Dietary intake of advanced glycation endproducts (AGEs) and cancer risk across more than 20 anatomical sites: A multinational cohort study.
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ABSTRACT:
SUBMITTER: Cordova R
PROVIDER: S-EPMC9558686 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
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Dietary intake of advanced glycation endproducts (AGEs) and cancer risk across more than 20 anatomical sites: A multinational cohort study.
Córdova Reynalda R Mayén Ana-Lucia AL Knaze Viktoria V Aglago Elom Kouassivi EK Schalkwijk Casper C Wagner Karl-Heinz KH Overvad Kim K Tjønneland Anne A Kyrø Cecilie C Katzke Verena Andrea VA Cornet Charlotte Le CL Schulze Matthias Bernd MB Birukov Anna A Palli Domenico D Grioni Sara S Pasanisi Fabrizio F Catalano Alberto A Sandanger Torkjel Manning TM Gram Inger Torhild IT Skeie Guri G Crous-Bou Marta M Molina-Montes Esther E Amiano Pilar P Colorado-Yohar Sandra Milena SM Ardanaz Eva E Drake Isabel I Manjer Jonas J Johansson Ingegerd I Esberg Anders A Perez-Cornago Aurora A Weiderpass Elisabete E Jenab Mazda M Freisling Heinz H
Cancer communications (London, England) 20220804 10
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Project description:Advanced glycation endproducts (AGEs) may contribute to liver carcinogenesis because of their proinflammatory and prooxidative properties. Diet is a major source of AGEs, but there is sparse human evidence on the role of AGEs intake in liver cancer etiology. We examined the association between dietary AGEs and the risk of hepatobiliary cancers in the European Prospective Investigation into Cancer and Nutrition prospective cohort (n = 450 111). Dietary intake of three AGEs, Nε -[carboxymethyl]lysine (CML), Nε -[1-carboxyethyl]lysine (CEL) and Nδ -[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1), was estimated using country-specific dietary questionnaires linked to an AGEs database. Cause-specific hazard ratios (HR) and their 95% confidence intervals (CI) for associations between dietary AGEs and risk of hepatocellular carcinoma (HCC), gallbladder and biliary tract cancers were estimated using multivariable Cox proportional hazard regression. After a median follow-up time of 14.9 years, 255 cases of HCC, 100 cases of gallbladder cancer and 173 biliary tract cancers were ascertained. Higher intakes of dietary AGEs were inversely associated with the risk of HCC (per 1 SD increment, HR-CML = 0.87, 95% CI: 0.76-0.99, HR-CEL = 0.84, 95% CI: 0.74-0.96 and HR-MH-G1 = 0.84, 95% CI: 0.74-0.97). In contrast, positive associations were observed with risk of gallbladder cancer (per 1 SD, HR-CML = 1.28, 95% CI: 1.05-1.56, HR-CEL = 1.17; 95% CI: 0.96-1.40, HR-MH-G1 = 1.27, 95% CI: 1.06-1.54). No associations were observed for cancers of the intra and extrahepatic bile ducts. Our findings suggest that higher intakes of dietary AGEs are inversely associated with the risk of HCC and positively associated with the risk of gallbladder cancer.
| S-EPMC8360042 | biostudies-literature
Project description:Advanced glycation endproducts (AGEs) are a heterogeneous group of compounds that form via non-enzymatic glycation of proteins throughout our lifespan and at a higher rate in certain chronic diseases such as diabetes. AGEs contribute to the progression of fibrosis, in part by stimulating cellular pathways that affect gene expression. Long-lived ECM proteins are targets for non-enzymatic glycation but the question of whether the AGE-modified ECM leads to excess ECM accumulation and fibrosis remains unanswered. In this study, cellular changes due to AGE accretion in the ECM were investigated. Non-enzymatic glycation of proteins in a decellularized fibroblast ECM was achieved by incubating the ECM in a solution of methylglyoxal (MGO). Mass spectrometry of fibronectin (FN) isolated from the glycated matrix identified twenty-eight previously unidentified MGO-derived AGE modification sites including functional sites such as the RGD integrin-binding sequence. Mesangial cells grown on the glycated, decellularized matrix assembled increased amounts of FN matrix. Soluble AGE-modified bovine serum albumin (BSA) also stimulated FN matrix assembly and this effect was reduced by function-blocking antibodies against the receptor for AGE (RAGE). These results indicate that cells respond to AGEs by increasing matrix assembly and that RAGE is involved in this response. This raises the possibility that the accumulation of ECM during the progression of fibrosis may be enhanced by cell interactions with AGEs on a glycated ECM.
| S-EPMC5237628 | biostudies-literature
Project description:Aging is a strong risk factor for brain dementia and cognitive decline. Age-related accumulation of metabolites such as advanced glycation end products (AGEs) could serve as danger signals to initiate and accelerate disease process and neurodegeneration. The underlying causes and consequences of cerebral AGEs accumulation remain largely unknown. Here, we comprehensively investigate age-related accumulation of AGEs and dicarbonyls, including methylglyoxal (MG), glyoxal (GO), and 3-deoxyglucosone (3-DG), and the effects of mitochondrial reactive oxygen species (ROS) on cerebral AGEs accumulation, mitochondrial function, and oxidative stress in the aging human and mouse brain. We demonstrate that AGEs, including arginine and lysine derived N(6)-carboxymethyl lysine (CML), Nε-(1-Carboxyethyl)-l-lysine (CEL), and methylglyoxal-derived hydroimidazolone-1 (MG-H1), were significantly elevated in the cerebral cortex and hippocampus with advanced age in mice. Accordingly, aging mouse and human brains revealed decrease in activities of mitochondrial respiratory chain complexes I & IV and ATP levels, and increased ROS. Notably, administration of mitoTEMPO (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mTEMPO), a scavenger of mitochondrial ROS, not only suppressed ROS production but also reduced aged-induced accumulation of AGEs and dicarbonyls. mTEMPO treatment improved mitochondrial respiratory function and restored ATP levels. Our findings provide evidence linking age-related accumulation of toxic metabolites (AGEs) to mitochondrial oxidative stress. This highlights a novel mechanism by which AGEs-dependent signaling promotes carbonyl stress and sustained mitochondrial dysfunction. Eliminating formation and accumulation of AGEs may represent a new therapeutic avenue for combating cognitive decline and mitochondrial degeneration relevant to aging and neurodegenerative diseases including Alzheimer's disease.
| S-EPMC8552367 | biostudies-literature
Project description:Advanced glycation end-products (AGEs) may promote oxidative stress and inflammation and have been linked to multiple chronic diseases, including cancer. However, the association of AGEs with mortality after colorectal cancer (CRC) diagnosis has not been previously investigated. Multivariable Cox proportional hazards models were used to calculate hazard ratios and corresponding 95% confidence intervals for associations between dietary intake of AGEs with CRC-specific and all-cause mortality among 5801 participant cases diagnosed with CRC in the European Prospective Investigation into Cancer and Nutrition study between 1993 and 2013. Dietary intakes of AGEs were estimated using country-specific dietary questionnaires, linked to an AGE database, that accounted for food preparation and processing. During a median of 58 months of follow-up, 2421 cases died (1841 from CRC). Individually or combined, dietary intakes of AGEs were not associated with all-cause and CRC-specific mortality among cases. However, there was a suggestion for a positive association between AGEs and all-cause or CRC-specific mortality among CRC cases without type II diabetes (all-cause, Pinteraction = 0.05) and CRC cases with the longest follow-up between recruitment and cancer diagnosis (CRC-specific, Pinteraction = 0.003; all-cause, Pinteraction = 0.01). Our study suggests that pre-diagnostic dietary intakes of AGEs were not associated with CRC-specific or all-cause mortality among CRC patients. Further investigations using biomarkers of AGEs and stratifying by sex, diabetes status, and timing of exposure to AGEs are warranted.
| S-EPMC8704988 | biostudies-literature
Project description:Advanced glycation endproducts (AGEs) can be found in protein- and sugar-rich food products processed at high temperatures, which make up a vast amount of the Western diet. The effect of AGE-rich food products on human health is not yet clear and controversy still exists due to possible contamination of samples with endotoxin and the use of endogenous formed AGEs. AGEs occur in food products, both as protein-bound and individual molecules. Which form exactly induces a pro-inflammatory effect is also unknown. In this study, we exposed human macrophage-like cells to dietary AGEs, both in a protein matrix and individual AGEs. It was ensured that all samples did not contain endotoxin concentrations > 0.06 EU/mL. The dietary AGEs induced TNF-alpha secretion of human macrophage-like cells. This effect was decreased by the addition of N(ε)-carboxymethyllysine (CML)-antibodies or a receptor for advanced glycation endproducts (RAGE) antagonist. None of the individual AGEs induce any TNF-alpha, indicating that AGEs should be bound to proteins to exert an inflammatory reaction. These findings show that dietary AGEs directly stimulate the inflammatory response of human innate immune cells and help us define the risk of regular consumption of AGE-rich food products on human health.
| S-EPMC6315629 | biostudies-literature
Project description:AimsNon-invasively assessed skin autofluorescence (SAF) measures advanced glycation endproducts (AGEs) in the dermis. SAF correlates with dermal AGEs in Caucasians and Asians, but studies in dark-skinned subjects are lacking. In this pilot we aimed to assess whether SAF signal is representative of intrinsic fluorescence (IF) and AGE accumulation in dark skin.MethodsSkin biopsies were obtained in 12 dark-skinned subjects (6 healthy subjects, median age 22 years; 6 diabetes mellitus (DM) subjects, 65 years). SAF was measured with the AGE Reader, IF using confocal microscopy, and AGE distribution with specific antibodies. CML and MG-H1 were quantified with UPLC-MS/MS and pentosidine with HPLC and fluorescent detection.ResultsSAF correlated with IF from the dermis (405nm, r = 0.58, p < 0.05), but not with CML (r = 0.54, p = 0.07). CML correlated with IF from the dermis (405nm, r = 0.90, p < 0.01). UV reflectance and the coefficient of variation of SAF were negatively correlated (r = -0.80, p < 0.01). CML and MG-H1 were predominantly present around blood vessels, in collagen and fibroblasts in the dermis.ConclusionThis proof of concept study is the first to compare non-invasive SAF with AGE levels measured in skin biopsies in dark-skinned subjects. SAF did not correlate with individual AGEs from biopsies, but was associated with IF. However, the intra-individual variance was high, limiting its application in dark-skinned subjects on an individual basis.
| S-EPMC7674296 | biostudies-literature
Project description:BackgroundWe recently reported strong associations between eight skin collagen AGEs and two solubility markers from skin biopsies obtained at DCCT study closeout and the long-term progression of microvascular disease in EDIC, despite adjustment for mean glycemia. Herein we investigated the hypothesis that some of these AGEs (fluorescence to be reported elsewhere) correlate with long-term subclinical cardiovascular disease (CVD) measurements, i.e. coronary artery calcium score (CAC) at EDIC year 7-9 (n = 187), change of carotid intima-media thickness (IMT) from EDIC year 1 to year 6 and 12 (n = 127), and cardiac MRI outcomes at EDIC year 15-16 (n = 142).MethodsSkin collagen AGE measurements obtained from stored specimens were related to clinical data from the DCCT/EDIC using Spearman correlations and multivariable logistic regression analyses.ResultsSpearman correlations showed furosine (early glycation) was associated with future mean CAC (p < 0.05) and CAC >0 (p = 0.039), [corrected] but not with CAC score <100 vs. >100. Glucosepane and pentosidine crosslinks, methylglyoxal hydroimidazolones (MG-H1) and pepsin solubility (inversely) correlated with IMT change from year 1 to 6(all P < 0.05). Left ventricular (LV) mass (cMRI) correlated with MG-H1, and inversely with pepsin solubility (both p < 0.05), while the ratio LV mass/end diastolic volume correlated with furosine and MG-H1 (both p < 0.05), and highly with CML (p < 0.01). In multivariate analysis only furosine (p = 0.01) was associated with CAC. In contrast IMT was inversely associated with lower collagen pepsin solubility and positively with glucosepane,ConclusionsIn type 1 diabetes, multiple AGEs are associated with IMT progression in spite of adjustment for A1c implying a likely participatory role of glycation and AGE mediated crosslinking on matrix accumulation in coronary arteries. This may also apply to functional cardiac MRI outcomes, especially left ventricular mass. In contrast, early glycation measured by furosine, but not AGEs, was associated with CAC score, implying hyperglycemia as a risk factor in calcium deposition perhaps via processes independent of glycation.Trial registrationRegistered at Clinical trial reg. nos. NCT00360815 and NCT00360893, http://www.clinicaltrials.gov.
| S-EPMC4560872 | biostudies-literature
Project description:The epidemics of insulin resistance (IR) and type 2 diabetes (T2D) affect the first world as well as less-developed countries, and now affect children as well. Persistently elevated oxidative stress and inflammation (OS/Infl) precede these polygenic conditions. A hallmark of contemporary lifestyle is a preference for thermally processed nutrients, replete with pro-OS/Infl advanced glycation endproducts (AGEs), which enhance appetite and cause overnutrition. We propose that chronic ingestion of oral AGEs promotes IR and T2D. The mechanism(s) involved in these findings were assessed in four generations of C57BL6 mice fed isocaloric diets with or without AGEs [synthetic methyl-glyoxal-derivatives (MG(+))]. F3/MG(+) mice manifested increased adiposity and premature IR, marked by severe deficiency of anti-AGE advanced glycation receptor 1 (AGER1) and of survival factor sirtuin 1 (SIRT1) in white adipose tissue (WAT), skeletal muscle, and liver. Impaired 2-deoxy-glucose uptake was associated with marked changes in insulin receptor (InsR), IRS-1, IRS-2, Akt activation, and a macrophage and adipocyte shift to a pro-OS/inflammatory (M1) phenotype. These features were absent in F3/MG(-) mice. MG stimulation of 3T3-L1 adipocytes led to suppressed AGER1 and SIRT1, and altered InsR, IRS-1, IRS-2 phosphorylation, and nuclear factor kappa-light chain enhancer of activated B cells (Nf-?B) p65 acetylation. Gene modulation revealed these effects to be coregulated by AGER1 and SIRT1. Thus, prolonged oral exposure to MG-AGEs can deplete host-defenses AGER1 and SIRT1, raise basal OS/Infl, and increase susceptibility to dysmetabolic IR. Because exposure to AGEs can be decreased, these insights provide an important framework for alleviating a major lifestyle-linked disease epidemic.
| S-EPMC3465382 | biostudies-literature
Project description:Multiple sclerosis (MS) is a demyelinating autoimmune disease in which innate and adaptive immune cells infiltrate the central nervous system (CNS) and damage the myelin sheaths surrounding the axons. Upon activation, infiltrated macrophages, CNS-resident microglia, and astrocytes switch their metabolism toward glycolysis, resulting in the formation of α-dicarbonyls, such as methylglyoxal (MGO) and glyoxal (GO). These potent glycating agents lead to the formation of advanced glycation endproducts (AGEs) after reaction with amino acids. We hypothesize that AGE levels are increased in MS lesions due to the inflammatory activation of macrophages and astrocytes. First, we measured tissue levels of AGEs in brain samples of MS patients and controls. Analysis of MS patient and non-demented control (NDC) specimens showed a significant increase in protein-bound Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), the major AGE, compared to white matter of NDCs (107 ± 11 vs. 154 ± 21, p < 0.05). In addition, immunohistochemistry revealed that MGO-derived AGEs were specifically present in astrocytes, whereas the receptor for AGEs, RAGE, was detected on microglia/macrophages. Moreover, in cerebrospinal fluid from MS patients, α-dicarbonyls and free AGEs correlated with their respective levels in the plasma, whereas this was not observed for protein-bound AGEs. Taken together, our data show that MG-H1 is produced by astrocytes. This suggests that AGEs secreted by astrocytes have paracrine effects on RAGE-positive macrophages/microglia and thereby contribute to the pathology of MS.
| S-EPMC6491451 | biostudies-literature
Project description:The receptor for advanced glycation endproducts (RAGE) is expressed in T cells after activation with antigen and is constitutively expressed in T cells from patients at-risk for and with type 1 diabetes mellitus (T1D). RAGE expression was associated with an activated T cell phenotype, leading us to examine whether RAGE is involved in T cell signaling. In primary CD4+ and CD8+ T cells from patients with T1D or healthy control subjects, RAGE- cells showed reduced phosphorylation of Erk. To study T cell receptor signaling in RAGE+ or-T cells, we compared signaling in RAGE+/+ Jurkat cells, Jurkat cells with RAGE eliminated by CRISPR/Cas9, or silenced with siRNA. In RAGE KO Jurkat cells, there was reduced phosphorylation of Zap70, Erk and MEK, but not Lck or CD3ξ. RAGE KO cells produced less IL-2 when activated with anti-CD3 +/- anti-CD28. Stimulation with PMA restored signaling and (with ionomycin) IL-2 production. Silencing RAGE with siRNA also decreased signaling. Our studies show that RAGE expression in human T cells is associated with an activated signaling cascade. These findings suggest a link between inflammatory products that are found in patients with diabetes, other autoimmune diseases, and inflammation that may enhance T cell reactivity.
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