Lokhandwala, “Exercise decreases oxidative stress and inflammation and restores renal dopamine D1 receptor function in old rats,” American Journal of Physiology—Renal Physiology, vol. 293, no. 3, pp. F914–F919, 2007. View at Publisher · View at Google Scholar · View at Scopus
  111. I. Fleming and R. Busse, “Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 284, no. 1, pp. R1–R12, 2003. View at Scopus
  112. T. Fukai, M. R. Siegfried, M. Ushio-Fukai, Y. Cheng, G. Kojda, and D. G. Harrison, “Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training,” Journal of Clinical Investigation, vol. 105, no. 11, pp. 631–1639, 2000. View at Scopus
  113. G. Kojda, Y. C. Cheng, J. Burchfield, and D. G. Harrison, “Dysfunctional regulation of endothelial nitric oxide synthase (eNOS) expression in response to exercise in mice lacking one eNOS gene,” Circulation, vol. 103, no. 23, pp. 2839–2844, 2001. View at Scopus
  114. R. Hambrecht, V. Adams, S. Erbs et al., “Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase,” Circulation, vol. 107, no. 25, pp. 3152–3158, 2003. View at Publisher · View at Google Scholar · View at Scopus
  115. R. Hambrecht, A. Wolf, S. Gielen et al., “Effect of exercise on coronary endothelial function in patients with coronary artery disease,” The New England Journal of Medicine, vol. 342, no. 7, pp. 454–460, 2000. View at Publisher · View at Google Scholar · View at Scopus
  116. R. Hambrecht, S. Gielen, A. Linke et al., “Effects of exercise training on left ventricular function and peripheral resistance in patients with chronic heart failure: a randomized trial,” Journal of the American Medical Association, vol. 283, no. 23, pp. 3095–3101, 2000. View at Scopus
  117. B. D. Johnson, K. J. Mather, and J. P. Wallace, “Mechanotransduction of shear in the endothelium: basic studies and clinical implications,” Vascular Medicine, vol. 16, pp. 365–377, 2011. View at Publisher · View at Google Scholar
  118. F. R. M. Laurindo, M. D. A. Pedro, H. V. Barbeiro et al., “Vascular free radical release: ex vivo and in vivo evidence for a flow- dependent endothelial mechanism,” Circulation Research, vol. 74, no. 4, pp. 700–709, 1994. View at Scopus
  119. G. W. de Keulenaer, D. C. Chappell, N. Ishizaka, R. M. Nerem, R. W. Alexander, and K. K. Griendling, “Oscillatory and steady laminar shear stress differentially affect human endothelial redox state: role of a superoxide-producing NADH oxidase,” Circulation Research, vol. 82, no. 10, pp. 1094–1101, 1998. View at Scopus
  120. G. R. Drummond, H. Cai, M. E. Davis, S. Ramasamy, and D. G. Harrison, “Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide,” Circulation Research, vol. 86, no. 3, pp. 347–354, 2000. View at Scopus
  121. H. Cai, M. E. Davis, G. R. Drummond, and D. G. Harrison, “Induction of endothelial NO synthase by hydrogen peroxide via a Ca2+/calmodulin-dependent protein kinase II/janus kinase 2-dependent pathway,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 10, pp. 1571–1576, 2001. View at Scopus
  122. J. W. E. Rush, J. R. Turk, and M. H. Laughlin, “Exercise training regulates SOD-1 and oxidative stress in porcine aortic endothelium,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 284, no. 4, pp. H1378–H1387, 2003. View at Scopus
  123. S. Maeda, J. Sugawara, M. Yoshizawa et al., “Involvement of endothelin-1 in habitual exercise-induced increase in arterial compliance,” Acta Physiologica, vol. 196, no. 2, pp. 223–229, 2009. View at Publisher · View at Google Scholar · View at Scopus
  124. C. Kasapis and P. D. Thompson, “The effects of physical activity on serum C-reactive protein and inflammatory markers: a systematic review,” Journal of the American College of Cardiology, vol. 45, no. 10, pp. 1563–1569, 2005. View at Publisher · View at Google Scholar · View at Scopus
  125. E. P. Plaisance and P. W. Grandjean, “Physical activity and high-sensitivity C-reactive protein,” Sports Medicine, vol. 36, no. 5, pp. 443–458, 2006. View at Publisher · View at Google Scholar · View at Scopus
  126. K. E. Fallon, S. K. Fallon, and T. Boston, “The acute phase response and exercise: court and field sports,” British Journal of Sports Medicine, vol. 35, no. 3, pp. 170–173, 2001. View at Publisher · View at Google Scholar · View at Scopus
  127. D. C. Nieman, J. M. Davis, D. A. Henson et al., “Carbohydrate ingestion influences skeletal muscle cytokine mRNA and plasma cytokine levels after a 3-h run,” Journal of Applied Physiology, vol. 94, no. 5, pp. 1917–1925, 2003. View at Scopus
  128. C. Keller, A. Steensberg, H. Pilegaard et al., “Transcriptional activation of the IL-6 gene in human contracting skeletal muscle: influence of muscle glycogen content,” The FASEB Journal, vol. 15, no. 14, pp. 2748–2750, 2001. View at Scopus
  129. M. A. Febbraio and B. K. Pedersen, “Contraction-induced myokine production and release: is skeletal muscle an endocrine organ?” Exercise and Sport Sciences Reviews, vol. 33, no. 3, pp. 114–119, 2005. View at Publisher · View at Google Scholar · View at Scopus
  130. A. R. Nielsen, R. Mounier, P. Plomgaard et al., “Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition,” Journal of Physiology, vol. 584, no. 1, pp. 305–312, 2007. View at Publisher · View at Google Scholar · View at Scopus
  131. B. K. Pedersen and M. A. Febbraio, “Point: interleukin-6 does have a beneficial role in insulin sensitivity and glucose homeostasis,” Journal of Applied Physiology, vol. 102, no. 2, pp. 814–819, 2007. View at Publisher · View at Google Scholar · View at Scopus
  132. B. K. Pedersen and H. Bruunsgaard, “Possible beneficial role of exercise in modulating low-grade inflammation in the elderly,” Scandinavian Journal of Medicine and Science in Sports, vol. 13, no. 1, pp. 56–62, 2003. View at Publisher · View at Google Scholar · View at Scopus
  133. A. Festa, R. D'Agostino Jr., G. Howard, L. Mykkänen, R. P. Tracy, and S. M. Haffner, “Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS),” Circulation, vol. 102, no. 1, pp. 42–47, 2000. View at Scopus
  134. R. Starkie, S. R. Ostrowski, S. Jauffred, M. Febbraio, and B. K. Pedersen, “Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans,” The FASEB Journal, vol. 17, no. 8, pp. 884–886, 2003. View at Scopus
  135. C. Keller, P. Keller, M. Giralt, J. Hidalgo, and B. K. Pedersen, “Exercise normalises overexpression of TNF-α in knockout mice,” Biochemical and Biophysical Research Communications, vol. 321, no. 1, pp. 179–182, 2004. View at Publisher · View at Google Scholar · View at Scopus
  136. T. van der Poll, S. M. Coyle, K. Barbosa, C. C. Braxton, and S. F. Lowry, “Epinephrine inhibits tumor necrosis factor-α and potentiates interleukin 10 production during human endotoxemia,” Journal of Clinical Investigation, vol. 97, no. 3, pp. 713–719, 1996. View at Scopus
  137. E. W. Petersen, A. L. Carey, M. Sacchetti et al., “Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro,” American Journal of Physiology—Endocrinology and Metabolism, vol. 288, no. 1, pp. E155–E162, 2005. View at Publisher · View at Google Scholar · View at Scopus
  138. V. Wallenius, K. Wallenius, B. Ahrén et al., “Interleukin-6-deficient mice develop mature-onset obesity,” Nature Medicine, vol. 8, no. 1, pp. 75–79, 2002. View at Publisher · View at Google Scholar · View at Scopus
  139. G. van Hall, A. Steensberg, M. Sacchetti et al., “Interleukin-6 stimulates lipolysis and fat oxidation in humans,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 7, pp. 3005–3010, 2003. View at Publisher · View at Google Scholar · View at Scopus
  140. C. Brandt and B. K. Pedersen, “The role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases,” Journal of Biomedicine and Biotechnology, vol. 2010, Article ID 520258, 6 pages, 2010. View at Publisher · View at Google Scholar · View at Scopus
  141. E. Hopps, B. Canino, and G. Caimi, “Effects of exercise on inflammation markers in type 2 diabetic subjects,” Acta Diabetologica, vol. 48, no. 3, pp. 183–189, 2011. View at Publisher · View at Google Scholar · View at Scopus
  142. L. S. Quinn, B. G. Anderson, R. H. Drivdahl, B. Alvarez, and J. M. Argilés, “Overexpression of interleukin-15 induces skeletal muscle hypertrophy in vitro: implications for treatment of muscle wasting disorders,” Experimental Cell Research, vol. 280, no. 1, pp. 55–63, 2002. View at Publisher · View at Google Scholar · View at Scopus
  143. M. Figueras, S. Busquets, N. Carbó et al., “Interleukin-15 is able to suppress the increased DNA fragmentation associated with muscle wasting in tumour-bearing rats,” FEBS Letters, vol. 569, no. 1–3, pp. 201–206, 2004. View at Publisher · View at Google Scholar · View at Scopus
  144. E. Marzetti, L. Groban, S. E. Wohlgemuth et al., “Effects of short-term GH supplementation and treadmill exercise training on physical performance and skeletal muscle apoptosis in old rats,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 294, no. 2, pp. R558–R567, 2008. View at Publisher · View at Google Scholar · View at Scopus
  145. E. Marzetti, J. M. Lawler, A. Hiona, T. Manini, A. Y. Seo, and C. Leeuwenburgh, “Modulation of age-induced apoptotic signaling and cellular remodeling by exercise and calorie restriction in skeletal muscle,” Free Radical Biology and Medicine, vol. 44, no. 2, pp. 160–168, 2008. View at Publisher · View at Google Scholar · View at Scopus