Novel biomolecules of ageing, sex differences and potential underlying mechanisms of telomere shortening in coronary artery disease

Opstad, Trine Baur; Kalstad, Are Annesønn; Pettersen, A.Å.; Arnesen, Harald; Seljeflot, Ingebjørg

doi:10.1016/j.exger.2019.01.020

Cited by 28 publications

(24 citation statements)

References 41 publications

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“…But with TERT transcription bidirectional regulation, telomere can be regulated by controlling level and prolong telomere length, slow down cell senescence, restore organ function, maintain body homeostasis and prolong life of organism to a certain extent. Recent study has shown that GDF11 has a positive effect on the maintenance of telomere length which supports the conclusions of this study, but that paper does not provide speci c mechanism analysis 34 . In this study, bioinformatics analyses showed that GDF11 could through SMAD/CTCF/MYC signaling pathway, SP1 and ETS2 regulate TERT to maintain telomere length, which provides direction and target for subsequent experimental veri cation.…”

Section: Discussionsupporting

confidence: 77%

Bioinformatics Network Analyses of Growth Differentiation Factor 11 Anti-aging Study

Zhang

Yang

Bao

2020

Preprint

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Growth differentiation factor 11 (GDF11) has been implicated in rejuvenative functions in age-related diseases. The molecular mechanisms connecting GDF11 with these anti-aging phenomena (reverse age-related cardiac hypertrophy, vascular and neurogenic rejuvenation, et al.) are still unclear. In this study, we aim to uncover the molecular functions of GDF11 using bioinformatics and network-driven analyses at human gene and transcription levels using gene co-expression network analysis and transcription factor network analysis. Our data suggests that GDF11 is involved in variety of functions such as apoptosis, DNA repair and telomere maintenance and interaction with key transcription factors such as MYC proto-oncogene (MYC), specificity protein 1 (SP1) and ETS proto oncogene 2 (ETS2). Our findings shed lights on the functions of GDF11 and provide insights into the role of GDF11 in aging.

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Section: Discussionsupporting

confidence: 77%

Bioinformatics Network Analyses of Growth Differentiation Factor 11 Anti-aging Study

Zhang

Yang

Bao

2020

Preprint

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“… 11 Circulating levels of SIRT1 are inversely related to levels of proinflammatory cytokines in patients with coronary artery disease; low SIRT1 levels are accompanied by increased telomere attrition. 49 SIRT1 expression is decreased in peripheral blood monocytes in patients with Type 2 diabetes 50 and in patients with obesity with increased epicardial adipose tissue volume. 51 The expression of SIRT1 is suppressed both in peripheral leucocytes and cardiomyocytes of patients with chronic cardiomyopathy.…”

Section: Sirt1 and Akt/mtor Signalling In The Regulation Of Organismamentioning

confidence: 96%

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure

Packer

2020

European Heart Journal

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The two primary molecular regulators of lifespan are sirtuin-1 (SIRT1) and mammalian target of rapamycin complex 1 (mTORC1). Each plays a central role in two highly interconnected pathways that modulate the balance between cellular growth and survival. The activation of SIRT1 [along with peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) and adenosine monophosphate-activated protein kinase (AMPK)] and the suppression of mTORC1 (along with its upstream regulator, Akt) act to prolong organismal longevity and retard cardiac ageing. Both activation of SIRT1/PGC-1α and inhibition of mTORC1 shifts the balance of cellular priorities so as to promote cardiomyocyte survival over growth, leading to cardioprotective effects in experimental models. These benefits may be related to direct actions to modulate oxidative stress, organellar function, proinflammatory pathways, and maladaptive hypertrophy. In addition, a primary shared benefit of both SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 inhibition is the enhancement of autophagy, a lysosome-dependent degradative pathway, which clears the cytosol of dysfunctional organelles and misfolded proteins that drive the ageing process by increasing oxidative and endoplasmic reticulum stress. Autophagy underlies the ability of SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 suppression to extend lifespan, mitigate cardiac ageing, alleviate cellular stress, and ameliorate the development and progression of cardiomyopathy; silencing of autophagy genes abolishes these benefits. Loss of SIRT1/PGC-1α/AMPK function or hyperactivation of Akt/mTORC1 is a consistent feature of experimental cardiomyopathy, and reversal of these abnormalities mitigates the development of heart failure. Interestingly, most treatments that have been shown to be clinically effective in the treatment of chronic heart failure with a reduced ejection fraction have been reported experimentally to exert favourable effects to activate SIRT1/PGC-1α/AMPK and/or suppress Akt/mTORC1, and thereby, to promote autophagic flux. Therefore, the impairment of autophagy resulting from derangements in longevity gene signalling is likely to represent a seminal event in the evolution and progression of cardiomyopathy.

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“…We have previously observed associations between LTLs and the longevity factors sirtuin 1 (SIRT1) and growth-differentiating factor 11 (GDF11) in both healthy and CHD patients 17,18 . SIRT1, the most studied of seven sirtuins, is thought to stabilize telomere ends 19 , and to play a role in glucose metabolism through induced expression of the insulin gene.…”

Section: Introductionmentioning

confidence: 99%

Reduced leukocyte telomere lengths and sirtuin 1 gene expression in long‐term survivors of type 1 diabetes: A Dialong substudy

Opstad

Berg

Holte

et al. 2020

J of Diabetes Invest

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Aims/Introduction: The shortening of leukocyte telomere length with age has been associated with coronary disease, whereas the association with type 1 diabetes is unclear. We aimed to explore telomere lengths in diabetes patients with regard to coronary artery disease, compared with healthy controls. The longevity factors sirtuin 1 and growth-differentiating factor 11 were investigated accordingly. Materials and Methods: We carried out a cross-sectional study of 102 participants with long-term type 1 diabetes and 75 controls (mean age 62 and 63 years, respectively), where 88 cases and 60 controls without diagnosed coronary artery disease completed computed tomography coronary angiography. Telomere lengths and gene expression of sirtuin 1 and growth-differentiating factor 11 were quantified in leukocytes. Results: Telomere lengths and sirtuin 1 were reduced in diabetes patients versus controls, medians (25th to 75th percentiles): 0.97 (0.82-1.15) versus 1.08 (0.85-1.29) and 0.88 (0.65-1.14) vs 1.01 (0.78-1.36), respectively, adjusted P < 0.05, both. Previous coronary artery disease in diabetes patients (n = 15) was associated with lower sirtuin 1 and growth-differentiating factor 11 messenger ribonucleic acid expression (adjusted P < 0.03, both). In the combined diabetes and control group, previous artery coronary disease (n = 18) presented with significantly shorter telomeres (adjusted P = 0.038). Newly diagnosed obstructive coronary artery disease, defined as >50% stenosis, was not associated with the investigated variables. Conclusions: Long-term type 1 diabetes presented with reduced telomeres and sirtuin 1 expression, with additional reduction in diabetes patients with previous coronary artery disease, showing their importance for cardiovascular disease development with potential as novel biomarkers in diabetes and coronary artery disease.

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Novel biomolecules of ageing, sex differences and potential underlying mechanisms of telomere shortening in coronary artery disease

Cited by 28 publications

References 41 publications

Bioinformatics Network Analyses of Growth Differentiation Factor 11 Anti-aging Study

Bioinformatics Network Analyses of Growth Differentiation Factor 11 Anti-aging Study

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure

Reduced leukocyte telomere lengths and sirtuin 1 gene expression in long‐term survivors of type 1 diabetes: A Dialong substudy

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