References: Advanced Glycation End Products

"Much of what passes for food these days, isn't."                      
 
What Are AGEs?
Are Dietary AGEs Involved in Aging?
Can Dietary AGEs be Absorbed into the Body?
Can Dietary AGEs be Absorbed into the Body?
AGEs in Food
AGEs and Inflammation
AGEs and Specific Diseases
      Alzheimer's Disease
      Cataracts
      Diabetes
      Heart Disease
      Osteoporosis

What Are AGEs?

In the human body glucose reacts with protein amino groups to begin a modification process called glycation (non-enzymatic reaction). An example of an early stage glycation product is Hemoglobin A1c (HbA1c, an indicator of long-term, 3–4 week glucose control in diabetic patients). Over the course of weeks to months early stage glycation products undergo more rearrangements to form fluorescent advanced glycation end products (AGEs). These irreversibly bind to and cross-link long-lived proteins such as collagen, which causes connective tissue and artery walls to become rigid with age. High blood glucose in diabetics greatly increases the formation of protein-bound AGEs and causes acceleration of tissue and arterial damage. Protein–bound AGEs are implicated in blood vessel, kidney and retinal (back of eye) damage. (Makita et al. Hemoglobin-AGE: A Circulating Marker of Advanced Glycosylation"

Are Dietary AGEs Involved in Aging?

Does Accumulation of Advanced Glycation End Products Contribute to the Aging Phenotype? Semba et al. (2010) A review of Scientific Literature: Results: Recent epidemiological studies demonstrate that elevated circulating AGEs are associated with increased risk of developing many chronic diseases that disproportionally affect older individuals. Conclusions: Based on these data, we propose that accumulation of AGEs accelerate the multisystem functional decline that occurs with aging, and therefore contribute to the aging phenotype. Exposure to AGEs can be reduced by restriction of dietary intake of AGEs and drug treatment with AGE inhibitors and AGE breakers. Modification of intake and circulating levels of AGEs may be a possible strategy to promote health in old age, especially because most Western foods are processed at high temperature and are rich in AGEs.

Oral Glycotoxins [AGEs] Determine the Effects of Calorie Restriction on Oxidant Stress, Age-Related Diseases, and Lifespan by Weijing Cai et al.(2008) "We previously showed that the content of advanced glycation end products (AGEs) in the diet correlates with serum AGE levels, oxidant stress (OS), organ dysfunction, and lifespan. We now show that the addition of a chemically defined AGE (methyl-glyoxal-BSA) to low-AGE mouse chow increased serum levels of AGEs and OS, demonstrating that dietary AGEs are oxidants that can induce systemic OS [oxidant stress]." Calorie restricted, high AGE fed mice had higher fasting insulin levels, significant depletion of endogenous antioxidant reserves, more cardiovascular fibrosis and kidney disease of aging, and 13% longer lifespan, than calorie restricted low AGE fed mice.

Glucose metabolite glyoxal induces senescence in telomerase-immortalized human mesenchymal stem cells (glyoxal, a highly reactive precursor of AGEs), Larsen et al. (2012) "We have previously reported that GO (glyoxal) accelerates ageing and causes premature senescence in normal human skin fibroblasts." Exposure of mesenchymal stem cells to 0.75 and 1mM glyoxal induced cellular senescence within 3 days and was accompanied by DNA breaks and increased levels of AGE. "The results... imply that an imbalanced glucose metabolism (as in diabetes-2) can reduce the functioning ability of stem cells in vivo both during ageing and during stem cell-based therapeutic interventions."

Can Dietary AGEs be Absorbed into the Body?

Diet-derived advanced glycation end products are major contributors to the body's AGE pool and induce inflammation in healthy subjects. Uribarri et al. Abstract: " 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. This review focuses on the generation of AGEs during the cooking of food, the gastrointestinal absorption of these compounds, and their biological effects in vitro and in vivo. 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."

Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy. Koschinsky et al. "Thirty-eight diabetics (DM) ... and five healthy subjects (NL) received a single meal of egg white (56 g protein), cooked with (AGE-diet) or without fructose (100 g) (CL-diet).... The AGE-diet, but not the CL-diet, produced distinct elevations in serum AGE levels in direct proportion to amount ingested (r = 0.8, P < 0.05): the area under the curve for serum ( approximately 10% of ingested AGE) correlated directly with severity of KD (Kidney Disease); renal excretion of dietary AGE, although normally incomplete (only approximately 30% of amount absorbed), in DM it correlated inversely with degree of albuminuria, and directly with creatinine clearance (r = 0.8, P < 0.05), reduced to <5% in DM with renal failure. Post-AGE-meal serum exhibited increased AGE-crosslinking activity (two times above baseline serum AGE, three times above negative control), which was inhibited by aminoguanidine. In conclusion, (i) the renal excretion of orally absorbed AGEs is markedly suppressed in diabetic nephropathy patients, (ii) daily influx of dietary AGEs includes glycotoxins that may constitute an added chronic risk for renal-vascular injury in DM, and (iii) dietary restriction of AGE food intake may greatly reduce the burden of AGEs in diabetic patients and possibly improve prognosis."

"Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy" Vlassara et al (2002) Serum AGEs were increased by 28.2% on a high AGE diet and reduced by 33% on a low AGE diet. Also inflammatory mediators such as C-reactive protein and TNF-alpha were significantly higher on the high AGE diet.

AGEs in Food

"Advanced glycation end products in foods and a practical guide to their reduction in the diet." Urbarri et al. "Modern diets are largely heat-processed and as a result contain high levels of advanced glycation end products (AGEs). Dietary advanced glycation end products (dAGEs) are known to contribute to increased oxidant stress and inflammation, which are linked to the recent epidemics of diabetes and cardiovascular disease....dry heat promotes new 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. High fat spreads, butter, cream cheese, margarine and mayonnaise were high in dAGEs, followed my oils and nuts (Olive oil seemed very high). A dry cereal, Life, and Goldfish crackers were significantly higher in dAGEs than white or wheat bread. Cheeses were very high. Broiling or pan frying salmon or steak (naturally high in dAGEs) resulted in much higher dAGEs than in the raw meat. This article includes a table (#2) of dAGEs contents of selected foods. The comprehensive table #1 of 549 foods is available online for subscribers to the Journal of the American Dietetic Association, www.adajournal.org.

"Advanced glycoxidation end products in commonly consumed foods" Goldberg et al. "Foods of the fat group showed the highest amount of AGE content with a mean of 100±19 kU/g. High values were also observed for the meat and meat-substitute group, 43±7 kU/g. The carbohydrate group contained the lowest values of AGEs, 3.4±1.8 kU/g. (However, within this group, commercially prepared breakfast foods and snacks show significant AGE content, eg, 30-g servings of toasted frozen waffles and biscotti contained 1,000 kU AGE and Rice Krispies contained 600 kU/serving. Processing of some ready-to-eat cereals, includes heating at temperatures over 230°C and undergo an extrusion process under high pressure, which causes major chemical changes, thermal degradation, dehydration, depolarization, and recombination, all of which can promote glycoxidation (34)). The amount of AGEs present in all food categories was related to cooking temperature, length of cooking time, and presence of moisture. Broiling (225°C) and frying (177°C) resulted in the highest levels of AGEs, followed by roasting (177°C) and boiling (100°C)." Tables 2-6 (dAGE content of 250 foods) are available on-line at www.adajournal.org

Abstract: Chemical changes during extrusion cooking in Recent Advances by Camire, ME. "Cooking extruders process a variety of foods, feeds, and industrial materials.... Starch gelatinization and protein denaturation are the most important reactions during extrusion. Proteins, starches, and non-starch polysaccharides can fragment, creating reactive molecules that may form new linkages not found in nature.  Also see "Chemical changes during extrusion cooking" by Camire in The Nutrition Handbood for Food Processors, Clare Chapman.(see a preview of book, page 320) In the cooking extrusion process, total protein changes little by nitrogen testing, but nutritional value can. Animal feeding studies or in vitro protein digestibility testing needs to be done to confirm suitability. Protein cross-linking, aggregation and fragmentation are among reactions reported in the literature. Excessive Maillard browning (a form of glycation product) can result in losses of lysine (may indicate change due to glycation; carboxymethyllysine is the most commonly used measure of AGEs in food) up to 50% (de la Gueriviere et al, 1985.) High barrel temperature, low moisture, and high shear increase Maillard reactions. Lysine can be preserved if extruder operating conditions and formulations are carefully balanced.

A listing of AGEs content of a wide range of foods from one of the above studies at Inhuman Experiment

Abstract: Protein fructosylation: fructose and the Maillard reaction, Dill, WL. "Fructose, as is the case for other reducing sugars, undergoes the Maillard reaction with proteins and amino acids....It would appear that the initial stages of the reaction occur more rapidly with fructose than with glucose. The Maillard reaction with any sugar, including fructose, results in a decrease in protein quality due to the loss of amino acid residues and decreased protein digestibility. Maillard products can inhibit the uptake and metabolism of free amino acids and of other nutrients such as zinc and some advanced Maillard products have mutagenic and/or anticarcinogenic properties. In vivo the Maillard reactions between proteins and fructose, glucose, and other reducing sugars may play a role in aging and in some of the clinical complications of diabetes."

"Extrusion processing has become an important food process in the manufacture of pasta, ready-to-eat cereals, snacks, pet foods, and textured vegetable protein (TVP). An extruder consists of tightly fitting screw rotating within a stationary barrel. Preground and conditioned ingredients enter the screw where they are conveyed, mixed, and heated by a variety of processes. The product exits the extruder through a die where it usually puffs and changes texture from the release of steam and normal forces ....Pertinent literature on the extrusion of cereal/snack products, full-fat soy, TVP, pet foods (dry and semi-moist), pasta, and beverage or other food bases are discussed. In many of these applications, the extruder is a high temperature, short time process which minimizes losses in vitamins and amino acids. Color, flavor, and product shape and texture are also affected by the extrusion process ....Emphasis is placed on the use of extrusion to denature antinutritional factors and the improvement of protein quality and digestibility." in Food Extrusion. Harper, JM.

AGEs and Inflammation:

PDF of a Review Article: Amplifiers of Systemic Inflammation The Role of Advanced Glycation and Lipoxidation End Products in Foods by Stig Bengmark (2008) "Chronic diseases are repeatedly associated with accumulation in the body of glycated and lipoxidated proteins and peptides. PubMed reports in excess of 5000 papers plus about 14,000 articles about the related HbA1c RAGE, a member of the immunoglobulin super-family of cell surface molecules and receptors for advanced glycation end products, functions as a master switch, induces sustained activation of NF-κB, suppresses a series of endogenous auto-regulatory functions and converts long-lasting pro-inflammatory signals into sustained cellular dysfunction and disease. RAGE is activated by high levels of dysfunctioning proteins in body fluids and tissues and is strongly associated with chronic diseases from allergy and Alzheimer to rheumatoid arthritis and urogenital disorders. Heat-treatment, irradiation and ionization of foods increase the content in foods of advanced glycated end-products (AGE) and advanced lipoxidated end-products (ALE). Some processed foods, much like tobacco smoking, are major contributors to accumulation of glycated and lipoxidated molecules in the tissues. Change of life style: avoidance of foods rich in deranged proteins and peptides and increased consumption of antioxidants, especially polyphenols counteracts such a development."

PDF of "Advanced glycation end products (AGEs) activate mast cells." Sick et al. "Advanced glycation endproducts activated mast cells and may contribute to a vicious cycle involving generation of ROS (reactive oxygen species), increased formation of AGEs, activation of RAGE and to the increased low-grade inflammation typical of chronic diseases."

Another abstract "Advanced glycation end products induce the expression of interleukin-6 and interleukin-8 by receptor for advanced glycation end product-mediated activation of mitogen-activated protein kinases and nuclear factor-κB in human osteoarthritis chondrocytes" Rasheed, et al. "AGE-BSA induced the expression of IL-6 and IL-8 in OA chondrocytes" IL-6 (interleukin-6) is secreted by T cells and macrophages to stimulate immune response, both proinflammatory and protective against infection. IL-8 (interleukin-8) is a chemokine that recruits cells such as mast cells and neutrophils to sites of inflammation, in this case arthritic cartilage.

"Comparison of nutrition and plasma AGEs in vegetarian and omnivorous groups shows that the higher intake of fructose in alternative nutrition of healthy subjects may cause an increase of AGE levels." in Advanced Gycation End Products and Nutrition, Krajcovicova-Kudlackova, et al.

"Effects of low- and high-advanced glycation endproduct meals on macro- and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitus" Negrean et al. "In patients with T2DM (Type 2 Diabetes Mellitus), a HAGE (High AGE) meal induces a more pronounced acute impairment of vascular function than does an otherwise identical LAGE (Low AGE) meal. Therefore, chemical modifications of food by means of cooking play a major role in influencing the extent of postprandial vascular dysfunction."

AGEs and Specific Diseases:

Alzheimer's Disease:

Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans, Cai et al. (2014) "Suppression of NAD+-dependent sirtuin 1 (SIRT1) is linked to dementia or Alzheimer’s disease (AD) and the metabolic syndrome (MS). Because advanced glycation end products (AGEs) promote MS and neurotoxicity, we conducted studies of C57BL6 mice fed isocaloric diets containing defined AGEs [methyl-glyoxal derivatives (MG)] to determine whether food AGEs promote AD and MS. MG+-fed, but not MG−-fed, mice developed brain SIRT1 deficiency, amyloid-β deposits, cognitive and motor deficits, and MS. These findings were validated in older healthy humans with high baseline circulating MG levels by a time-dependent decline in cognition and insulin sensitivity. The data suggest that food-derived AGEs, an environmental factor, contribute to both AD and MS by causing chronic SIRT1 suppression. Importantly, reduction of food-derived AGEs is feasible and may provide an effective treatment strategy for both these epidemics."

Advanced glycation endproducts in ageing and Alzheimer's disease, Munch et al. Abstract: "Accumulation of advanced glycation endproducts (AGE) in the brain is a feature of ageing and degeneration, ans especially in Alzheimer's disease (AD). Increased AGE levels explain many of the neuropathological and biochemical features of AD such as extensive protein crosslinking (ß-amyloid and MAP-τ), oxidative stress and neuronal cell death. Oxidative stress and AGEs initiate a positive feedback loop, where normal age-related changes develop into a pathophysiological cascade. Combined intervention using antioxidants, metal chelators, anti-inflammatory drugs and AGE-inhibitors may be a promising neuroprotective strategy."

Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Viteck et al. Article: "Plaque fractions of AD (Alzheimer Disease) brains were found to contain about 3-fold more AGE adducts per mg of protein than preparations from healthy, age-matched controls. These results suggest that the in vivo half-life of B-amyloid is prolonged in AD, resulting in greater accumulation of AGE modifications which in turn may act to promote accumulation of additional amyloid.

Possible involvement of advanced glycation end-products (AGEs) in the pathogenesis of Alzheimer's disease. Takeuchi M. and Yamagishi S." Alzheimer's disease (AD) is the most common cause of dementia in developed countries. AD is characterized pathologically by the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), the major constituents of which are amyloid betaprotein and tau protein, respectively. Advanced glycation end-products (AGEs), senescent macroprotein derivatives formed at an accelerated rate under normal aging, can be identified immunohistochemically in both SPs and NFTs in AD patients. Further, recent clinical evidence has suggested diabetes mellitus as one of the risk factors for the development and progression of AD. Continuous hyperglycemia is a causative factor for diabetic vascular complications, and it enhances the generation of AGEs through the non-enzymatic glycation, thereby being involved in the pathogenesis of AD as well... In this review, we discuss the pathophysiological role for AGEs in the development and progression of AD, especially focusing on Glycer-AGE."

Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. Sasaki, N. et al.

Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans. Weijing Cae et al (2014) Abstract: "Age-associated dementia and Alzheimer’s disease (AD) are currently epidemic. Neither their cause nor connection to the metabolic syndrome (MS) is clear. Suppression of deacetylase survival factor sirtuin 1 (SIRT1), a key host defense, is a central feature of AD. Age-related MS and diabetes are also causally associated with suppressed SIRT1 partly due to oxidant glycotoxins [advanced glycation end products (AGEs)]. Changes in the modern diet include excessive nutrient-bound AGEs, such as neurotoxic methyl-glyoxal derivatives (MG). To determine whether dietary AGEs promote AD, we evaluated WT mice pair-fed three diets throughout life: low-AGE (MG−), MG-supplemented low-AGE (MG+), and regular (Reg) chow. Older MG+-fed mice, similar to old Reg controls, developed MS, increased brain amyloid-β42, deposits of AGEs, gliosis, and cognitive deficits, accompanied by suppressed SIRT1, nicotinamide phosphoribosyltransferase, AGE receptor 1, and PPARγ. These changes were not due to aging or caloric intake, as neither these changes nor the MS were present in age-matched, pair-fed MG− mice. The mouse data were enhanced by significant temporal correlations between high circulating AGEs and impaired cognition, as well as insulin sensitivity in older humans, in whom dietary and serum MG levels strongly and inversely associated with SIRT1 gene expression. The data identify a specific AGE (MG) as a modifiable risk factor for AD and MS, possibly acting via suppressed SIRT1 and other host defenses, to promote chronic oxidant stress and inflammation. Because SIRT1 deficiency in humans is both preventable and reversible by AGE reduction, a therapeutic strategy that includes AGE reduction may offer a new strategy to combat the epidemics of AD and MS."

Cataracts:

"Advanced glycation end products formed oxidatively and nonoxidatively occurred to a higher degree in cataractous lenses than in noncataractous lenses. The strong relationship between the lenses' AGE content, color/opacity, and the state of the cataract may indicate that advanced glycation plays a pivotal role in cataract formation." in an Abstract, "Increased levels of advanced glycation end products in human cataractous lenses."Franke et al.

    Abstract: [The oxidative stress in the cataract formation], Obara, Y. Details the increase of oxidative stress in fluids surounding cataracts. Increased levels of lipid peroxide and glycated protein in diabetic cataractous lenses. Iron and copper ions exist in lens tissue. "In particular, the subepithelial region of the lens stained strongly for copper ions. The increased level of copper ions in cataractous lenses is likely related to the increased peroxidation in this tissue." (rc, Of interest is there are also increased levels of metal ions in Alzheimer brain plaques and other inflamed tissues).

Diabetes:

Advanced glycation end-products: modifiable environmental factors profoundly mediate insulin resistance Ottum and Mistry (2015) "High advanced glycation end-products overwhelm innate defenses of enzymes and receptor-mediated endocytosis and promote cell damage via the pro-inflammatory and pro-oxidant receptor for advanced glycation end-products. Oxidative stress disturbs cell signal transduction, especially insulin-mediated metabolic responses. Here we review emerging evidence that restriction of dietary advanced glycation end-products significantly reduces total systemic load and insulin resistance in animals and humans in diabetes, polycystic ovary syndrome, healthy populations and dementia. Of clinical importance, this insulin sensitizing effect is independent of physical activity, caloric intake and adiposity level."

Heart Disease:

Diastolic Dysfunction of Aging Is Independent of Myocardial Structure but Associated with Plasma Advanced Glycation End-Product Levels Campbell et al. "Heart failure is associated with abnormalities of myocardial structure, and plasma levels of the advanced glycation end-product (AGE) Nε-(carboxymethyl)lysine (CML) correlate with the severity and prognosis of heart failure. Aging is associated with diastolic dysfunction and increased risk of heart failure, and we investigated the hypothesis that diastolic dysfunction of aging humans is associated with altered myocardial structure and plasma AGE levels." Conclusion: "Diastolic dysfunction of aging was independent of myocardial structure but was associated with plasma AGE levels."

Osteoporosis:

Circulating Levels of Carboxy-Methyl-Lysine (CML) Are Associated With Hip Fracture Risk: The Cardiovascular Health Study (Barzilay et al. May 2014) – ABSTRACT "Advanced glycation end products (AGE) in bone tissue are associated with impaired biomechanical properties and increased fracture risk. Here we examine ... serum levels of the AGE carboxy-methyl-lysine (CML) .... We followed 3373 participants, average age 78 years ... for a median of 9.22 years. .... There were 348 hip fractures during follow-up, with incidence rates of hip fracture by CML quartiles of 0.94, 1.34, 1.18, and 1.69 per 100 participant-years. ... In the cohort with BMD testing, total hip BMD was not significantly associated with CML levels. We conclude that increasing levels of CML are associated with hip fracture risk in older adults, independent of hip BMD. These results implicate AGE in the pathogenesis of hip fractures. © 2014 American Society for Bone and Mineral Research."

 


   © 2011 Rochelle Cocco