Accumulation Of AGEs Research Articles

Receptor for the Advanced Glycation End Products (RAGE) Pathway in Adipose Tissue Metabolism.

Advanced glycation end products (AGEs) are mediators in the process of cellular dysfunction in response to hyperglycemia. Numerous data indicate that the accumulation of AGEs in the extracellular matrix plays a key role in the development of obesity-related adipose tissue dysfunction. Through binding of their membrane receptor (RAGE), AGEs affect numerous intracellular pathways and impair adipocyte differentiation, metabolism, and secretory activity. Therefore, inhibiting the production and accumulation of AGEs, as well as interfering with the metabolic pathways they activate, may be a promising therapeutic strategy for restoring normal adipose tissue function and, thus, combating obesity-related comorbidities. This narrative review summarizes data on the involvement of the RAGE pathway in adipose tissue dysfunction in obesity and the development of its metabolic complications. The paper begins with a brief review of AGE synthesis and the RAGE signaling pathway. The effect of the RAGE pathway on adipose tissue development and activity is then presented. Next, data from animal and human studies on the involvement of the RAGE pathway in obesity, diabetes, and cardiovascular diseases are summarized. Finally, therapeutic perspectives based on interference with the RAGE pathway are discussed.

Type II Diabetes Mellitus Causes Extracellular Matrix Alterations in the Posterior Cornea That Increase Graft Thickness and Rigidity.

There is a pressing need to investigate the impact of type II diabetes mellitus on the posterior cornea in donor tissues given its increasing prevalence and potential impact on endothelial keratoplasty surgical outcomes. Immortalized human cultured corneal endothelial cells (CECs; HCEC-B4G12) were grown in hyperglycemic media for 2 weeks. Extracellular matrix (ECM) adhesive glycoprotein expression and advanced glycation end products (AGEs) in cultured cells and corneoscleral donor tissues, as well as the elastic modulus for the Descemet membrane (DMs) and CECs of diabetic and nondiabetic donor corneas, were measured. In CEC cultures, increasing hyperglycemia resulted in increased transforming growth factor beta-induced (TGFBI) protein expression and colocalization with AGEs in the ECM. In donor corneas, the thicknesses of the DM and the interfacial matrix (IFM) between the DM and stroma both increased from 8.42 ± 1.35 µm and 0.504 ± 0.13 µm in normal corneas, respectively, to 11.13 ± 2.91 µm (DM) and 0.681 ± 0.24 µm (IFM) in non-advanced diabetes (P = 0.013 and P = 0.075, respectively) and 11.31 ± 1.76 µm (DM) and 0.744 ± 0.18 µm (IFM) in advanced diabetes (AD; P = 0.0002 and P = 0.003, respectively). Immunofluorescence in AD tissues versus controls showed increased AGEs (P < 0.001) and markedly increased labeling intensity for adhesive glycoproteins, including TGFBI, that colocalized with AGEs. The elastic modulus significantly increased between AD and control tissues for the DMs (P < 0.0001) and CECs (P < 0.0001). Diabetes and hyperglycemia alter human CEC ECM structure and composition, likely contributing to previously documented complications of endothelial keratoplasty using diabetic donor tissue, including tearing during graft preparation and reduced graft survival. AGE accumulation in the DM and IFM may be a useful biomarker for determining diabetic impact on posterior corneal tissue.

#4520 THE USE OF FAR INFRARED LIGHT DURING HEMODIALYSIS SEEMS TO MAINTAIN ARTERIOVENOUS FISTULA BLOOD FLOW BETTER THAN USING A HEAT PAD - A PILOT STUDY

Abstract Background and Aims The use of the native arteriovenous fistula (AVF) in chronic hemodialysis (HD) patients yields great challenges to keep a patent AVF, especially among those with diabetes mellitus and cardiovascular disease. Often repeated radiological interventions or surgery of the AVF is necessary. Accumulation of advanced glycation end products (AGE) in tissue is shown to contribute to the complications of diabetes mellitus and uremia [1]. Far infrared light (FIR) irradiation of the AVF have shown protective effects in maintaining AVF blood flow [2,3]. Using a heat pad (HP) to stimulate vascular flow is another alternative. Primary aim of the study was to compare if the use of a HP is as good as FIR to maintain AVF blood flow. Secondary aim: Evaluate change in AGE accumulation in tissue after FIR and HP treatment. Method This pilot study included HD patients with a native lower arm AVF. Eighteen patients were randomly assigned to treatment during HD; Ten patients to FIR and another group of eight patients to use HP (Two of the HP-patients refused to fulfill the study). Before and after a period of 15 HD treatments each, blood tests, AVF blood-flow measured with a Transsonic® and skin autofluorescence (SAF, measuring AGE) were analyzed. The distance of the FIR emitter to the AVF puncture area was 25 cm. The HP-group was exposed to a waterfilled rubber HP that kept a temperature of 40-41°C and was positioned to the backside of the AVF arm to avoid dislodgement of or compressing needles. The patient was her/his own control and non-parametric Mann-Whitney U- and Wilcoxon sign ranked tests were used. Results The blood flow of the AVF was similar at start in the FIR group versus the HP-group median 921 ml/min IQR (714-1210) vs. 610 ml/min, IQR (538-861), p = 0.118, while after 15 treatments the blood flow was maintained in the FIR group but was lower in the HP-group; median 902 ml/min IQR (718-1241) vs. 635 ml/min IQR (531-772), p = 0.022. The FIR exposure did not alter the SAF content (in arbitrary units -AU) after treatment and was similar in the FIR group (median 3.2 AU, IQR 2.2-3.6) and in the HP group (median 3.2, IQR 2.4-3.3), p-value = 0.864.During the follow-up period after 3 and 6 months, PTA was performed due stenosis with decreased blood flow of the AVF in 3/10 patients in the FIR group and 1/6 patients in the HP group. Data are given as median and interquartile range (IQR). A two-sided p-value of &amp;lt;0.05 was defined as significant. Conclusion This pilot study showed that the access flow after FIR versus HP exposure during 15 HD treatments was better maintained among patients treated with FIR than with HP. SAF as a predictor for atherosclerosis was not changed. Long-term exposure to FIR may be necessary.

Skin autofluorescence as an indicator of advanced glycation end-product accumulation in the prognosis of age-related cardiovascular disease: literature review

Advanced glycation end products (AGEs) are represented by heterogeneous molecular structures and their accumulation in organs and tissues reflects the intensity of oxidative stress and glycemia. As a physiological process, aging is associated with AGE accumulation and changing the morphology and functions of the vascular wall. Accelerated AGE accumulation initiates inflammation, contributing to the development of cardiovascular diseases, such as arterial hypertension, coronary heart diseases, and atherosclerosis of peripheral arteries; conditions associated with high cardiovascular risks such as prediabetes, diabetes mellitus type 2, and chronic kidney diseases are also characterized by the accelerated AGEs accumulation. The ability of AGEs to fluorescence underlies noninvasively in blood serum, tissues, and skin using a well-proven technique of autofluorescence, which is little known to domestic specialists. This review presents the possibilities of autofluorescence to reflect arterial wall remodeling, which includes stiffness, vascular endothelial function, atherosclerotic plaque formation, and instability, using modern materials. The review emphasizes the evidence base regarding the ability of this method to predict mortality and cardiovascular events in a large population from low to high risk.

A Role for Advanced Glycation End Products in Molecular Ageing.

Ageing is a composite process that involves numerous changes at the cellular, tissue, organ and whole-body levels. These changes result in decreased functioning of the organism and the development of certain conditions, which ultimately lead to an increased risk of death. Advanced glycation end products (AGEs) are a family of compounds with a diverse chemical nature. They are the products of non-enzymatic reactions between reducing sugars and proteins, lipids or nucleic acids and are synthesised in high amounts in both physiological and pathological conditions. Accumulation of these molecules increases the level of damage to tissue/organs structures (immune elements, connective tissue, brain, pancreatic beta cells, nephrons, and muscles), which consequently triggers the development of age-related diseases, such as diabetes mellitus, neurodegeneration, and cardiovascular and kidney disorders. Irrespective of the role of AGEs in the initiation or progression of chronic disorders, a reduction in their levels would certainly provide health benefits. In this review, we provide an overview of the role of AGEs in these areas. Moreover, we provide examples of lifestyle interventions, such as caloric restriction or physical activities, that may modulate AGE formation and accumulation and help to promote healthy ageing.

CircRNA-406918 enhances the degradation of advanced glycation end products in photoaged human dermal fibroblasts via targeting cathepsin D.

Lysosomal cathepsin D (CTSD) can degrade internalized advanced glycation end products (AGEs) in dermal fibroblasts. CTSD expression is decreased in photoaged fibroblasts, which contributes to intracellular AGEs deposition and further plays a role in AGEs accumulation of photoaged skin. The mechanism under downregulated CTSD expression is unclear. To explore possible mechanism of regulating CTSD expression in photoaged fibroblasts. Dermal fibroblasts were induced into photoaging with repetitive ultraviolet A (UVA) irradiation. The competing endogenous RNA (ceRNA) networks were constructed to predict candidate circRNAs or miRNAs related with CTSD expression. AGEs-BSA degradation by fibroblasts was studied with flow cytometry, ELISA, and confocal microscopy. Effects of overexpressing circRNA-406918 via lentiviral transduction on CTSD expression, autophagy, AGE-BSA degradation were analyzed in photoaged fibroblasts. The correlation between circRNA-406918 and CTSD expression or AGEs accumulation in sun-exposed and sun-protected skin was studied. CTSD expression, autophagy, and AGEs-BSA degradation were significantly decreased in photoaged fibroblasts. CircRNA-406918 was identified to regulate CTSD expression, autophagy, and senescence in photoaged fibroblasts. Overexpressing circRNA-406918 potently decreased senescence and increased CTSD expression, autophagic flux, and AGEs-BSA degradation in photoaged fibroblasts. Moreover, circRNA-406918 level was positively correlated with CTSD mRNA expression and negatively associated with AGEs accumulation in photodamaged skin. Further, circRNA-406918 was predicted to mediate CTSD expression through sponging eight miRNAs. These findings suggest that circRNA-406918 regulates CTSD expression and AGEs degradation in UVA-induced photoaged fibroblasts and might exert a role in AGEs accumulation in photoaged skin.

Glycolaldehyde-derived advanced glycation end products promote macrophage proliferation via the JAK-STAT signaling pathway.

Advanced glycation end products (AGEs) are heterogeneous proinflammatory molecules produced by a non-enzymatic glycation reaction between reducing sugars (and their metabolites) and biomolecules with amino groups, such as proteins. Although increases in and the accumulation of AGEs have been implicated in the onset and exacerbation of lifestyle- or age-related diseases, including diabetes, their physiological functions have not yet been elucidated in detail. The present study investigated the cellular responses of the macrophage cell line RAW264.7 stimulated by glycolaldehyde-derived AGEs (Glycol-AGEs) known as representative toxic AGEs. The results obtained showed that Glycol-AGEs significantly promoted the proliferation of RAW264.7 cells at a low concentration range (1-10µg/mL) in a concentration-dependent manner. On the other hand, neither TNF-α production nor cytotoxicity were induced by the same concentrations of Glycol-AGEs. The increases observed in cell proliferation by low concentrations of Glycol-AGEs were also detected in receptor triple knockout (RAGE-TLR4-TLR2 KO) cells as well as in wild-type cells. Increases in cell proliferation were not affected by various kinase inhibitors, including MAP kinase inhibitors, but were significantly suppressed by JAK2 and STAT5 inhibitors. In addition, the expression of some cell cycle-related genes was up-regulated by the stimulation with Glycol-AGEs. These results suggest a novel physiological role for AGEs in the promotion of cell proliferation via the JAK-STAT pathway.

High-Resolution Detection of Translocation of Oral Bacteria to the Gut

Ectopic enrichment of oral microbes in the gut is a notable alteration in gut microbial balance. These microbes are likely delivered from the oral cavity with saliva and food; however, evidence of oral–gut microbial transmission is insufficient and needs further investigation. In this observational study, we examined 144 pairs of saliva and stool samples collected from community-dwelling adults to verify the oral–gut microbial link and identify the relevant influencing factors on the increased abundance of oral microbes within the gut. The bacterial composition of each sample was determined using PacBio single-molecule long-read sequencing of the full-length 16S ribosomal RNA gene and amplicon sequence variant (ASV) analysis. Although the bacterial compositions of salivary and gut microbiota were distinctly different, at least 1 ASV was shared between salivary and gut microbiota in 72.9% of subjects. Shared ASVs accounted for 0.0% to 63.1% (median 0.14%) of the gut microbiota in each subject and frequently included abundant Streptococcus salivarius and Streptococcus parasanguinis. Their total relative abundance in the gut was significantly higher in older subjects or those with dental plaque accumulation. The gut microbiota with ≥5% of shared ASVs displayed a higher abundance of Streptococcus, Lactobacillus, and Klebsiella and a lower abundance of Faecalibacterium, Blautia, Megamonas, and Parabacteroides. Our study presents evidence for the translocation of oral bacteria to the gut in community-dwelling adults and suggests that aging and dental plaque accumulation contribute to an increased abundance of oral microbes in the gut, which might be relevant to the compositional shift in the gut commensals.

Exercise therapy for sarcopenia and diabetes.

Aging is characterized by the gradual deterioration of function at the molecular, cellular, tissue, and organism levels in humans. The typical diseases caused by changes in body composition, as well as functional decline in the human body's organs due to aging include sarcopenia and metabolic disorders. The accumulation of dysfunctional aging β cells with age can cause decreased glucose tolerance and diabetes. Muscle decline has a multifactorial origin, involving lifestyle habits, disease triggers, and age-dependent biological changes. The reduced function of β cells in elderly people lowers insulin sensitivity, which affects protein synthesis and interferes with muscle synthesis. The functional decrease and aggravation of disease in elderly people with less regular exercise or physical activity causes imbalances in food intake and a continuous, vicious cycle. In contrast, resistance exercise increases the function of β cells and protein synthesis in elderly people. In this review, we discuss regular physical activities or exercises to prevent and improve health, which is sarcopenia as decreased muscle mass and metabolic disorders as diabetes in the elderly.

The AGE-RAGE Axis and the Pathophysiology of Multimorbidity in COPD.

Chronic obstructive pulmonary disease (COPD) is a disease of the airways and lungs due to an enhanced inflammatory response, commonly caused by cigarette smoking. Patients with COPD are often multimorbid, as they commonly suffer from multiple chronic (inflammatory) conditions. This intensifies the burden of individual diseases, negatively affects quality of life, and complicates disease management. COPD and comorbidities share genetic and lifestyle-related risk factors and pathobiological mechanisms, including chronic inflammation and oxidative stress. The receptor for advanced glycation end products (RAGE) is an important driver of chronic inflammation. Advanced glycation end products (AGEs) are RAGE ligands that accumulate due to aging, inflammation, oxidative stress, and carbohydrate metabolism. AGEs cause further inflammation and oxidative stress through RAGE, but also through RAGE-independent mechanisms. This review describes the complexity of RAGE signaling and the causes of AGE accumulation, followed by a comprehensive overview of alterations reported on AGEs and RAGE in COPD and in important co-morbidities. Furthermore, it describes the mechanisms by which AGEs and RAGE contribute to the pathophysiology of individual disease conditions and how they execute crosstalk between organ systems. A section on therapeutic strategies that target AGEs and RAGE and could alleviate patients from multimorbid conditions using single therapeutics concludes this review.

Loss of Ncoa7 leads to oxidative stress in kidney intercalated cells

Oxidative stress (OS) results from excessive production of reactive oxygen species, relative to endogenous antioxidant defenses, leading to cellular damage. The metabolically active kidney is vulnerable to OS, which is a key step in the progression of many renal pathologies. Furthermore, many non-renal pathologies are characterized by OS. Therefore, although our work focuses on kidney epithelial cells, it has significant implications for understanding how OS is regulated at a molecular level in many organs and cell types.The V-ATPase, or proton pump, is required for the acidification of intracellular compartments. Recently, we identified a family of V-ATPase interacting proteins defined by their TLDc domain (Ncoa7, Oxr1, Tbc1d24, Tldc1, and Tldc2). TLDc proteins are protective against OS in the nervous system and mutations cause human neurological pathologies. However, little is known about the molecular mechanisms that provide these protective properties. The V-ATPase, like TLDc proteins, also protects against OS. Therefore, we hypothesize that TLDc proteins play a V-ATPase-dependent protective role against OS. This is supported by our previous findings that mutating an amino acid in Ncoa7 that is protective against OS abolishes the interaction with the V-ATPase, and Ncoa7 knockout (KO) decreases V-ATPase-dependent urinary acidification in mice.To test this, we focused on Ncoa7 because it showed the most robust protective effect against OS in previous studies and is highly expressed in the kidney where it is enriched in epithelial intercalated cells (ICs). RNA sequencing of isolated ICs from Ncoa7 KO mice revealed significant downregulation of antioxidant enzymes including glutathione peroxidase-3 (Gpx3) and carbonyl reductase-2 (Cbr2). Immunofluorescence (IF) showed Cbr2 enrichment in medullary ICs from control mouse kidneys and a decrease in Cbr2 fluorescent signal intensity in ICs from Ncoa7 KO mice. Furthermore, Cbr2 localizes to the mitochondria of ICs, a significant source of cellular OS.To investigate whether the loss of Ncoa7 promotes OS in ICs we examined changes in OS markers by IF. We monitored the expression of Advanced Glycation End products (AGEs) and malondialdehyde (MDA) in fixed kidney sections using specific antibodies. AGEs are generated by glycation events accompanying OS and their formation can be suppressed by Gpx3. MDA is a product of lipid oxidation due to OS and can be reduced by Cbr2. ICs in Ncoa7 KO mice exhibited a striking accumulation of both AGEs and MDA, often found in large V-ATPase-bound intracellular compartments. Furthermore, knockdown of Ncoa7 in cultured kidney cells increased expression of AGEs, supporting loss of Ncoa7 as the mechanism behind the increased accumulation of intracellular AGEs.Based on these data we conclude that loss of Ncoa7 promotes OS in renal intercalated cells potentially through a regulatory interaction with the V-ATPase, which leads to decreased expression of antioxidant enzymes. NIH/NIDDK T32DK007540-33 and NIH/NIDDK R01DK121848 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Topical Application of Deglycating Enzymes as an Alternative Non-Invasive Treatment for Presbyopia.

Presbyopia is an age-related vision disorder that is a global public health problem. Up to 85% of people aged ≥40 years develop presbyopia. In 2015, 1.8 billion people globally had presbyopia. Of those with significant near vision disabilities due to uncorrected presbyopia, 94% live in developing countries. Presbyopia is undercorrected in many countries, with reading glasses available for only 6-45% of patients living in developing countries. The high prevalence of uncorrected presbyopia in these parts of the world is due to the lack of adequate diagnosis and affordable treatment. The formation of advanced glycation end products (AGEs) is a non-enzymatic process known as the Maillard reaction. The accumulation of AGEs in the lens contributes to lens aging (leading to presbyopia and cataract formation). Non-enzymatic lens protein glycation induces the gradual accumulation of AGEs in aging lenses. AGE-reducing compounds may be effective at preventing and treating AGE-related processes. Fructosyl-amino acid oxidase (FAOD) is active on both fructosyl lysine and fructosyl valine. As the crosslinks encountered in presbyopia are mainly non-disulfide bridges, and based on the positive results of deglycating enzymes in cataracts (another disease caused by glycation of lens proteins), we studied the ex vivo effects of topical FAOD treatment on the power of human lenses as a new potential non-invasive treatment for presbyopia. This study demonstrated that topical FAOD treatment resulted in an increase in lens power, which is approximately equivalent to the correction obtained by most reading glasses. The best results were obtained for the newer lenses. Simultaneously, a decrease in lens opacity was observed, which improved lens quality. We also demonstrated that topical FAOD treatment results in a breakdown of AGEs, as evidenced by gel permeation chromatography and a marked reduction in autofluorescence. This study demonstrated the therapeutic potential of topical FAOD treatment in presbyopia.

Chronological Age and DNA Damage Accumulation in Blood Mononuclear Cells: A Linear Association in Healthy Humans after 50 Years of Age.

Aging is characterized by the progressive deregulation of homeostatic mechanisms causing the accumulation of macromolecular damage, including DNA damage, progressive decline in organ function and chronic diseases. Since several features of the aging phenotype are closely related to defects in the DNA damage response (DDR) network, we have herein investigated the relationship between chronological age and DDR signals in peripheral blood mononuclear cells (PBMCs) from healthy individuals. DDR-associated parameters, including endogenous DNA damage (single-strand breaks and double-strand breaks (DSBs) measured by the alkaline comet assay (Olive Tail Moment (OTM); DSBs-only by γH2AX immunofluorescence staining), DSBs repair capacity, oxidative stress, and apurinic/apyrimidinic sites were evaluated in PBMCs of 243 individuals aged 18-75 years, free of any major comorbidity. While OTM values showed marginal correlation with age until 50 years (rs = 0.41, p = 0.11), a linear relationship was observed after 50 years (r = 0.95, p < 0.001). Moreover, individuals older than 50 years showed increased endogenous DSBs levels (γH2Ax), higher oxidative stress, augmented apurinic/apyrimidinic sites and decreased DSBs repair capacity than those with age lower than 50 years (all p < 0.001). Results were reproduced when we examined men and women separately. Prospective studies confirming the value of DNA damage accumulation as a biomarker of aging, as well as the presence of a relevant agethreshold, are warranted.

Advanced glycosylation end products as metabolic predictors of systemic pro-inflammatory and prooxidant status in patients with end-stage renal disease

Controlling systemic proinflammatory and prooxidant effectors is essential for mitigating cardiovascular risk and mortality in patients with end-stage renal disease (ESRD). However, monitoring these processes is still challenging due to the high uncertainty about their determinants and predictors. Thus, we investigated the relationship between advanced glycosylation end products (AGE), proinflammatory and prooxidant effectors in ESRD patients undergoing hemodialysis (HD). In addition to nutritional profile and dialysis efficiency, AGE, cytokines, chemokines, C-reactive protein (CRP), total (TAC) and non-protein (npAC) antioxidant capacity, lipid and protein oxidation were analyzed in blood samples from 43 HD patients. AGE, CRP, cytokines, chemokines, protein carbonyl (PCn), and malondialdehyde (MDA) were upregulated, while TAC and npAC were down-regulated in HD patients compared to heath subjects. Dialysis efficiency, TAC and npAC were reduced, while leucocytes counting, pre- and post-HD urea, TNF, IL-6, IL-10, CCL-2, MIP-1β, PCn, and MDA were increased in patients with higher AGE accumulation compared to those with lower AGE levels. Serum levels of CRP, protein carbonyl, malondialdehyde, and all cytokines and chemokines analyzed were correlated with AGE circulating levels for patients with higher AGE accumulation. AGE was inversely correlated with IL-10, TAC and npAC in patients with higher AGE accumulation. AGE exhibited predictive value (determination coefficient) to explain CRP, cytokines, chemokines, PCN, MDA, TAC and npAC variability in patients with higher AGE levels. Taken together, our findings provide evidence that AGE accumulation is associated with important proinflammatory and prooxidant effectors in patients with ESRD undergoing hemodialysis. Thus, AGE monitoring may be relevant to predict systemic inflammatory stress and the balance between oxidant and antioxidant status in these patients.

SMTP-44D Inhibits Atherosclerotic Plaque Formation in Apolipoprotein-E Null Mice Partly by Suppressing the AGEs-RAGE Axis

SMTP-44D has been reported to have anti-oxidative and anti-inflammatory reactions, including reduced expression of receptor for advanced glycation end products (RAGE) in experimental diabetic neuropathy. Although activation of RAGE with its ligands, and advanced glycation end products (AGEs), play a crucial role in atherosclerotic cardiovascular disease, a leading cause of death in diabetic patients, it remains unclear whether SMTP-44D could inhibit experimental atherosclerosis by suppressing the AGEs-RAGE axis. In this study, we investigated the effects of SMTP-44D on atherosclerotic plaque formation and expression of AGEs in apolipoprotein-E null (Apoe-/-) mice. We further studied here whether and how SMTP-44D inhibited foam cell formation of macrophages isolated from Apoe-/- mice ex vivo. Although administration of SMTP-44D to Apoe-/- mice did not affect clinical or biochemical parameters, it significantly decreased the surface area of atherosclerotic lesions and reduced the atheromatous plaque size, macrophage infiltration, and AGEs accumulation in the aortic roots. SMTP-44D bound to immobilized RAGE and subsequently attenuated the interaction of AGEs with RAGE in vitro. Furthermore, foam cell formation evaluated by Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and gene expression of RAGE, cyclin-dependent kinase 5 (Cdk5) and CD36 in macrophages isolated from SMTP-44D-treated Apoe-/- mice were significantly decreased compared with those from saline-treated mice. Gene expression levels of RAGE and Cdk5 were highly correlated with each other, the latter of which was also positively associated with that of CD36. The present study suggests that SMTP-44D may inhibit atherosclerotic plaque formation in Apoe-/- mice partly by blocking the AGEs-RAGE-induced ox-LDL uptake into macrophages via the suppression of Cdk5-CD36 pathway.

RAGE is a critical factor of sex-based differences in age-induced kidney damage.

Introduction: Advanced glycation end products (AGEs) are a heterogeneous group of molecules with potential pathophysiological effects on the kidneys. Fibrosis together with the accumulation of AGEs has been investigated for its contribution to age-related decline in renal function. AGEs mediate their effects in large parts through their interactions with the receptor for AGEs (RAGE). RAGE is a transmembrane protein that belongs to the immunoglobulin superfamily and has the ability to interact with multiple pro-inflammatory/pro-oxidative ligands. The role of RAGE in aging kidneys has not been fully characterized, especially for sex-based differences. Methods: Therefore, we analyzed constitutive RAGE knockout (KO) mice in an age- and sex-dependent manner. Paraffin-embedded kidney sections were used for histological analysis and protein expression of fibrosis and damage markers. RNA expression analysis from the kidney cortex was done by qPCR for AGE receptors, kidney damage, and early inflammation/fibrosis factors. FACS analysis was used for immune cell profiling of the kidneys. Results: Histological analysis revealed enhanced infiltration of immune cells (positive for B220) in aged (>70weeks old) KO mice in both sexes. FACS analysis revealed a similar pattern of enhanced B-1a cells in aged KO mice. There was an age-based increase in pro-fibrotic and pro-inflammatory markers (IL-6, TNF, TGF-β1, and SNAIL1) in KO male mice that presumably contributed to renal fibrosis and renal damage (glomerular and tubular). In fact, in KO mice, there was an age-dependent increase in renal damage (assessed by NGAL and KIM1) that was accompanied by increased fibrosis (assessed by CTGF). This effect was more pronounced in male KO mice than in the female KO mice. In contrast to the KO animals, no significant increase in damage markers was detectable in wild-type animals at the age examined (>70weeks old). Moreover, there is an age-based increase in AGEs and scavenger receptor MSR-A2 in the kidneys. Discussion: Our data suggest that the loss of the clearance receptor RAGE in male animals further accelerates age-dependent renal damage; this could be in part due to an increase in AGEs load during aging and the absence of protective female hormones. By contrast, in females, RAGE expression seems to play only a minor role when compared to tissue pathology.

Galectin-3 and RAGE differentially control advanced glycation endproduct-induced collagen damage in murine intervertebral disc organ culture.

Back and neck pain are leading causes of global disability that are associated with intervertebral disc (IVD) degeneration. Causes of IVD degeneration are multifactorial, and diet, age, and diabetes have all been linked to IVD degeneration. Advanced glycation endproducts (AGEs) accumulate in the IVD as a result of aging, diet, and diabetes, and AGE accumulation in the IVD has been shown to induce oxidative stress and catabolic activity that result in collagen damage. An association between AGE accumulation and IVD degeneration is emerging, yet mechanism behind this association remains unclear. The Receptor for AGEs (RAGE) is thought to induce catabolic responses in the IVD, and the AGE receptor Galectin 3 (Gal3) had a protective effect in other tissue systems but has not been evaluated in the IVD. This study used an IVD organ culture model with genetically modified mice to analyze the roles of RAGE and Gal3 in an AGE challenge. Gal3 was protective against an AGE challenge in the murine IVD ex vivo, limiting collagen damage and biomechanical property changes. Gal3 receptor levels in the AF significantly decreased upon an AGE challenge. RAGE was necessary for AGE-induced collagen damage in the IVD, and RAGE receptor levels in the AF significantly increased upon AGE challenge. These findings suggest both RAGE and Gal3 are important in the IVD response to AGEs and highlight Gal3 as an important receptor with protective effects on collagen damage. This research improves understanding the mechanisms of AGE-induced IVD degeneration and suggests Gal3 receptor modulation as a potential target for preventative and therapeutic treatment for IVD degeneration.

Sex-specificities in offspring neurodevelopment and behaviour upon maternal glycation: Putative underlying neurometabolic and synaptic changes

AimLactation is an important programming window for metabolic disease and neuronal alterations later in life. We aimed to study the effect of maternal glycation during lactation on offspring neurodevelopment and behaviour, assessing possible sex differences and underpinning molecular players. MethodsFemale Wistar rats were treated with Glyoxalase-1 inhibitor S-p-Bromobenzylguthione cyclopentyl diester (BBGC 5 mg/kg). A control and vehicle group treated with dimethyl sulfoxide were also considered. Male and female offspring were tested at infancy for neurodevelopment hallmarks. After weaning, triglycerides and total antioxidant capacity were measured in breast milk. At adolescence, offspring were tested for locomotor ability, anxious-like behaviour, and recognition memory. Metabolic parameters were assessed, and the hippocampus and prefrontal cortex were collected for molecular analysis. Key findingsMaternal glycation reduced triglycerides and total antioxidant capacity levels in breast milk. At infancy, both male and female offspring presented an anticipation on the achievement of neurodevelopmental milestones. At adolescence, male offspring exposed to maternal glycation presented hyperlocomotion, whereas offspring of both sexes presented a risk-taking phenotype, accompanied by increase GABAA receptor levels in the hippocampus. Females also demonstrated GABAA and PSD-95 changes in prefrontal cortex. Furthermore, lower levels of GLO1 and consequently higher accumulation of AGES were also observed in both male and female offspring hippocampus. SignificanceEarly exposure to maternal glycation induces changes in milk composition leading to neurodevelopment changes at infancy, and sex-specific behavioural and neurometabolic changes at adolescence, further evidencing that lactation period is a critical metabolic programming window and in sculpting behaviour.

Age or lifestyle-induced accumulation of genotoxicity is associated with a length-dependent decrease in gene expression

DNA damage has long been advocated as a molecular driver of aging. DNA damage occurs in a stochastic manner, and is therefore more likely to accumulate in longer genes. The length-dependent accumulation of transcription-blocking damage, unlike that of somatic mutations, should be reflected in gene expression datasets of aging. We analyzed gene expression as a function of gene length in several single-cell RNA sequencing datasets of mouse and human aging. We found a pervasive age-associated length-dependent underexpression of genes across species, tissues, and cell types. Furthermore, we observed length-dependent underexpression associated with UV-radiation and smoke exposure, and in progeroid diseases, Cockayne syndrome, and trichothiodystrophy. Finally, we studied published gene sets showing global age-related changes. Genes underexpressed with aging were significantly longer than overexpressed genes. These data highlight a previously undetected hallmark of aging and show that accumulation of genotoxicity in long genes could lead to reduced RNA polymerase II processivity.

Advanced Glycation End Products and Psoriasis

Advanced glycation end products (AGEs) are biologically active compounds formed physiologically throughout a sequence of chemical reactions, to generate highly oxidant-reactive aldehydes that combine covalently to proteins. They accumulate slowly in tissues during ageing but also in metabolic and selected inflammatory disorders. Accumulation of AGEs occurs more rapidly and intensely in the skin and serum of patients with type 2 diabetes, obesity, cardiovascular diseases, chronic renal insufficiency, and non-alcoholic fatty liver disease and also in the skin of patients with psoriasis. All of the above conditions are intimately associated with psoriasis. Interaction of AGEs with their receptors (RAGEs) stimulates cellular signaling with the formation of reactive oxygen species and activation of nuclear factor kappa light chain enhancer of activated B (NF-kB), which is a key regulator in the expression of inflammatory mediators and the production of oxidative stress. Thus, AGEs may play an interesting pathogenic role in the intersection of inflammatory and metabolic diseases, may represent a biomarker of inflammation and a potential target for novel therapeutic strategies. This is a narrative review with the objective to summarize current evidence on the role of AGEs in psoriasis.