The objective of this study was to determine the effects of aging and exercise training on SIRT1 activity and to identify a pathway linking SIRT1 to antioxidant response and cell cycle regulation in rats. SIRT1 is a NAD(+)-dependent deacetylase involved in the oxidative stress response and aging. The effects of aging and of moderate and prolonged exercise training in rats are unknown. We measured SIRT1 activity in heart and adipose tissue of young (6 months old), sedentary old (24 months), and trained old (24 months) rats using an assay kit. Peroxidative damage was determined by measuring levels of thiobarbituric reactive substances (TBARS) and the protein-aldehyde adduct 4-hydroxynonenal (4-HNE). MnSOD, catalase, and FOXO3a levels were evaluated by Western blot, and GADD45a, cyclin D(2), and FOXO3a mRNA by RT-PCR. Aging significantly reduced SIRT1 activity in heart, but not in adipose tissue, increased TBARS and 4-HNE and decreased Mn-SOD and catalase expression in both heart and adipose tissue. Aging did not affect FOXO3a protein expression in the heart or FOXO3a mRNA in adipose tissue. Exercise training significantly increased FOXO3a protein in the heart and FOXO3a mRNA in adipose tissue of aged rats. It also significantly increased Mn-SOD and catalase levels in both heart and adipose tissue. The exercise-induced increase in SIRT1 activity in the heart caused a decrease in cyclin D(2) and an increase in GADD45a mRNA expression. There was a similar decrease in cyclin D(2), and no changes in GADD45a mRNA expression in adipose tissue. We concluded that exercise training, which significantly increases SIRT1 activity, could counteract age-related systems impairment.
Our data indicate that exercise favourably affects angiogenesis and improves LV remodelling and contractility reserve in a rat model of severe chronic HF.
Oxidative stress is generally considered as the consequence of an imbalance between pro- and antioxidants species, which often results into indiscriminate and global damage at the organismal level. Elderly people are more susceptible to oxidative stress and this depends, almost in part, from a decreased performance of their endogenous antioxidant system. As many studies reported an inverse correlation between systemic levels of antioxidants and several diseases, primarily cardiovascular diseases, but also diabetes and neurological disorders, antioxidant supplementation has been foreseen as an effective preventive and therapeutic intervention for aging-associated pathologies. However, the expectations of this therapeutic approach have often been partially disappointed by clinical trials. The interplay of both endogenous and exogenous antioxidants with the systemic redox system is very complex and represents an issue that is still under debate. In this review a selection of recent clinical studies concerning antioxidants supplementation and the evaluation of their influence in aging-related diseases is analyzed. The controversial outcomes of antioxidants supplementation therapies, which might partially depend from an underestimation of the patient specific metabolic demand and genetic background, are presented.
Nitric Oxide (NO) is a small molecule that continues to attract much attention from the scientific community. Since its discovery, it has been evident that NO has a crucial role in the modulation of vascular tone. Moreover, NO is involved in multiple signal transduction pathways thus contributing to the regulation of many cellular functions. NO effects can be either dependent or independent on cGMP, and rely also upon several mechanisms such as the amount of NO, the compartmentalization of the enzymes responsible for its biosynthesis (NOS), and the local redox conditions. Several evidences highlighted the correlation among adrenoreceptors activity, vascular redox status and NO bioavailability. It was suggested a possible crosstalk between NO and oxidative stress hallmarks in the endothelium function and adaptation, and in sympathetic vasoconstriction control. Adrenergic vasoconstriction is a balance between a direct vasoconstrictive effect on smooth muscle and an indirect vasorelaxant action caused by α2- and β-adrenergic endothelial receptor-triggered NO release. An increased oxidative stress and a reduction of NO bioavailability shifts this equilibrium causing the enhanced vascular adrenergic responsiveness observed in hypertension. The activity of NOS contributes to manage the adrenergic pathway, thus supporting the idea that the endothelium might control or facilitate β-adrenergic effects on the vessels and the polymorphic variants in β2-receptors and NOS isoforms could influence aging, some pathological conditions and individual responses to drugs. This seems to be dependent, almost in part, on differences in the control of vascular tone exerted by NO. Given its involvement in such important mechanisms, the NO pathway is implicated in aging process and in both cardiovascular and non-cardiovascular conditions. Thus, it is essential to pinpoint NO involvement in the regulation of vascular tone for the effective clinical/therapeutic management of cardiovascular diseases (CVD).
Within the family of endogenous gasotransmitters, nitric oxide (NO) is the smallest gaseous intercellular messenger involved in the modulation of several processes, such as blood flow and platelet aggregation control, essential to maintain vascular homeostasis. NO is produced by nitric oxide synthases (NOS) and its effects are mediated by cGMP-dependent or cGMP-independent mechanisms. Growing evidence suggests a crosstalk between the NO signaling and the occurrence of oxidative stress in the onset and progression of vascular diseases, such as hypertension, heart failure, ischemia, and stroke. For these reasons, NO is considered as an emerging molecular target for developing therapeutic strategies for cardio- and cerebrovascular pathologies. Several natural derived compounds, such as polyphenols, are now proposed as modulators of NO-mediated pathways. The aim of this review is to highlight the experimental evidence on the involvement of nitric oxide in vascular homeostasis focusing on the therapeutic potential of targeting NO with some natural compounds in patients with vascular diseases.
Different types of exercise training induced different molecular effects in terms of survival, morphology, and antioxidant system efficiency. The in vitro technique used herein may help to shed light on the molecular basis of effects of long-term physical activity in humans.
The adrenergic system plays a central role in stress signaling and stress is often associated with increased production of ROS. However, ROS overproduction generates oxidative stress, that occurs in response to several stressors. β-adrenergic signaling is markedly attenuated in conditions such as heart failure, with downregulation and desensitization of the receptors and their uncoupling from adenylyl cyclase. Transgenic activation of β2-adrenoceptor leads to elevation of NADPH oxidase activity, with greater ROS production and p38MAPK phosphorylation. Inhibition of NADPH oxidase or ROS significantly reduced the p38MAPK signaling cascade. Chronic β2-adrenoceptor activation is associated with greater cardiac dilatation and dysfunction, augmented pro-inflammatory and profibrotic signaling, while antioxidant treatment protected hearts against these abnormalities, indicating ROS production to be central to the detrimental signaling of β2-adrenoceptors. It has been demonstrated that sirtuins are involved in modulating the cellular stress response directly by deacetylation of some factors. Sirt1 increases cellular stress resistance, by an increased insulin sensitivity, a decreased circulating free fatty acids and insulin-like growth factor (IGF-1), an increased activity of AMPK, increased activity of PGC-1a, and increased mitochondrial number. Sirt1 acts by involving signaling molecules such P-I-3-kinase-Akt, MAPK and p38-MAPK-β. βAR stimulation antagonizes the protective effect of the AKT pathway through inhibiting induction of Hif-1α and Sirt1 genes, key elements in cell survival. More studies are needed to better clarify the involvement of sirtuins in the β-adrenergic response and, overall, to better define the mechanisms by which tools such as exercise training are able to counteract the oxidative stress, by both activation of sirtuins and inhibition of GRK2 in many cardiovascular conditions and can be used to prevent or treat diseases such as heart failure.
Aging is a multifactorial process resulting in damage of molecules, cells, and tissues. It has been demonstrated that the expression and activity of antioxidant systems (SOD, HSPs) are modified in aging, with reduced cell ability to counteract the oxidant molecules, and consequent weak resistance to ROS accumulation. An important mechanism involved is represented by sirtuins, the activity of which is reduced by aging. Physical activity increases the expression and the activity of antioxidant enzymes, with consequent reduction of ROS. Positive effects of physical exercise in terms of antioxidant activity could be ascribable to a greater expression and activity of SOD enzymes, HSPs and SIRT1 activity. The antioxidant effects could increase, decrease, or not change in relation to the exercise protocol. Therefore, some authors by using a new approach based on the in vivo/vitro technique demonstrated that the highest survival and proliferation and the lowest senescence were obtained by performing an aerobic training. Therefore, the in vivo/vitro technique described could represent a good tool to better understand how the exercise training mediates its effects on aging-related diseases, as elderly with heart failure that represents a special population in which the exercise plays an important role in the improvement of cardiovascular function, quality of life, and survival.
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