Age and genetic determinants of variation of circulating levels of the receptor for advanced glycation end products (RAGE) in the general human population

Prakash, Jai; Pichchadze, Guram; Trofimov, Svetlana; Livshits, Gregory

doi:10.1016/j.mad.2015.01.001

Cited by 15 publications

(9 citation statements)

References 47 publications

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“…3). Our data extend previously published data showing that in a general population sRAGE levels is slightly but significantly higher in middle-age women compared to men [38,39]. The reason for this is currently unknown, but estrogen levels may be involved [43,44].…”

Section: Discussionsupporting

confidence: 89%

“…Experimental animal models suggest a protective role of sRAGE against inflammation associated with obesity and T2DM [14,28]. Several clinical studies have also reported significant negative correlation of sRAGE or esRAGE with BMI, WC, W/H and other obesity indices in a general population, obese and pre-diabetic subjects [36–39,51–53]. Much less is known about cRAGE variations in these pathological contexts.…”

Section: Discussionmentioning

confidence: 99%

“…Lower total sRAGE levels associate with increased body mass index (BMI), waist circumference (WC) and fat mass [37,38]. Recently, Prakash et al showed that levels of sRAGE decline with age and inversely associate with BMI and fat free mass (FFM) in an apparently healthy population [39]. Healthy centenarians have a significant higher plasma sRAGE amount than healthy young subject [40].…”

Section: Introductionmentioning

confidence: 99%

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Modulation of soluble receptor for advanced glycation end-products (RAGE) isoforms and their ligands in healthy aging

Scavello

Zeni

Tedesco

et al. 2019

Aging

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The receptor for advanced glycation end-products (RAGE) recognizes several ligands involved in inflammatory diseases. Two circulating soluble isoforms exist: esRAGE derived from alternative splicing and cRAGE generated by the membrane-bound RAGE (FL-RAGE) proteolysis. Together, esRAGE and cRAGE constitute sRAGE and function as decoy receptors preventing FL-RAGE/ligands binding. We determined serum concentration of both, esRAGE and cRAGE, and their ligands AGEs, HMGB1 and S100A8/A9 in a healthy population of 169 subjects aged 20-90 years. cRAGE showed a negative (r=-0.375, P<0.0001) while AGEs (r=0.160, P=0.0384) and S100A8/A9 (r=0.207, P=0.0091) a positive correlation with age. esRAGE did not change during aging and inversely correlated with Hemoglobin, ALT, insulin, HOMA index, Waist-Hip ratio (W/H), Waist Circumference (WC) and positively with AGEs. cRAGE exhibited also an inverse correlation with WC, W/H, PAI-1, HMGB1, AGEs and S100A8/A9. Age, W/H, HMGB1, S100A8/A9 and AGEs are independent predictors of cRAGE, whereas W/H and AGEs associate with esRAGE. Treatment of cells with glycated albumin reduced cRAGE production and upregulated FL-RAGE. These results indicate that in a healthy population cRAGE is a biomarker of aging while esRAGE represents a more reliable marker of obesity and insulin resistance. Hence, sRAGE isoforms levels could be differentially associated with age-related diseases risk factors.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modulation of soluble receptor for advanced glycation end-products (RAGE) isoforms and their ligands in healthy aging

Scavello

Zeni

Tedesco

et al. 2019

Aging

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“…Herein, we are the first to characterize the circulating concentrations of the two most prominent sRAGE isoforms across the glucose tolerance continuum and demonstrate that total sRAGE, cRAGE, and cRAGE:esRAGE were associated with the proportional odds for progression across the glucose tolerance continuum using ordinal logistic regression. Our data are, admittedly, limited by not being age matched across all groups, as others have demonstrated that chronological age plays a significant role in sRAGE concentrations (36). However, juxtaposition of the T2DM phenotype against a young, lean, healthy phenotype demonstrates the degree to which circulating sRAGE isoforms in obesity, states of impaired glucose tolerance, and advanced age deviate from optimum health.…”

Section: Discussionmentioning

confidence: 67%

Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes

Miranda

Somal

Mey

et al. 2017

American Journal of Physiology-Endocrinology and Metabolism

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The soluble receptor for advanced glycation end products (sRAGE) may be protective against inflammation associated with obesity and type 2 diabetes (T2DM). The aim of this study was to determine the distribution of sRAGE isoforms and whether sRAGE isoforms are associated with risk of T2DM development in subjects spanning the glucose tolerance continuum. In this retrospective analysis, circulating total sRAGE and endogenous secretory RAGE (esRAGE) were quantified via ELISA, and cleaved RAGE (cRAGE) was calculated in 274 individuals stratified by glucose tolerance status (GTS) and obesity. Group differences were probed by ANOVA, and multivariate ordinal logistic regression was used to test the association between sRAGE isoform concentrations and the proportional odds of developing diabetes, vs. normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). When stratified by GTS, total sRAGE, cRAGE, and esRAGE were all lower with IGT and T2DM, while the ratio of cRAGE to esRAGE (cRAGE:esRAGE) was only lower ( < 0.01) with T2DM compared with NGT. When stratified by GTS and obesity, cRAGE:esRAGE was higher with obesity and lower with IGT ( < 0.0001) compared with lean, NGT. In ordinal logistic regression models, greater total sRAGE (odds ratio, 0.91; < 0.01) and cRAGE (odds ratio, 0.84; < 0.01) were associated with lower proportional odds of developing T2DM. Reduced values of sRAGE isoforms observed with both obesity and IGT are independently associated with greater proportional odds of developing T2DM. The mechanisms by which each respective isoform contributes to obesity and insulin resistance may reveal novel treatment strategies for diabetes.

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“…The RAGE levels of the young healthy subjects in this project were relatively high compared to the general male population (Prakash et al . ). Thus, the changes observed in vascular function were not related to changes in AGE plasma concentration.…”

Section: Discussionmentioning

confidence: 97%

Endothelial mechanotransduction proteins and vascular function are altered by dietary sucrose supplementation in healthy young male subjects

Gliemann

Rytter

Lindskrog

et al. 2017

The Journal of Physiology

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Endothelial mechanotransduction is important for vascular function but alterations and activation of vascular mechanosensory proteins have not been investigated in humans. In endothelial cell culture, simple sugars effectively impair mechanosensor proteins. To study mechanosensor- and vascular function in humans, 12 young healthy male subjects supplemented their diet with 3 × 75 g sucrose day for 14 days in a randomized cross-over design. Before and after the intervention period, the hyperaemic response to passive lower leg movement and active knee extensor exercise was determined by ultrasound doppler. A muscle biopsy was obtained from the thigh muscle before and after acute passive leg movement to allow assessment of protein amounts and the phosphorylation status of mechanosensory proteins and NADPH oxidase. The sucrose intervention led to a reduced flow response to passive movement (by 17 ± 2%) and to 12 W of active exercise (by 9 ± 1%), indicating impaired vascular function. A reduced flow response to passive and active exercise was paralleled by a significant up-regulation of platelet endothelial cell adhesion molecule (PECAM-1), endothelial nitric oxide synthase, NADPH oxidase and the Rho family GTPase Rac1 protein expression in the muscle tissue, as well as an increased basal phosphorylation status of vascular endothelial growth factor receptor 2 and a reduced phosphorylation status of PECAM-1. The phosphorylation status was not acutely altered with passive leg movement. These findings indicate that a regular intake of high levels of sucrose can impair vascular mechanotransduction and increase the oxidative stress potential, and suggest that dietary excessive sugar intake may contribute to the development of vascular disease.

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Age and genetic determinants of variation of circulating levels of the receptor for advanced glycation end products (RAGE) in the general human population

Cited by 15 publications

References 47 publications

Modulation of soluble receptor for advanced glycation end-products (RAGE) isoforms and their ligands in healthy aging

Modulation of soluble receptor for advanced glycation end-products (RAGE) isoforms and their ligands in healthy aging

Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes

Endothelial mechanotransduction proteins and vascular function are altered by dietary sucrose supplementation in healthy young male subjects

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