Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span

22 páginas, 4 figuras.A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.This work was supported by grants from the American Heart Association (0425834T to J.A.B. and 0435140N to A.C.) and from the NIH (RO1GM068072, AG19972, and AG19719 to D.A.S.), (HL077256 to Z.U.), (HD034089 to L.W), (2RO1 EY011733 to N.S.W.), Spanish grant (BFU2005-03017 to P.N.), and by the generous support of Mr. Paul F. Glenn and The Paul F. Glenn Laboratories for the Biological Mechanisms of Aging.Peer reviewe

Role of NAD(P)H Oxidase in Superoxide Generation and Endothelial Dysfunction in Goto-Kakizaki (GK) Rats as a Model of Nonobese NIDDM

Background: Cardiovascular disease is the leading cause of mortality in diabetics, and it has a complex etiology that operates on several levels. Endothelial dysfunction and increased generation of reactive oxygen species are believed to be an underlying cause of vascular dysfunction and coronary artery disease in diabetes. This impairment is likely the result of decreased bioavailability of nitric oxide (NO) within the vasculature. However, it is unclear whether hyperglycemia per se stimulates NADPH oxidase-derived superoxide generation in vascular tissue. Methods and Results: This study focused on whether NADPH oxidase-derived superoxide is elevated in vasculature tissue evoking endothelial/smooth muscle dysfunction in the hyperglycemic (16964 mg%) Goto-Kakizaki (GK) rat. By dihydroethidine fluorescence staining, we determined that aorta superoxide levels were significantly elevated in 9 month-old GK compared with age matched Wistar (GK; 19566%, Wistar; 10063.5%). Consistent with these findings, 10 26 mol/L acetylcholine-induced relaxation of the carotid artery was significantly reduced in GK rats compared with age matched Wistar (GK; 4167%, Wistar; 10065%) and measurements in the aorta showed a similar trend (p =.08). In contrast, relaxation to the NO donor SNAP was unaltered in GK compared to Wistar. Endothelial dysfunction was reversed by lowering of superoxide with apocynin, a specific Nox inhibitor. Conclusions: The major findings from this study are that chronic hyperglycemia induces significant vascular dysfunction i

Hyperactive S6K1 Mediates Oxidative Stress and Endothelial Dysfunction in Aging: Inhibition by Resveratrol

Mammalian target of rapamycin (mTOR)/S6K1 signalling emerges as a critical regulator of aging. Yet, a role of mTOR/S6K1 in aging-associated vascular endothelial dysfunction remains unknown. In this study, we investigated the role of S6K1 in aging-associated endothelial dysfunction and effects of the polyphenol resveratrol on S6K1 in aging endothelial cells. We show here that senescent endothelial cells displayed higher S6K1 activity, increased superoxide production and decreased bioactive nitric oxide (NO) levels than young endothelial cells, which is contributed by eNOS uncoupling. Silencing S6K1 in senescent cells reduced superoxide generation and enhanced NO production. Conversely, over-expression of a constitutively active S6K1 mutant in young endothelial cells mimicked endothelial dysfunction of the senescent cells through eNOS uncoupling and induced premature cellular senescence. Like the mTOR/S6K1 inhibitor rapamycin, resveratrol inhibited S6K1 signalling, resulting in decreased superoxide generation and enhanced NO levels in the senescent cells. Consistent with the data from cultured cells, an enhanced S6K1 activity, increased superoxide generation, and decreased bioactive NO levels associated with eNOS uncoupling were also detected in aortas of old WKY rats (aged 20–24 months) as compared to the young animals (1–3 months). Treatment of aortas of old rats with resveratrol or rapamycin inhibited S6K1 activity, oxidative stress, and improved endothelial NO production. Our data demonstrate a causal role of the hyperactive S6K1 in eNOS uncoupling leading to endothelial dysfunction and vascular aging. Resveratrol improves endothelial function in aging, at least in part, through inhibition of S6K1. Targeting S6K1 may thus represent a novel therapeutic approach for aging-associated vascular disease

Differential proinflammatory and prooxidant effects of bone morphogenetic protein-4 in coronary and pulmonary arterial endothelial cells

There is increasing evidence that TGF-β family member cytokine bone morphogenetic protein (BMP)-4 plays different pathophysiological roles in the pulmonary and systemic circulation. Upregulation of BMP-4 has been linked to atherosclerosis and hypertension in the systemic circulation, whereas disruption of BMP-4 signaling is associated with the development of pulmonary hypertension. To test the hypothesis that BMP-4 elicits differential effects in the pulmonary and systemic circulation, we compared the prooxidant and proinflammatory effects of BMP-4 in cultured human coronary arterial endothelial cells (CAECs) and pulmonary arterial endothelial cells (PAECs). We found that BMP-4 (from 0.3 to 10 ng/ml) in CAECs increased O2•− and H2O2 generation, induced NF-κB activation, upregulated ICAM-1, and induced monocyte adhesiveness to ECs. In contrast, BMP-4 failed to induce oxidative stress or endothelial activation in PAECs. Also, BMP-4 treatment impaired acetylcholine-induced relaxation and increased O2•− production in cultured rat carotid arteries, whereas cultured rat pulmonary arteries were protected from these adverse effects of BMP-4. Thus, we propose that BMP-4 exerts prooxidant, prohypertensive, and proinflammatory effects only in the systemic circulation, whereas pulmonary arteries are protected from these adverse effects of BMP-4. The vascular bed-specific endothelial effects of BMP-4 are likely to contribute to its differential pathophysiological role in the systemic and pulmonary circulation

Cognitive and metacognitive aspects of the development of lifelong learning competencies in law students

Lifelong learning is one of the main trends in educational and social policy in Europe, aimed at ensuring professional realization and social integrity of an individual. The article describes cognitive and metacognitive aspects of the formation of learning competence, as well as predisposition of law students to lifelong learning. A survey of 218 students and masters was conducted, data on the most popular and effective forms of knowledge acquisition (experience of formal, nonformal and informal learning over the past year), plans for further education and career development were collected. The dynamics of learning at different years of study is described. A group of students with pronounced learning and focus on lifelong learning (45% of the sample) was identified. A comparative analysis of two samples was carried out and qualities that could be considered markers of the LLL orientation were identified: a high level of metacognitive knowledge and metacognitive activity, reflective competence (at the cognitive, metacognitive and personal level), internal involvement in learning, focus on achieving professionalism and personal development, general self-efficacy, the prevalence of progressive and creative motives over consumer ones. Conclusions are drawn about the predominant role of metacognitions and personality determinants in the formation of lifelong learning competency among students. Reflection aimed at recognizing one’s own cognitive processes and understanding their contribution to personal development is the main mechanism for the formation of meta-cognitive abilities. The results obtained in the study determine the ways of pedagogical support and psychological intervention to ensure the development of lifelong learning competencies in different categories of students