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Effects of a Diet Low in Advanced Glycation End Products in Humans
Jaime Uribarri, MD
Abstract Advanced glycation end products (AGEs) are a heterogeneous group of compounds that can form through different spontaneous, nonenzymatic pathways and that can produce significant pro-oxidant and pro-inflammatory actions. In addition to the AGEs formed endogenously under the influence of hyperglycemia and/or increased oxidative stress, data accumulated in the past two decades suggest that AGEs formed in food during cooking with heat application are an important contributor to the body’s AGE pool. These exogenous AGEs share the same in-vitro activity as their endogenous counterparts, and experimentally, they have been shown to be associated with development of diabetes, insulin resistance, and atherosclerosis in mice. In this review
the author reviews the available data dealing with the effects of dietary AGEs in humans and describes in detail all the clinical trials studying the effect of a lowAGE diet in healthy subjects as well as in individuals with diabetes and chronic kidney disease. All these data have generated a new paradigm of disease suggesting that excessive consumption of AGEs secondary to a Western lifestyle represents an independent risk factor for inappropriate, chronic oxidative stress and chronic inflammation during life, which over time facilitates the emergence of diseases. Reducing the AGE content of common foods by simple changes in culinary techniques may prove a feasible, safe, and easily applicable intervention for both health and disease.
dvanced glycation end products (AGEs) are a large and heterogeneous group of compounds that form by the nonenzymatic reaction of sugars with free amino groups on proteins, peptides, or amino acids. This formation is the classical Maillard reaction, named after the French chemist who first identified it and also called browning reaction because of the characteristic color that it imparts to the food. Researchers now know, however, that AGEs may also form through many other biological pathways that generate reactive aldehydes, including those related to the oxidation of sugars, lipids, and amino acids, as well as through the glycolytic pathway.1 AGEs can produce tissue damage by two main mechanisms. First, they can covalently cross-link proteins leading to direct alterations in their structure, and therefore, in their function. For example, glycation of LDL cholesterol leads to its delayed receptor-mediated clearance and subsequent deposition in the vessel wall, contributing to atherosclerosis.2 Second, acting through both receptor-dependent and receptor-independent pathways, AGEs can increase intracellular generation of reactive oxygen species and inflammatory cytokines. For example, the interaction of AGEs with the receptor for advanced glycation end products (RAGE) initiates a cascade of intracellular events leading to inflammation and oxidative stress (OS).3 Recently, a direct or indirect induction of endoplasmic reticulum stress by AGEs has been suggested as an impor-
tant factor in the causation of different metabolic diseases.4 AGEs form endogenously at a physiologic rate, which is markedly increased in hyperglycemia and in any condition of high OS.5 AGEs, however, can also be introduced into the body from exogenous sources, mostly tobacco and food. Tobacco curing in the presence of reducing sugars generates AGEs. Increased levels of circulating and tissue AGEs have been found in smokers compared to nonsmokers.6 Recently, diet has been recognized as an important exogenous source of AGEs. Heating of food has a significant effect in creating diverse carbonyl derivatives of glycoxidation and lipoxidation reactions, and these derivatives can be absorbed by the gastrointestinal system, contributing significantly to the body’s total AGE burden.7,8 Food-derived AGEs exhibit the same protein crosslinking and intracellular pro-inflammatory and pro-OS actions as their endogenous counterparts when tested in vitro.9 In mice, a reduction of dietary AGE intake is accompanied by a significant reduction of circulating AGE levels as well as a reduction in diseases related to inflammation and oxidative stress, such as atherosclerosis, diabetes, and chronic kidney disease.5 This review will focus on the human data that has accumulated over the past two decades on the role of food-derived AGEs in causing chronic human disease.
Integrative Medicine • Vol. 11, No. 5 • October 2012
Uribarri—Effects of Low-AGE Diet
and participants picked them up twice a week for the duration of the study. VCAM-1. These findings are in line with the baseline cross-sectional data and support the proposed link between exogenous oxidant load. and the changes correlated with changes in sCML and sMG. sMG. acute experiments with an oral AGE load show a rapid and significant increase in circulating AGE levels within few hours. dietary AGE intake varied spontaneously. and endothelial dysfunction. After adjusting for gender. equally divided among younger and older ages. hsCRP.16 These findings suggest that healthy persons habitually consuming high AGE diets may have abnormally high levels of serum AGEs that may exceed the capacity of native defenses to remove or neutralize them. 4 • October 2012 47 . significantly correlated with levels of sCML. The first study was a crossover study between low and regular AGE diets for a period of 6 weeks.14-16 Second and more important. Use ISSN#1543953X. as measured by impaired flow-mediated dilatation and acute increase of circulating markers of endothelial dysfunction. one based on mild steam cooking (low AGE) and the other one on high temperature cooking (high AGE).com. and mononuclear TNFα below baseline normal values. another group of investigators has shown a close association between dietary and blood levels of AGEs. Oral AGE Loads Although no direct demonstration of AGE absorption has been clearly documented. with parallel reductions in the plasma levels of 8-isoprostanes.23 After 4 months. stew. visit imjournal.11-13 A significant relationship between the AGE content of food and circulating levels of AGEs has been described. Another randomized study of healthy volunteers. and several markers of inflammation in diabetic patients. and TNFα levels.7. 8-isoprostane. and vascular cell adhesion molecule-1 (VCAM-1). patients were randomized to follow either their regular AGE diet or a low-AGE diet for 4 months.7. each one followed for 1 month.8. More recently. To share or copy this article. please visit copyright. including high-sensitivity C-reactive protein (hsCRP). but of crossover design. No. To subscribe. Moreover. compared the effect of two diets. adjusted for caloric and nutritional intake. changes in serum CML significantly correlated with changes in 8-isoprostanes.10 Several experiments in humans strongly suggest the same. The low-AGE-diet subjects showed a significant decrease of circulating AGEs (both sCML and sMG). Of note. poach. and mononuclear TNFα in the same direction. VCAM1.24 Diabetic Patients: Low-AGE Intervention Low-AGE interventions have been performed in two groups of diabetic subjects. at quarterly intervals over a period of 2 years. Thus. 8-isoprostanes.21 The study’s dietitian instructed the subjects on Uribarri—Effects of Low-AGE Diet Integrative Medicine • Vol. Subjects were selected for participation in the study only if their habitual. They were advised to boil. OS. significant indirect evidence of such absorption exists. or steam food while avoiding frying. the salutary changes due to the low-AGE intervention were similar among younger and older participants.11. and mononuclear tumor necrosis factor alpha (TNFα). confirmed the associations between dietary and serum AGEs and circulating markers of inflammation and OS. such as plasminogen activator inhibitor-1 (PAI-1). VCAM-1. a common denominator for most chronic diseases. This effect of AGEs on endothelial function was blocked if subjects received prior therapy with benfotiamine. The low-AGE diet significantly decreased circulating CML levels and improved insulin sensitivity.17-21 A single oral AGE load not only leads to a rapid increase in circulating AGE levels but also is associated with acute decrease of endothelial function. experiments in rats using radiolabeled AGEs demonstrate direct absorption. They were instructed on how to modify their cooking technique and told not to change the quantity or nutritional composition of their food. 8-isoprostanes.com the Studies Normal Subjects: Acute. 11. dietary AGE intake. Moreover. Frequent phone calls by the study’s dietitian were necessary to assure compliance with the dietary plan.13 Normal Subjects: Cross-Sectional Data A cross-sectional study of healthy subjects of different ages showed a significant correlation between serum levels of two distinct AGEs—Nε-carboxy-methyl-lysine (sCML) and methyl-glyoxal derivatives (sMG)—and levels of circulating markers of inflammation. such as AGEs.22 Normal Subjects: Longitudinal Observations in Healthy Subjects with No Dietary Intervention Repeated measures of serum AGEs and dietary AGEs. leading to high OS. VCAM-1.17 In the second study.13 The AGE load contained in the study’s beverage was similar to what would be found in half of a typical 100-g cheeseburger. and systemic oxidant and inflammation burden. dietary AGE intake was high-normal. were randomly assigned to either their own regular diet or a low-AGE diet for 4 months (AGE levels 50% below the amount consumed normally).This article is protected by copyright. significant reductions in serum CML and serum MG levels were noted. or grilling. baking. First.20 The two diets were of equal caloric and nutritional content. All foods were prepared in the kitchen of the institution’s clinical research center. Normal Subjects: Low-AGE Intervention Healthy subjects. These practices allowed modification only of the AGE content but not the nutritional content of food. age and renal clearance serum AGE levels were the best predictors of OS. Participants received instructions on how to prepare the diet at home. their entry levels of serum AGEs and related markers were also at the upper end of the normal range.11-13 Chronic experiments with a modification of the dietary AGE content have also confirmed a close association between levels of dietary and circulating AGEs. as assessed by the HOMA index.16 During this period of observation.
Dietary AGEs and Chronic Diseases CVD Inflammation Oxidative Stress Endothelial dysfunction Dietary AGEs Diabetes Kidney disease how to prepare their own food at home and followed them closely.19 Diabetic CKD Subjects on a Regular AGE Diet But Exposed to an Agent That Binds AGEs in the GI Tract A group of 20 CKD patients with type 2 diabetes participated in a randomized. and mononuclear TNFα but also decreased HOMA.com Table 1. not calcium carbonate. To share or copy this article.This article is protected by copyright. but not the calcium carbonate. 4 • October 2012 Uribarri—Effects of Low-AGE Diet . binds AGEs quite effectively.20 End-Stage Renal Disease (ESRD) Patients on Peritoneal Dialysis: Low-AGE Intervention A group of nondiabetic ESRD patients on maintenance. Treatment with the sevelamer. no diabetes Diabetics Healthy Study design Cross-over Two parallel groups (high and low AGE) Two parallel groups (high and low AGE) Two parallel groups (high and low AGE) Two parallel groups (high and low AGE) Outcome Decrease sAGEs and markers of OS and inflammation Decrease sAGEs and markers of inflammation Decrease sAGEs and markers of OS and inflammation Decrease sAGEs.20 The effects of the low-AGE diet in these CKD participants mimicked those in healthy participants (40% to 60% reduction in inflammation and OS) and were completely in line with studies of diabetic patients treated with a low-AGE diet. 8-isoprostane. More important. this scenario seems to be reversible following a rather simple dietary intervention (Table 1). Low-AGE-Diet Clinical Trials Author/year Vlassara 2002 16 Population Diabetics ESRD. Use ISSN#1543953X. 11. They prepared their own food at home under the strict supervision of a dietitian. reproduced all the previous findings observed on the low-dietary-AGE intervention. no diabetes Healthy and CKD. and TNFα (25).25 Summary The evidence discussed in this review demonstrates that the modern diet is an important contributor to the circulating AGE pool in both the healthy and the disease states.21 Chronic Kidney Disease (CKD) Patients: Low-AGE Intervention A group of CKD patients. the precursors of disease (Figure 1). markers of OS and inflammation and HOMA Decrease sAGEs and HOMA Uribarri 200317 Vlassara 200919 Uribarri 201020 Birlouez 201022 Figure 1. 8-isoprostane. crossover study with one period of treatment with sevelamer carbonate (1600 mg tid with meals) and another one of calcium carbonate (1200 mg tid with meals) for 8 weeks each. Of interest. In-vitro studies showed that sevelamer. setting the stage for abnormally high OS and inflammation. Participants on the lowAGE diet had a significant fall in serum AGE and hsCRP levels. peritoneal dialysis was randomized to follow either their usual regular AGE intake or a low-AGE diet for 4 weeks. The author postulates that the sustained exposure to these exogenous pro-oxidant substances gradually erodes native defenses. namely. In fact.18. No. At the end of the study.com. without diabetes. sevelamer also decreased HbA1c significantly. those participants eating the low-AGE diet showed not only decreased circulating levels of AGEs. To subscribe. reduced circulating levels of AGEs. an index of insulin resistance. was randomized to follow either their regular AGE diet or a lowAGE diet for 4 months. dietary AGE modulation in different 48 Integrative Medicine • Vol. please visit copyright. visit imjournal.
Effects of Sevelamer on HbA1c. 2004.110(6):911-916. Il-1α and MCP-1 levels in type 2 diabetic patients. Negrean M. 6. Restriction of dietary glycotoxins reduces excessive advanced glycation end products in renal failure patients. Vlassara H. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Bucala R. Woodruff S.com. 2006. Cai W. Diet-derived advanced glycation end products are major contributors to the body’s AGE pool and induce inflammation in healthy subjects.5 Lovaza ® Capsules Triglyceride form = 70% better bio-absorption. Stirban A. Short-term (several months). Founds H. 5. 9. Cai W.104(8):1287-1291. Lu M. Uribarri J. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response. Mitsuhashi T. Use ISSN#1543953X.49(7):429-434. Peppa M. Cai W.48(6):1308-1315. Ann NY Acad Sci.This article is protected by copyright. 1997. inflammation. Sandu O.and high-advanced glycation endproduct meals on macro. Zhu L. Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy. 1997. 2009. Eur J Nutr. Single oral challenge by advanced glycation end products acutely impairs endothelial function in diabetic and nondiabetic subjects. Peppa M. 11. To share or copy this article. Cai W. Vlassara H. Vlassara H. Saaveda G. Glycoxidation and inflammation in renal failure patients. most potent triglyceride form Omega-3 fish oil you can buy! Half size capsules available! “I’ve been looking for the best fish oil for 10 years. 19. Cai W. He C. Gao QD. Cai W. Ramdas M. visit imjournal. Uribarri J. The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature. Oxidative stress-inducing carbonyl compounds from common foods: novel mediators of cellular dysfunction. 2010. Tessier FJ. Uribarri J.106(5):1040-1051. Protection against loss of innate defenses in adulthood by low advanced glycation end products (AGE) intake: role of the antiinflammatory AGE receptor-1. Hsu CC.34(7):1610-1616. Ramsamy R.94(25):13915-13920. 7. Diabetes Care.43(4):690-695. Cerami C. J Am Diet Assoc. 800 mg Omega-3. 2002. Uribarri J. Clin J Am Soc Nephrol. Cai W. no PCB’s.240 mg DHA per capsule Tested by lot: IFOS 5 star certified. Mol Med. et al. 2007:62(4):427-433.and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes.91(20):9441-9445. Cai W. Peppa M. et al. Mitsuhashi T. Proc Natl Acad Sci USA. Tuttle KR.42(3):532-538. et al. et al. The purest. Schmidt AM. et al.29(9):2064-2071. 1999. 2. Proc Natl Acad Sci USA. 2004.94(12):6474-6479. glycated LDL. no heavy metals. 2007. Cai W. Vlassara H. wild caught Sardines and Anchovies Try Vitality with your patients today. He C. et al. 2005 Jun. Diabetes Care. Uribarri J. 15. Association of dietary AGEs with circulating AGEs. et al.95! Visit www. et al.30(10):2579-2582. J Gerontol A Biol Sci Med Sci.99(24):15596-155601. Stratmann B. 2010. Aamopoulos C. Uribarri J. 22. Striker G. 2010. Vega G. Am J Kidney Dis. et al. 17. Modification of low density lipoprotein by advanced glycatione end products contributes to the dsylipidemia of diabetes and renal insufficiency. Diamante-Kandarakis E. Koschinsky T. Goodman S.7(6):934-942. 14. et al. 21. Negrean M. et al. and advanced glycation end products in diabetic kidney disease. Goodman S. Chao PC. 8. Clin J Am Soc Nephrol. et al. 2008 Apr. I’ve finally found it in Vitality ultra pure Omega-3” -Dr. 2003. Uribarri J. J Clin Endocrinol Metab. 1994. Am J Kid Dis.91(5):1220-1226. cure or prevent any disease. Stirban A. 10. References 1.cardiol. . To subscribe. Advanced glycation end products and nephrotoxicity of high-protein diets. Ken Kronhaus. Crandall J. J Am Soc Nephrol.com populations is a feasible. Uribarri J.94(11):4483-4491. Cai W. oxidative stress. Tobacco smoke is a source of toxic reactive glycation products. Uribarri J. Piperi C. Advanced glycation end products in foods and a practical guide to their reduction in the diet. 2011. He CJ. J Am Diet Assoc. This product is not intended to diagnose. J Clin Endocrinol Metab. Uribarri J. Crosstalk between advanced glycation and endoplasmic reticulum stress: emerging therapeutic targeting for metabolic diseases. We’ll refund your purchase if you’re not satisfied! These statements have not been evaluated by the FDA. Nicholl I. Am J Clin Nutr. 3. effective. dietary-AGE modulation in diabetic patients and in healthy subjects is associated with suppressed inflammation/OS and in diabetic patients with improvement of insulin resistance. Uribarri J. no Dioxins Sourced from Nordic. and aging. 2002. treat. 24. Vlassara H. Proc Natl Acad Sci USA. Benfotiamine prevents macro. Goldberg T. Diabetes Care. Proc Natl Acad Sci USA. et al. 25. 16. Peppa M. Guo YR. Advanced glycoxidation end products in commonly consumed foods. Peppa M. Diabetes. Effects of low. please visit copyright. Circ Res. 2006. Vlassara H. 13. 20. Am J Clin Nutr.97(7):2231-2242.net\promo or call 1-888-809-6424 Satisfaction Guaranteed. 2012. 23. Ann NY Acad Sci. Dietary glycotoxins correlate with circulating advanced glycation end product levels in renal failure patients.14(3):728–731. Vlassara H. 2012. Peppa M. a major risk factor for diabetic angiopathy. Advanced glycation end products homeostasis: exogenous oxidants and innate defense. Stirban A. 460 mg EPA. Peppa M. Cardiologist No fish burps guaranteed! 1 Vitality = 1.and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitus. and safe intervention. 12. et al. Vlassara H.1043:461-466. 18. Huang CN. Dietary glycotoxins: inhibition of reactive products by aminoguanidine facilitates renal clearance and reduces tissue sequestration. Introductory offer: 4 months supply for only $29.126:46-52. Birlouez-Aragon I.1(6):1293-1299. 2010. et al. A diet based on high-heattreated foods promotes risk factors for diabetes mellitus and cardiovascular disease. 4. Yan SF. Cai W. Yin MC. Sander D. 2007:85(5):1236-1243. Cai W. et al. Inflammatory mediators are induced by dietary glycotoxins. 2003. Papavassiliou AG. Goldberg T. Makita Z. Stratmann B. Sabol J.8(7):337-346. Dalagiorgiu G. MD.
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