Current perspectives on the health risks associated with the consumption of advanced glycation end products: recommendations for dietary management

Figures & data

Figure 1 Chemical structure of some advanced glycation end products (AGEs): crossline, 2-(2-furoyl)-4(5)-(2-furanyl)-1H-imidazole (FFI), glyoxal-lysine dimer (GOLD), methylglyoxal-lysine dimer (MOLD), pentosidine, N3-(carboxyethyl)lysine (CEL), N-carboxymethyl lysine (CML), and pyrraline.

Figure 2 Schematic representation of advanced glycation end product (AGE) mechanisms of action.

Notes: Receptor-mediated mechanisms include two different types of receptors: receptors responsible for AGE degradation/detoxification – namely, MSR and AGE-specific receptors – and the multi-ligand receptor for AGEs – receptor for advanced glycation end products (RAGE) – that mediates pro-atherogenic, inflammatory, and immune responses. Receptor-independent mechanisms of action include formation of cross-links with basic components in the basement membrane of the extracellular matrix permanently modifying its structural characteristics.^6,10
Abbreviations: IL-1a, interleukin-1a; IL-6, interleukin-6, MSR, macrophage scavenger receptor; NF-κB, nuclear factor-kappa B, RAGE, receptor for advanced glycation end products; TNF-α, Tumor necrosis factor-alpha; VCAM-1, vascular cell adhesion molecule-1.

Table 1 Advanced glycation end product (AGE) content in commonly consumed foodsa

Food item	AGE contentb
Salmon, raw (90 g)	502
Salmon, broiled (10 minutes, 90 g)	1,348
Beef, boiled (1 hour, 90 g)	2,000
Beef, broiled (15 minutes, 90 g)	5,367
Beef, stir fried (20 minutes) and broiled (15 minutes, 90 g)	6,166
Chicken, boiled (1 hour, 90 g)	1,011
Chicken, broiled (15 minutes, 90 g)	5,245
Beans, red kidney, raw (100 g)	116
Beans, red kidney, canned (100 g)	191
White potato, boiled (25 minutes, 100 g)	17
French fries (100 g)	1,522
Broccoli (100 g)	226
Tomato (100 g)	23
Apple (100 g)	13

Notes:

a Data derived from Goldberg et al;³

b AGE content denotes kilounits per serving; AGE measured by enzyme-linked immunosorbent assay using an antibody against N-carboxymethyl lysine.

Table 2 Interventions targeting the advanced glycation end product (AGE) pathway

Mechanism of action	Therapeutic agent	Biological effects
Dietary restriction of AGE		Animal studies^Citation31,Citation50,Citation75^–^Citation77
		Prevents/Improves
		Insulin resistance
		Abdominal obesity/body weight
		Diabetes mellitus type 2
		Diabetic nephropathy
		Diabetic-impaired wound healing
		Extends life span
		Human studies
		Healthy subjects^Citation78^–^Citation80
		↓ Basal oxidative stress
		↓ Inflammation
		↓ Serum AGEs
		Improves markers of insulin resistance
		Subjects with diabetes or renal failure^Citation13,Citation15,Citation34
		↓ Serum AGEs
		↓ Inflammation
		Improves vascular function and insulin resistance
Blockage of AGE formation	Aminoguanidine^Citation83^–^Citation85	Animal studies
		↓ Retinopathy
		↓ Nephropathy
		↓ Neuropathy
	N-(2-Acetamido Methyl) hydrazinecarboximide amide hydrochloride (ALT-946)^Citation86,Citation87	↓ Nephropathy
	3-benzyloxycarbonylmethyl-4-methyl-thiazol-3-ium bromide (C36)^Citation88	↓ Diabetic cardiovascular dysfunction
	Pyridoxamine^Citation90,Citation91	↓ Nephropathy
		↓ Dyslipidemia
Cross-link breakers	N-phenacylthiazolium (PTB)^Citation92	Animal studies
		↓ AGE
	Alagebrium (ALT-711)^Citation93,Citation94,Citation96	Animal studies
		↓ Diabetic cardiomyopathy and atherosclerosis
		↓ Nephropathy
		Human studies
		↓ Diastolic heart function
RAGE blockade	sRAGE^Citation100^–^Citation103	Animal studies
		↓ Diabetic atherosclerosis
		and retinopathy (sRAGE)
	Antihypertensive drugs^Citation99	Antioxidative properties – prevention of diabetic vascular complications?
	PEDF^Citation99	Antioxidative properties
	Statins^Citation99	Antioxidative properties
	Bisphosphonates^Citation99	Antioxidative properties
	PARP inhibitors^Citation104,Citation105	Animal studies
		↓ Early peripheral diabetic neuropathy Improve endothelial and myocardial function
Other agents	Kremezin (AST-120)^Citation106	↓ AGE levels in chronic renal failure

Abbreviations: PARP, poly(ADP-ribose) polymerase; PEDF, pigment-epithelium-derived factor; RAGE, receptor for advanced glycation end products; sRAGE, soluble receptor for advanced glycation end products; ↓, decrease/reduce.

Table 3 Recommendations for lowering advanced glycation end product (AGE) consumption

Recommendations	Permit	Avoid
Foods	Fresh fruits and vegetables Seafood Whole grains Bread Low-fat milk	Sugary items such as candy, cookies, and beverages Processed foods such as packaged meats, cheese, and snack-type foods High-fat meats Fats, such as butter, margarine, full-fat cheeses Fried foods
Cooking methods	Low temperatures for long time periods Presence of high water content: boiling, steaming, poaching, stewing	High temperatures for short time periods Dry heat: grilling, frying, roasting, baking, and barbecuing
Lifestyle modifications	Exercise Normal weight	Obesity Tobacco smoke

AhmedNAdvanced glycation endproducts – role in pathology of diabetic complicationsDiabetes Res Clin Pract20056713 2115620429

 PubMed Web of Science ®Google Scholar

GoldinABeckmanJASchmidtAMCreagerMAAdvanced glycation end products: sparking the development of diabetic vascular injuryCirculation20061146597 60516894049

 PubMed Web of Science ®Google Scholar

GoldbergTCaiWPeppaMAdvanced glycoxidation end products in commonly consumed foodsJ Am Diet Assoc200410481287 129115281050

 PubMedGoogle Scholar

SanduOSongKCaiWZhengFUribarriJVlassaraHInsulin resistance and type 2 diabetes in high-fat-fed mice are linked to high glycotoxin intakeDiabetes20055482314 231916046296

 PubMed Web of Science ®Google Scholar

CaiWHeJCZhuLReduced oxidant stress and extended lifespan in mice exposed to a low glycotoxin diet: association with increased AGER1 expressionAm J Pathol200717061893 190217525257

 PubMed Web of Science ®Google Scholar

HofmannSMDongHJLiZImproved insulin sensitivity is associated with restricted intake of dietary glycoxidation products in the db/db mouseDiabetes20025172082 208912086936

 PubMed Web of Science ®Google Scholar

VlassaraHStrikerGEAGE restriction in diabetes mellitus: a paradigm shiftNat Rev Endocrinol201179526 53921610689

 PubMed Web of Science ®Google Scholar

PouillartPMauprivezHAit-AmeurLStrategy for the study of the health impact of dietary Maillard products in clinical studies: the example of the ICARE clinical study on healthy adultsAnn N Y Acad Sci20081126173 17618448812

 PubMed Web of Science ®Google Scholar

Birlouez-AragonISaavedraGTessierFJA diet based on high-heat-treated foods promotes risk factors for diabetes mellitus and cardiovascular diseasesAm J Clin Nutr20109151220 122620335546

 PubMed Web of Science ®Google Scholar

VlassaraHCaiWCrandallJInflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathyProc Natl Acad Sci U S A2002992415596 1560112429856

 PubMed Web of Science ®Google Scholar

UribarriJPeppaMCaiWRestriction of dietary glycotoxins reduces excessive advanced glycation end products in renal failure patientsJ Am Soc Nephrol2003143728 73112595509

 PubMed Web of Science ®Google Scholar

NegreanMStirbanAStratmannBEffects of low- and high-advanced glycation endproduct meals on macro- and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitusAm J Clin Nutr20078551236 124317490958

 PubMed Web of Science ®Google Scholar

HammesHPBrownleeMEdelsteinDSaleckMMartinSFederlinKAminoguanidine inhibits the development of accelerated diabetic retinopathy in the spontaneous hypertensive ratDiabetologia199437132 358150227

 PubMed Web of Science ®Google Scholar

NishizawaYWadaRBabaMTakeuchiMHanyu-ItabashiCYagihashiSNeuropathy induced by exogenously administered advanced glycation end-products in ratsJ Diabetes Investig201011–240 49

 Web of Science ®Google Scholar

ForbesJMSoulisTThallasVRenoprotective effects of a novel inhibitor of advanced glycationDiabetologia2001441108 11411206401

 PubMed Web of Science ®Google Scholar

Wilkinson-BerkaJLKellyDJKoernerSMALT-946 and aminoguanidine, inhibitors of advanced glycation, improve severe nephropathy in the diabetic transgenic (mREN-2)27 ratDiabetes200251113283 328912401720

 PubMed Web of Science ®Google Scholar

ChengGWangLLLongLBeneficial effects of C36, a novel breaker of advanced glycation endproducts cross-links, on the cardiovascular system of diabetic ratsBr J Pharmacol200715281196 120617965740

 PubMed Web of Science ®Google Scholar

StittAGardinerTAAldersonNLThe AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetesDiabetes20025192826 283212196477

 PubMed Web of Science ®Google Scholar

DegenhardtTPAldersonNLArringtonDDPyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic ratKidney Int2002613939 95011849448

 PubMed Web of Science ®Google Scholar

VasanSZhangXZhangXAn agent cleaving glucose-derived protein crosslinks in vitro and in vivoNature19963826588275 2788717046

 PubMed Web of Science ®Google Scholar

CandidoRForbesJMThomasMCA breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changesCirc Res2003927785 79212623881

 PubMed Web of Science ®Google Scholar

CoughlanMTForbesJMCooperMERole of the AGE crosslink breaker, alagebrium, as a renoprotective agent in diabetesKidney Int Suppl2007106S54 S6017653212

 PubMed Web of Science ®Google Scholar

LittleWCZileMRKitzmanDWHundleyWGO’BrienTXDegroofRCThe effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failureJ Card Fail2005113191 19515812746

 PubMed Web of Science ®Google Scholar

ParkLRamanKGLeeKJSuppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproductsNat Med1998491025 10319734395

 PubMed Web of Science ®Google Scholar

KajiYUsuiTIshidaSInhibition of diabetic leukostasis and blood-retinal barrier breakdown with a soluble form of a receptor for advanced glycation end productsInvest Ophthalmol Vis Sci2007482858 86517251488

 PubMed Web of Science ®Google Scholar

YamagishiSNakamuraKMatsuiTUedaSFukamiKOkudaSAgents that block advanced glycation end product (AGE)-RAGE (receptor for AGEs)-oxidative stress system: a novel therapeutic strategy for diabetic vascular complicationsExpert Opin Investig Drugs2008177983 996

 PubMed Web of Science ®Google Scholar

LiFDrelVRSzabóCStevensMJObrosovaIGLow-dose poly(ADP-ribose) polymerase inhibitor-containing combination therapies reverse early peripheral diabetic neuropathyDiabetes20055451514 152215855340

 PubMed Web of Science ®Google Scholar

PacherPLiaudetLSorianoFGMableyJGSzabóESzabóCThe role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetesDiabetes2002512514 52111812763

 PubMed Web of Science ®Google Scholar

UedaSYamagishiSTakeuchiMOral adsorbent AST-120 decreases serum levels of AGEs in patients with chronic renal failureMol Med2006127–8180 18417088950

 PubMed Web of Science ®Google Scholar