Compiled by Barbara Connor, M.Ac., L.Ac.Feb. 19, 2013
Table of Contents
Introduction
Signaling Pathways Involved in Diabetic Complications
The Role of Advanced Glycation End Products (AGEs) and Receptor for AGEs (RAGE) in Age-Related Disorders
Glycated Insulin and AGEs
Hemoglobin A1c (HbA1c) and C-reactive Protein
AGEs and Cancer
AGEs and Cardiovascular Disease
AGEs and Cognitive Decline
AGEs, Inflammation and Diet
Natural Compounds that Prevent the Accumulation of AGEs
References
Introduction
Prooxidants such as advanced glycation end products (AGEs) play a significant role in the pathogenesis of chronic diseases, such as cardiovascular disease, chronic kidney disease, and diabetes. Until recently, studies of AGEs concentrated on complications in diabetics. (Vlassara et al 2009)
We shall see later on in this article that AGEs are also associated with cancer and cognitive decline.Advanced glycation end products are a heterogeneous group of macromolecules that are formed by the nonenzymatic glycation of proteins, lipids, and nucleic acids. Humans are exposed to two main sources of AGEs: exogenous AGEs that are ingested in foods and endogenous AGEs that are formed in the body. The Western diet is rich in AGEs. AGEs are formed when food is processed at elevated temperatures, such as during deep-frying, broiling, roasting, grilling; high-temperature processing for certain processed foods such as pasteurized dairy products, cheeses, sausages, and processed meats; and commercial breakfast cereals. Endogenous AGEs are generated at higher rates in diabetics due to altered glucose metabolism. (Semba et al 2010)
Diabetes mellitus is a chronic disease characterised by hyperglycaemia (high blood sugar) which is the earliest trigger in the development of vascular damage in these patients. During the process of the development of atherosclerosis, several molecular, receptorial and cellular factors provide a continuous mechanism of vascular complications. The major long-term complications of both type 1 and type 2 diabetes can be divided into microvascular (represented by nephropathy*, retinopathy and neuropathy) and macrovascular (cerebrovascular, coronary artery and peripheral vascular disease). (Chiarelli & Marzio 2010)
* Diabetic nephropathy is a complication of diabetes in which hyperglycaemia triggers inflammation, endothelial dysfunction and oxidative stress leading to kidney damage. Glycation** of proteins has been linked to mechanisms of disease – particularly the development of chronic clinical complications associated with diabetes mellitus – retinopathy, neuropathy and nephropathy, non-diabetic nephropathy, macrovascular disease, Alzheimer’s disease, cataracts and ageing. The concentration of fructosamine in blood plasma of normal, healthy human subjects is about 140 µM, and increases 2–3-fold in diabetes mellitus . This is the early glycation process and Schiff’s base and fructosamines have been called collectively early glycation adducts. (Thornalley et al 1999)
** Glycation is the result of the covalent bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose without the controlling action of an enzyme.
The Role of Advanced Glycation End Products (AGEs) and Receptor for AGEs (RAGE) in Age-Related Disorders
A non-enzymatic reaction between ketones or aldehydes and the amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules and to the development and progression of various age-related disorders such as vascular complications of diabetes, Alzheimer’s disease, cancer growth and metastasis, insulin resistance and degenerative bone disease. Under hyperglycemic and/or oxidative stress conditions, this process begins with the conversion of reversible Schiff base adducts, and then to more stable, covalently-bound Amadori rearrangement products. Over a course of days to weeks, these early glycation products undergo further reactions and rearrangements to become irreversibly crossed-linked, fluorescent protein derivatives termed advanced glycation end products (AGEs). (Yamagishi S 2011)
There is a growing body of evidence that AGE and their receptor RAGE (receptor for AGEs) interaction elicits oxidative stress, inflammatory reactions and thrombosis, thereby being involved in vascular aging and damage. These observations suggest that the AGE-RAGE system is a novel therapeutic target for preventing diabetic vascular complications. (Yamagishi S 2011)
Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that is expressed ubiquitously in the lungs. Engagement of RAGE leads to activation of multiple intracellular signaling pathways, including NF-kappaB and subsequent transcription of several proinflammatory mediators. Data suggest that RAGE plays a detrimental role in the host response to S. pneumoniae pneumonia by facilitating the bacterial growth and dissemination and concurrently enhancing the pulmonary inflammatory and procoagulant response. (van Zoelen et al 2009)
Signaling Pathways Involved in Diabetic Complications
Organ damage can be triggered by both extracellular and intracellular hyperglycaemia. Increased extracellular glucose leads to non-enzymatic glycosylation of proteins and subsequent formation of advanced glycation end products (AGE) that interact with the receptor for AGE (RAGE) on the plasma membrane and promote the production of reactive oxygen species (ROS). Increased intracellular glucose drives mitochondrial activity, increases the activity of protein kinase C (PKC) and NADPH oxidase and promotes increased flux through the polyol pathway, all of which have many effects on cellular metabolism and phenotype. (Calcutt et al 2009)
The consequences of excessive ROS production in the vasculature are where ROS-driven changes in cell phenotype are mediated by a range of signaling pathways and transcription factors such as AP1, activator protein 1; AR, aldose reductase; CCL2, CC-chemokine ligand 2 (also known as MCP1); CDC42, cell division cycle 42; EGR1, early growth response protein 1; ERK, extracellular signal-regulated kinase; ICAM1, intercellular adhesion molecule 1; JAK, Janus-activated kinase; JNK, Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; PI3K, phosphoinositide 3-kinase; RNS, reactive nitrogen species; SDH, sorbitol dehydrogenase; STAT, signal transducer and activator of transcription; and VCAM1, vascular cell adhesion molecule. Cells of the kidneys, eyes and nervous system also undergo cell- and organ-specific phenotypic changes as a result of hyperglycaemia-mediated ROS production. ROS production, ROS-unrelated pathogenic consequences of hyperglycaemia and hyperglycaemia-independent mechanisms, such as impaired insulin signalling, are likely to collectively mediate the organ-specific pathologies of diabetic complications. (Calcutt et al 2009)
Glycated Insulin and Advanced Glycation End Products
Diabetes mellitus is suggested to impact about 1 to 2% of the world’s population.1 Central to the clinical condition is a predisposition toward high blood sugar levels, glucose in particular. While the consequences of persistent hyperglycemia are well documented (microvascular disease with atherosclerosis and compromised renal function, retinopathy and neuropathy), the exact role carbohydrates play in the development of these debilitating conditions has not always been clear.2,3
Glucose is the principal metabolic sugar in humans. Monosaccharides such as glucose, galactose, fructose and mannose normally exist in equilibrium between two forms: an open-chain or extended “stickman” form and a closed ring (a Haworth projection form). For glucose, galactose and mannose, an open-chain form exposes a reactive aldehyde (or carbonyl) group on carbon atom /#1. This is normally reactive under physiological conditions, causing these sugars to be classified as “reducing” sugars. The aldehyde is particularly reactive toward free amino groups such as those occuring on lysine and arginine residues.1,4
When a reducing sugar’s carbonyl group and a free amine interact, they form an aldimine, or Schiff base, which is reversible. This is, however, the first step toward a later irreversible sugar-amino group complex that is generally known as glycation. The ability of a reducing sugar to form a Schiff base is dependent upon the amount that exists in an open-chain form. Only 0.002% of glucose is normally open-chain, versus 0.005%, 0.020% and 0.700% of mannose, galactose and fructose, respectively. 5 Thus, glucose spends less time in its reactive carbonyl form than other sugars, making it the “safe” sugar from a glycation-related, teleological point of view. Nevertheless, glucose-mediated glycation by way of Schiff base formation does occur, and is now being recognized as an inevitable, if not pathological, consequence of normal physiology.
The Amadori product is considered the first glycation product. This will undergo spontaneous and/or microenvironmentally-induced breakdown and rearrangement to form stable end products (advanced glycation endproducts; AGEs). The glycation process occurs both within and outside cells by a variety of sugars.3 The exact products formed vary by the sugar involved and the mechanism of rearrangement.
Three general types of glycation products are known:
a fluorescent structure (i.e. pentosidine) that cross-links lysine and arginine
a non-fluorescent structure (i.e. imidazole) that also cross-links amino acids
a non-cross-linking adduct that is covalently attached to a lysine or arginine (i.e. carboxymethyl lysine; CML).1
The consequences of glycation vary, depending upon the product formed and the molecular structures involved. In general, it could be said that glycation compromises normal molecular structure, function and/or half-life. Add to this the fact that glycated structures are also targets of specific clearance receptors whose ligation promotes inflammation, then one may quickly conclude that glycation has a considerable downside.3,6,7
In a high glucose environment, almost all proteins could be targets for glycation. Four molecules, which are relevant to diabetes, have been studied in some detail, including collagen, albumin, LDL and insulin. Collagen is known to be cross-linked by glucose-derived AGE. This is known to induce an expansion of collagen fibrils, inhibit lateral association of collagen molecules into a normal network-like structure, and promote endothelial cell proliferation and dissociation from basement membrane. This disrupts normal vascular architecture and causes increased vascular permeability.3
Albumin is often glycated, and high levels will promote VEGF expression and neovascularization in the retina,8 vascular smooth muscle proliferation and secretion of inflammatory mediators in the arteries,9 endothelial cell apoptosis with glomerular hyperfiltration in the kidney,10 and an anti-insulin effect in peripheral skeletal muscle.11 Glycation of LDL predisposes it to long-term retention in the tissues, particularly attached to vascular collagen.3,6 Although it has been proposed that retained LDL is more susceptible to oxidation, thus contributing to foam cell formation in vessels, recent data suggests this may not be the case.3,12,13 Finally, insulin, the mediator of glucose influx for most tissues, is also materially glycated in conditions of hyperglycemia.14
Relative to normal glycated insulin levels, diabetic serum can show as much as a two or three-fold increase in glycated insulin.14,15 In experimental models, this could represent as much as 10% of all circulating insulin.14Glycated insulin will show anywhere from 20 to 40% decreased potency in glucose uptake studies.15 Notably, it appears insulin glycation does not impact insulin-insulin receptor binding, so the effect must be at the post-receptor level.16
Hemoglobin A1c (HbA1c) and C-reactive Protein
Diabetes mellitus is a complex disease affecting almost every tissue and organ system, with metabolic ramifications extending far beyond impaired glucose metabolism. Biomarkers may reflect the presence and severity of hyperglycemia (ie, diabetes itself) or the presence and severity of the vascular complications of diabetes. In blood, hemoglobin A1c (HbA1c) may be considered as a biomarker for the presence and severity of hyperglycemia, implying diabetes or prediabetes, or, over time, as a “biomarker for a risk factor,” ie, hyperglycemia as a risk factor for diabetic retinopathy, nephropathy, and other vascular complications of diabetes. In tissues, glycation and oxidative stress resulting from hyperglycemia and dyslipidemia lead to widespread modification of biomolecules by advanced glycation end products (AGEs). (Lyons & Basu 2012)
HbA1c – The monitoring of glycemia (the concentration of glucose in the blood) is an essential component of diabetes care. It may be divided into self-monitoring of blood glucose (SMBG), which measures the immediate level of glycemia, and measurement of hemoglobin A1c (HbA1c), which reflects longer-term glycemia. SMBG was discussed in an earlier review. HbA1c is a measure of erythrocyte hemoglobin glycation, and since erythrocytes have about a 120 day life span, HbA1c reflects mean glycemia for the previous 3 months (weighted to the most recent month). There are several conditions that confound the HbA1c measurement such as hemolytic anaemia (lowers HbA1c) or aplastic anaemia (raises it), but in most circumstances HbA1c is a valid index of glycemia. The recommendation is to measure HbA1c every 3-6 months, and treat to a target level of < 7%. If these recommendations were successfully followed in most people with diabetes, long-term complications, especially microvascular complications, would be markedly reduced. (Saudek et al 2005)
HbA1c – Measurement of hemoglobin A1c (HbA1c) is considered the gold standard for monitoring chronic glycemia of diabetes patients. Hemoglobin A1c indicates an average of blood glucose levels over the past 3 months. Its close association with the risk for the development of long-term complications is well established. However, HbA1c does not inform patients about blood glucose values on a daily basis; therefore, frequent measurements of blood glucose levels are necessary for the day-to-day management of diabetes. (Makris & Spanou 2011)
C-reactive protein (CRP) is a key marker of inflammation in cardiovascular diseases, and is a mediator for developing atherosclerosis. C-reactive protein increases the expression of cell adhesion molecules, chemokines, RAGE and the production of ROS. Mahajan et al 2010 suggested that CRP upregulates RAGE expression. They also demonstrated that this upregulation could be reduced by MAPKs inhibitors; therefore, they suggested that p38, ERK and JNK signalling pathways were involved in CRP-induced RAGE expression. (Younessi & Yoonessi 2011)
Advanced Glycation End Products and Cancer
It is estimated that almost 25% of all cancers are somehow associated with chronic infection and inflammation. Accordingly, several evidences derived from both epidemiological studies and basic research have shown that organ-specific carcinogenesis is linked to the development of a chronic local inflammatory milieu, as reported for Helicobacter pylori-induced gastric inflammation and the occurrence of gastric cancer or gastric mucosa lymphoma, prostatitis and prostate cancer, inflammatory bowel disease and colon cancer, chronic cholecystitis and gall bladder carcinoma, just to mention a few examples. (Rojas et al 2010)
For many years, the association between the expression of the receptor for advanced glycation end-products (RAGE) and cancer has been well documented, as reported in gastric, prostate, lung, pancreas and liver malignancies. However, the contribution of RAGE to cancer biology seems to be much more functional than initially thought because it has now emerged as a relevant element that continuously fuels an inflammatory milieu at the tumor microenvironment. (Rojas et al 2010)
In the context of cancer, several clinical studies have demonstrated a strong association of RAGE expression with the malignant potential of various cancer types, such as gastric cancer, colon cancer, common bile duct cancer, pancreatic cancer, prostate cancer and oral squamous cell carcinoma, among others. Conversely, few reports have suggested that RAGE may have tumor suppressive functions, particularly in lung cancer. This contrasting suppressive function may arise from differences in control expression mechanisms, spliced variants and tissue-specific abundance of particular ligands. (Rojas et al 2010)
Hypoxia is a common feature of the tumor microenvironment. It is associated with tumor progression, increased aggressiveness, enhanced metastatic potential and poor prognosis. There is an increasing body of both in vitro and in vivo evidences supporting the functional interconnection between NF-κB and HIF-1α since NF-κB is a critical transcriptional activator of HIF-1α and that basal NF-κB activity is required for HIF-1α protein accumulation under hypoxia. Strikingly, increased RAGE expression has been shown to confer cell resistance to a hypoxic milieu through the acquisition of a hypoxia-resistant phenotype in hepatocellular carcinoma cells. (Rojas et al 2010)
Many RAGE ligands are expressed and secreted by cancer cells as well as by many cell types within the tumor microenvironment, including fibroblasts, leukocytes and vascular cells. These ligands interact in both autocrine and paracrine manners, promoting cell proliferation, cell invasion, angiogenesis and metastasis. Additionally, tumors rely primarily on anaerobic metabolism and show a higher rate of glucose uptake and glycolysis. One consequence of the rise of glycolysis is the non-enzymatic glycation of proteins, leading to the formation of advanced glycation end products (AGEs). (Rojas et al 2010)
HIF1α and NFkB are two transcription factors very frequently activated in tumors and involved in tumor growth, progression, and resistance to chemotherapy. In fact, HIF1α and NFkB together regulate transcription of over a thousand genes that, in turn, control vital cellular processes such as adaptation to the hypoxia, metabolic reprograming, inflammatory reparative response, extracellular matrix digestion, migration and invasion, adhesion, etc. Because of this wide involvement they could control in an integrated manner the origin of the malignant phenotype. Interestingly, hypoxia and inflammation have been sequentially bridged in tumors by the discovery that alarmin receptors genes such as RAGE, P2X7, and some TLRs, are activated by HIF1α; and that, in turn, alarmin receptors strongly activate NFkB and proinflammatory gene expression, evidencing all the hallmarks of the malignant phenotype. (Tafani et al 2013)
Much of the tissue damage and cellular dysfunction associated with hyperglycemia has been attributed to advanced glycation end products (AGEs) created by the nonenzymatic glycation of proteins. While AGE accumulation is a normal part of aging, it occurs at an accelerated rate in diabetes where progressive modifications can lead to irreversible cross-linking, impairing the actions of other molecules. Receptors for AGE (RAGE) mediate many more severe actions and potentiate the cellular response. RAGEs are upregulated by presence of AGE ligands, and AGE-RAGE binding protects the ligands, allowing them to persist in the environment. AGE-RAGE interaction has been shown to stimulate tumour cell growth or invasiveness in pancreatic cancer, melanoma, and glioma, while blocking the RAGE inhibits tumour formation and metastasis. The ovarian surface epithelium may be particularly susceptible to the effects of glycation damage because not only the tissue is well vascularized, but it is also in constant contact with peritoneal fluid, whose glucose content is reflective of blood glucose levels. (Kellenberger et al 2010)
Mechanistically, AGE-RAGE signaling has been linked to induction of an inflammatory response in the vasculature, as well as an increase in matrix metalloproteinases (MMPs)-2 and -9, and may, therefore, play a role in determining tumour invasiveness. Because AGE-RAGE signaling seems to be part of the chronic rather than acute response, its contributions to the development of tumour formation are quite plausible. (Kellenberger et al 2010)Ethyl pyruvate (EP) (a derivative of pyruvic acid — the end product of anerobic glycosis) administration inhibits the growth and invasion of gallbladder cancer cells possibly via down-regulation of the high mobility group box B1 (HMGB1)-receptor for advanced glycation end products (RAGE) axis, suggesting that EP may play a critical role in the treatment of cancer in conjunction with other therapeutic agents. (Li et al 2012)
Receptor for advanced glycation end-products (RAGE) is a member of immunoglobulin superfamily that serves as a transmembrance multiligand receptor. Its main ligands include advanced glycation end-products (AGEs), S100/calgranulins (such as S100P and S100A4), and high-mobility group box 1 protein (HMGB1). The engagement of full length RAGE with its ligands triggers rapid generation of intracellular reactive oxygen species and activates an array of cell signaling pathways that lead to the activation of the transcription factor NF-κB. RAGE has been shown to play a role in intestinal inflammation and tumorigenesis in experimental studies. RAGE has also been associated with invasion, metastasis, and poor prognosis of colorectal cancer in clinical studies. (Jiao et al 2012)
Advanced Glycation End Products and Cardiovascular Disease
AGEs are believed to have a key role in the development and progression of cardiovascular disease in patients with DM through the modification of the structure, function and mechanical properties of tissues through crosslinking intracellular as well as extracellular matrix proteins and through modulating cellular processes through binding to cell surface receptors [receptor for AGEs (RAGE)]. A number of studies have shown a correlation between serum AGE levels and the development and severity of heart failure. (Hegab et al 2012)
In patients with diabetes, cardiovascular complications are the principal cause of morbidity and mortality and account for up to 65% of diabetic fatalities. It has been reported that 33% of diabetic patients on insulin therapy will have died from cardiovascular disease by the age of 50 years. It is thought that AGEs have a central role in the pathophysiological processes that lead to the development of such cardiovascular complications observed in diabetes. (Hegab et al 2012)
Advanced glycation endproducts (AGEs) have been proposed as factors involved in the development and progression of chronic heart failure (CHF). Cross-linking by AGEs results in vascular and myocardial stiffening, which are hallmarks in the pathogenesis of CHF. Additionally, stimulation of receptors by AGEs may affect endothelial function and myocardial calcium uptake and may perpetuate coronary sclerosis in CHF. CHF is common in conditions with AGE accumulation, such as diabetes and renal failure. (Smit et al 2008)
Enhanced AGE accumulation is not restricted to patients with diabetes, but can also occur in renal failure, enhanced states of oxidative stress, and by an increased intake of AGEs. Several lines of evidence suggest that AGEs are related to the development and progression of heart failure in non-diabetic patients as well. (Hartog et al 2007)
In this study, elevated serum AGEs, sRAGE (total circulating RAGE), and esRAGE (endogenous secretory RAGE) were predictive of cardiovascular disease mortality, and appeared to be predictive of all-cause mortality at a level of marginal significance. The magnitude of the hazards ratios for mortality was greater for cardiovascular disease mortality than all-cause mortality for serum AGE, sRAGE, and esRAGE. These findings suggest that elevated AGE and its receptors may be more specifically involved in cardiovascular disease mortality. The study involved moderately to severely disabled women living in the community, and it is not known whether elevated serum AGEs and esRAGE are predictive of mortality in less disabled women or in men. (Semba et al 2009)
Advanced Glycation End Products and Cognitive Decline
Mounting evidence suggests that diabetes increases risk for cognitive impairment and dementia, including Alzheimer disease (AD),although the pathogenesis is unknown. Accumulation of advanced glycation end products (AGEs) in the brain is one possible mechanism linking diabetes to cognitive impairment. AGEs are a group of highly stable crosslinked products that form through a series of reactions between glucose and proteins. While AGEs form during normal aging, formation accelerates in diabetes in the setting of hyperglycemia and oxidative stress. Although all proteins are prone to AGE formation, deleterious AGE accumulation occurs in tissues with low turnover, including the CNS. (Yaffe et al 2011)In brains of patients with AD, AGEs, including pentosidine, colocalize with senile plaques and neurofibrillary tangles. One study showed evidence of more severe AD pathology with greater AGE levels in brains of patients with comorbid diabetes and AD compared to those with AD alone. In a case-control study serum level of the AGE pentosidine was elevated in patients with AD compared to controls. Circulating levels of AGE may provide a marker for risk of cognitive impairment. However, no studies have prospectively analyzed the association of circulating AGE levels and cognitive decline in elders without dementia. (Yaffe et al 2011)
Activation of microglia and resident macrophages in the brain by glycated proteins with subsequent oxidative stress and cytokine release may be an important factor in the progression of Alzheimer’s disease. (Younessi & Yoonessi 2011)In the majority of healthy adult tissues, RAGE is expressed at a low basal level. The up-regulation of RAGE has been associated with a diverse range of pathological events, from atherosclerosis to Alzheimer’s disease. (Buckley & Ehrhardt 2010)
Advanced Glycation End Products, Inflammation and Diet
AGEs, mainly through their interaction with receptors for advanced glycation end products (RAGEs), further activate signaling pathways, inducing formation of proinflammatory cytokines such as interleukin-6 (IL-6). (Jomova et al 2010)
Advanced glycation end products (AGEs) are a heterogeneous group of compounds that form continuously in the body. Their rate of endogenous formation is markedly increased in diabetes mellitus, a condition in which AGEs play a major pathological role. It is also known, however, that AGEs form during the cooking of foods, primarily as the result of the application of heat.We also present preliminary evidence of a direct association between dietary AGE intake and markers of systemic inflammation such as C-reactive protein in a large group of healthy subjects. Together with previous evidence from diabetics and renal failure patients, these data suggest that dietary AGEs may play an important role in the causation of chronic diseases associated with underlying inflammation. (Uribarri et al 2005)
Type 2 diabetes is characterized by hyperglycemia due to insulin resistance in peripheral tissues and deficient insulin secretion by pancreatic islet β-cells. Prolonged hyperglycemia leads to diabetic complications, including vascular and renal disease. Hyperglycemia also fosters the endogenous nonenzymatic glycoxidation of proteins, lipids, and nucleic acids, and results in the accumulation of heterogeneous molecules known as advanced glycation end products (AGEs). Compelling evidence implicates this accumulation of AGEs in the pathogenesis of diabetic complications. AGEs may exert their effects through altering protein function, causing abnormal interactions among matrix proteins, and interfering with cellular functions by increasing the expression of cytokines and the production of reactive oxidative species through their receptor, receptor for AGE (RAGE). (Zhao et al 2009)
Islet β-cell dysfunction is a central component of diabetic pathogenesis. Increased oxidative and endoplasmic reticulum (ER) stress, accelerated glucolipotoxicity, and activation of uncoupling protein 2 and inflammatory pathways appear to contribute to β-cell dysfunction. Although AGEs have been shown to increase the production of reactive oxidative species and activate inflammatory pathways, their role in β-cell dysfunction remains to be elucidated. This is mostly because β-cell function has already deteriorated by the time hyperglycemia occurs and because high glucose levels themselves impair β-cell function. (Zhao et al 2009)
AGEs are formed through a series of reactions from Schiff bases and Amadori products to stable irreversible end products, which accumulate in glomerular basement membrane, mesangial cells, endothelial cells, and podocytes of the patients with diabetic nephropathy (DN) and/or end-stage renal failure. Their receptors (RAGE) are expressed by mesangial cells, tubular cells, podocytes and endothelial cells. Furthermore, the AGEs-RAGE interaction is considered as a causative factor for DN through activating a series of intracellular signal-cascade pathways which might induce the generation of further signaling factors, such as vascular endothelial growth factor (VEGF), fibronectin, methyl-accepting chemotaxis protein-1 (MCP-1), transforming growth factor (TGFβ), nuclear factor-κβ (NFκβ), etc. Those signaling factors might cause mesangial expansion, glomerulosclerosis, glomerular hyperpermeability, and tubular inflammation, etc. AGEs have, therefore, been regarded as a focal target to inhibit the irreversible deterioration of DN. (Zhou et al 2012)
Diet is also an important source of AGEs. An estimated 10% of ingested AGEs are absorbed into the body’s circulation by the intestinal epithelium, and two thirds of those absorbed are retained. Increased dietary AGE intake has been associated with elevated serum AGE levels in diabetes subjects, as well as with atherosclerosis, nephropathy, and impaired wound healing in diabetic animal models. In contrast, reductions in AGE intake have prevented both type 1 and 2 diabetes as well as insulin resistance in experimental settings. (Zhao et al 2009)Restriction of diet-derived AGEs not only blocks the progression of atherosclerosis and renal injury, but also improves insulin resistance in animal models. AGE-poor diets reduce serum levels of inflammatory biomarkers in patients with diabetes or chronic renal failure. These observations suggest that the restriction of food-derived AGEs or the inhibition of absorption of dietary AGEs may be a novel target for therapeutic intervention in the AGE-related disorders. (Yamagishi et al 2007)
Examples of food with high exogenous AGEs include roasted duckskin, cake, donuts, soy sauce, Classic coke and Diet coke. (Koschinsky et al 1997)
Natural Compounds that Prevent the Accumulation of AGEs
Aged garlic and S-allyl cysteine – Both aged garlic extract and S-allyl cysteine inhibited formation of glucose and methylglyoxal derived advanced glycation endproducts and showed potent Amadorin activity when compared to pyridoxamine. S-allyl cysteine inhibited formation of carboxymethyllysine (CML), a non-crosslinked advanced glycation endproduct derived from oxidative processes. Further studies are required to assess whether aged garlic extract and S-allyl cysteine can protect against the harmful effects of glycation and free radicals in diabetes and ageing. (Ahmad et al 2007)
Alpha-lipoic acid – The contents of glucose, glycated protein, glycated haemoglobin and fructosamine were significantly lowered on alpha-lipoic acid (LA) administration to high fructose-fed rats. LA prevented in vitro glycation and the accumulation of advanced glycation end products. Further LA enhanced glucose utilization in the rat diaphragm. This effect was additive to that of insulin and did not interfere with the action of insulin. The findings provide evidence for the therapeutic utility of lipoic acid in diabetes and its complications. (Thirunavukkarasu et al 2005)
Carbohydrate-rich foods such as vegetables, fruits, whole grains, and milk – Dry heat promotes new dietary advanced glycation end products (dAGE) formation by >10- to 100-fold above the uncooked state across food categories. Animal-derived foods that are high in fat and protein are generally AGE-rich and prone to new AGE formation during cooking. In contrast, carbohydrate-rich foods such as vegetables, fruits, whole grains, and milk contain relatively few AGEs, even after cooking. The formation of new dAGEs during cooking was significantly reduced by cooking with moist heat, using shorter cooking times, cooking at lower temperatures, and by use of acidic ingredients such as lemon juice or vinegar. (Uribarri et al 2010)
Cinnamon bark – In this study, the inhibitory effect of cinnamon bark on the formation of advanced glycation endproducts (AGEs) was investigated in a bovine serum albumin (BSA)-glucose model. This is the first report that proanthocyanidins can effectively scavenge reactive carbonyl species and thus inhibit the formation of AGEs. (Peng et al 2008)
Cranberry phytochemical powder and its fractions significantly inhibited the formation of glycated hemoglobin. (Liu et al 2011)
EGCG – The results demonstrated that EGCG may exhibit protective effects against AGEs-induced injury in neuronal cells through its antioxidative properties, as well as by interfering with AGEs-RAGE interaction mediated pathways, suggesting a beneficial role for this tea catechin against neurodegenerative diseases. (Lee et al 2007)
Genistein & EGCG – Results from this study, as well as our previous findings on (-)-epigallocatechin 3-gallate (EGCG), phloridzin and phloretin, indicate that dietary flavonoids that have the same A ring structure as genistein, EGCG, phloridzin, and phloretin may have the potential to inhibit the formation of AGEs by trapping reactive dicarbonyl species. (Lv et al 2011)
Ginkgo biloba and alpha-lipoic acid – AGEs contents increased and RAGE expression was up-regulated in the circulation and local renal tissues in diabetic neuropathy (DN) rats. Ginkgo biloba and alpha-lipoic acid could inhibit AGEs production and down-regulate RAGE expressions by reducing oxidative stress, thus further improving the renal tissue structure and renal functions of DN rats. They had better application prospects in the treatment and prevention of DN. (Li et al 2011)
Guava (aqueous extract) – Psidium guajava at 0.01 mg/mL effectively inhibited with 63.45% efficiency on AGEs induced by glucose. We conclude that Psidium guajava virtually is a potent antiglycative agent, which can be of great value in the preventive glycation-associated cardiovascular and neurodegenerative diseases. (Hseih et al 2005)
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