By Bengmark, Stig
ABSTRACT. Background: High levels of glycated and lipoxidated proteins and peptides in the body are repeatedly associated with chronic diseases. These molecules are strongly associated with activation of a specific receptor called RAGE and a long-lasting exaggerated level of inflammation in the body. Methods: PubMed reports over 5000 papers plus > 13,500 articles about the related HbA^sub 1c^, most of them published in the past 5 years. Most of the available abstracts have been read and approximately 800 full papers have been studied. Results: RAGE, a member of the immunoglobulin superfamily of cell surface molecules and receptor for advanced glycation end products, known since 1992, functions as a master switch, induces sustained activation of nuclear factor kappaB (NFkappaB), suppresses a series of endogenous autoregulatory functions, and converts long-lasting proinflammatory signals into sustained cellular dysfunction and disease. Its activation is associated with high levels of dysfunctioning proteins in body fluids and tissues, and is strongly associated with a series of diseases from allergy and Alzheimers to rheumatoid arthritis and urogenital disorders. Heat treatment, irradiation, and ionization of foods increase the content of dysfunctioning molecules. Conclusions: More than half of the studies are performed in diabetes and chronic renal diseases; there are few studies in other diseases. Most of our knowledge is based on animal studies and in vitro studies. These effects are worth further exploration both experimentally and clinically. An avoidance of foods rich in deranged proteins and peptides, and the consumption of antioxidants, especially polyphenols, seem to counteract such a development. (Journal of Parenteral and Enteral Nutrition 31:430-440, 2007) It has been almost 100 years since Malliard1 described the nonenzymatic pathway for glycation of proteins and suggested that such chemically modified proteins could play a role in the pathogenesis of chronic diseases (ChDs), particularly diabetes (DM). However, it is only during the last 2 decades, and especially the last 5 years, that this concept has received wider attention among scientists. Still, most practicing physicians and nutrition experts are still unaware of the concept and its eventual implications on health. Contributory to the recent increase in interest is the observation that glycated hemoglobin, HbA^sub 1c^,2,3 is deeply involved in DM and in various age-associated diseases and, probably more important, the identification of several receptors in the body, which are involved in these processes, of which RAGEs are the most well known and studied.4,5 More than 5000 papers about the biology of advanced glycation products, plus over 13,500 articles about HbA^sub 1c^) are presently available on PubMed.
RAGE: A Master Switch
Metabolic syndrome, with all its clinical manifestations, is strongly associated with the development of ChDs. A discrete, often long-lasting, increased inflammation plays an important role in the development of and maintenance of this syndrome,6 and in the pathogenesis of ChDs. Common to ChDs are, in addition to the increased inflammatory state, a significant elevated oxidant stress (OS) and OS-induced gene expression.6-9 RAGE, a member of the immunoglobulin superfamily of cell surface molecules and receptor for advanced glycation end products (AGEs), functions as a master switch, converting long-lasting proinflammatory signals into sustained cellular dysfunction and disease (Table I).10- 11 This receptor and various other receptors for AGEs and lipoxidation end products (ALEs) play important roles in both oxidative stress and inflammation. RAGE induces a sustained activation of proinflammatory transcription factor NFkappaB and suppresses a series of endogenous autoregulatory functions.12 Experimental studies suggest that increased deposition of AGEs/ALEs in tissues is strongly associated with down-regulation of leptin expression in adipocytes and metabolic syndrome.13 Reducing the inflammatory environment through reduction of tissue accumulation of AGE and ALE ligands has also been shown to reduce sustained exaggerated inflammation and cellular dysfunction, and to improve outcome of disease.10,14
Tissue Accumulation of AGEs and ALEs
As described by Vlassara,14 industrial processes aimed to make food safer, flavorful, and colorful, such as heating, irradiation, and ionization, do this but in combination with gross overnutrition, and also contribute significantly to production of, exposure to, and accumulation of AGEs/ALEs in the body. Vlassara and her group16,16 have demonstrated in human studies significant correlation between ingested AGEs, circulating AGEs, and induction of markers of inflammation. In animal studies, dietary restriction of AGEs has shown “protective” effects against impaired immune function in induced ChDs and in complications to ChDs: DM-induced vasculopathy,17 nephropathy,18 and impaired wound healing.19 Furthermore, it was concluded that the animals remained nearly free of pathology despite the remaining presence of the underlying disease.14 Dietary AGE restriction in animals seemed to be as effective in extending lifespan as caloric restriction (CR).20 Similar observations have been made in human studies, in DM, vascular disease, and kidney disease: patients who were supplied a low-AGE diet responded with a considerable reduction in inflammatory markers and vascular dysfunction.15,21
Cytokines and cellular events associated with AGE or RAGE activation
AGEs constitute a complex and heterogenous group of compounds formed by nonenzymatic reactions of reducing sugars with amino acids, nucleic acids, peptides, and proteins. The first compounds produced, generally called Amadori products, will slowly undergo complex changes, cyclization, dehydration, oxidation, condensation, cross-linking, and polymerization, to finally form more irreversible chemical products, referred to as AGEs/ALEs. These processes are also called Maillard reactions and the products, Maillard products. Some highly reactive carbonyls such as glyoxal and methylglyoxal have been found to rapidly modify reactive side chains of proteins. The epsilon-amino group of lysine and the guanido group of arginine are identified as the most preferential targets for the highly reactive dicarbonyls, which makes lysine- and arginine-rich tissues and foods special targets for such processes. High intracellular and extracellular concentrations of reactive carbohydrates such as glucose, and especially the highly reactive fructose, are important triggers for increased glycation and formation of glyoxal, methylglyoxal, and 3-deoxyglucosan, which glycate proteins, which accumulate both intra- and extracellularly. Significantly elevated visceral AGE formation, serum AGE levels, caspase-3 activation, and cytoplasmic DNA fragmentation are observed in organs such as heart, liver, and kidneys in animals with dyslipidemia due to high-fat diet (32-42% fat),22 findings well in line with >50-year-old observations that a high-fat diet contributes to manifestations of diseases: thrombus formation, renal infarcts, and myocardial infarctions.23
Glyoxal and methylglyoxal formation constitutes an intermediate stage in the Maillard reaction, whereas pentoside, an often-studied glyco-oxidation product and fluorescent cross-link, is formed in the late stage of the reaction, where it becomes more stable and irreversible. Many AGE/ALE compounds have been identified in tissues, and new previously unknown substances are identified at a rate of 2-3 per year. Most studies thus far have focused only on a handful of these substances, apart from HbAlc, mainly pentoside, N^sup epsilon^-(carboxymethyDlysine (CML) and N^sup epsilon^- carboxyethyl) lysine (CEL). Recent and increasing evidence suggests that lipids are as important contributors as carbohydrates to chemical modification of proteins, accumulation in tissues of Maillard products, and pathogenesis of diseases.24 As diary products and meat are the dominating sources of fats and are usually exposed to higher temperature, it is these foods that are the largest contributor of ALEs to the body. Some Maillard products are formed from both carbohydrate and lipid sources; one such example is CML.25 Products derived only from carbohydrate sources, AGEs, are pentoside, crosslines, vesperlysines, and 3DG-imidozolones. MaIondialdehyde (MDA), acrolein adducts of lysine, histidine, and cysteine are specific AGEs.24
AGEs/ALEs and Disease
The levels of AGEs/ALEs in individuals with incipient or manifest ChDs are, when compared with healthy individuals, dramatically and significantly increased. There is, however, great variation in pattern of AGEs/ALEs in the tissues and in the circulation between various patients and groups of patients with ChDs. Both AGEs and ALEs will, when accumulated in tissues, significantly increase the level of inflammation in the body,26,27 reduce antioxidant defense,28 weaken the immune system,29 impair DNA repair mechanisms,30 and increase accumulation of toxins within the tissues26 and increase the rate of infection.26,27 The differences are great; glycated proteins are suggested to produce almost 50 times more free radicals than nonglycated proteins,31 and the plasma concentrations of free CML are reported to be increased about 8- fold with CEL reported at 22-fold in hemodialysis patients.32 Accumulation of modified insoluble, indigestible, and dysfunctional proteins (AGEs/ALEs) occurs predominantly in long-lived tissues such as collagen, neural myelins, and lenses. It leads to decreased elasticity of collagen-rich tissues, which seems to explain the agedependent (and ChD-dependent) increase in stiffness of lenses, joints, skeletal muscles, vascular walls, and an increase in systolic and decrease in diastolic pressure.33 AGEs/ALEs exert strong effects also on shortlived cells such as endothelial cells and pericytes, stimulate growth, interact with cell-surface receptor RAGE, and activate the NFkB pathway, induce vascular endothelium growth factor (VEGF), inhibit prostacycline production, and stimulate plasminogen activator inhibitor-1 (PAI-I) synthesis by endothelial and other cells. Table 1 summarizes documented cellular events and changes associated with AGE and RAGE activation.
Hormones Potentiate AGE/ALE-Induced Inflammation
The process of inflammation is, in addition to being dependent on the status of oxidation/antioxidation, also enhanced by hormones, especially growth and sex hormones, and low levels of vitamins, particularly vitamin D. 17ss-Estradiol, for example, has been shown to significantly up-regulate RAGE mRNA in human microvascular endothelial cells34 and VEGF-dependent angiogenesis.35 This could explain a common observation, exacerbation of diabetic vasculopathy and retinopathy during pregnancy. This assumption is further supported by the finding that RAGE mRNA activation on endothelial cells induced by 7beta-estradiol is abolished when an antiestrogen such as 4-OH tamoxifen is supplemented.36 These observations might also explain why commercial bovine milk, rich in not only AGEs/ALEs but also in estrogens (eg, 17ss-estradiol) have been associated with ChDs such as allergy,36 coronary heart disease,37,38 DM,39-41 Parkinson disease (PD).42 and various cancers such as breast,43’44 prostatic,45,46 testicular,46 and to some extent ovarian47,48 malignancies. It might not be a coincidence that ChDs and rate of complications to ChDs are significantly higher, especially during the winter, at higher altitudes (northern Europe, northern North America), where also secondary hyperparathyroidism, due to poor supply of vitamin D, is more often found.49,50 Parathyroid hormone is known to induce IL-6 and is claimed to significantly increase IL- 6 both in hyperthyroid patients (16-fold) and in overweight patients.49
The Role of AGE/ALE Tissue Deposition in Common ChDs
The deposition of dysfunctioning proteins in tissues will, when pronounced, result in accumulation of histologic changes referred to as amyloid, a common feature in various ChDs. These deposits of AGEs/ ALEs produce a significant fluorescence, and the degree of ALE/AGE in tissues and body fluids can easy and reliably be measured in organs such as the skin, blood, and lenses through estimation of their fluorescence.61 There is with aging a continuous but slow increase in content of AGEs/ALEs also in healthy individuals, but the increase is significantly more pronounced in individuals who are developing or have acquired ChDs. Pronounced increase in levels of AGEs/ALEs in tissues is reported to be strongly associated to metabolic syndrome4,52 and to down-regulation of leptin expression in adipocytes.63
Clinical Relevance of AGEs/ALEs in Specific Groups of Diseases
Accumulation of AGEs/ALEs in tissues and changes suggested to be induced by AGEs/ALEs have been reported in the following ChDs.
Allergy and autoimmune diseases. Thermal processing, curing, and roasting of foods introduce major changes in allergenicity of foods and will often introduce neoantigens and increase allergenicity. Further studies are needed, however, as reduced allergenicity has sometimes been reported.64,65 Heated foods like milk, roasted peanuts and soy are reported to induce significant increases in AGE levels and affect the IgE-binding capacity.56,57 Significantly elevated urinary levels of the AGE pentosine are observed in allergic children with clinical signs of exacerbation of atopic dermatitis.68
Alzheimers disease (AD) and other neurodegenerative diseases. Similarities between AD and type 2 diabetes (T2DM) exist to the extent that AD has been called “the diabetes of the brain.” The incidence of AD is also reported to be 2- to 5-fold increased in T2DM.59 A common feature of both diseases is accumulation of amyloid deposits, a process that progresses during the course of disease. Increased levels of AGEs/ALEs have repeatedly been demonstrated with immunohistochemical methods in senile plaques, tau proteins, amyloid beta proteins, and in neurofibrillary tangles. [degrees]’61 A 3- fold increase in content of AGE is also reported in the brains of AD patients compared with age-matched controls.62 Increased levels of AGEs and signs of oxidative damage are also observed in olfactory bulbs, known to be early targets of AD.62 A strong association between severity of disease, RAGE-expression in microglia, and increases in RAGE protein has been reported.63 Signs of amyloidosis, Pertubation of neuronal properties and functions, amplification of glial inflammatory response, increased oxidative stress, increased vascular dysfunction, increased Ass in the blood-brain barrier, and induction of autoantibodies were also reported.63 Involvement of AGEs/ALEs in the pathogenesis of other neurodegenerative diseases is also reported: PD,64,65 amyotrophic lateral sclerosis (ALS),66-68 Huntington disease, stroke,70 familial amyloidotic polyneuropathy,71 and Creutzfeldt-Jakob disease.72 Early accumulation of AGEs is also observed in Down syndrome and early antiglycation treatment suggested to reduce cognitive impairments.73 It was recently suggested that bovine spongiform encephalopathy (BSE), a disease with its significant similarities to AD, might also be associated with increased glycation and lipoxidation.74 AGEs, amyloid fibrils, and prions seem all to have the same target, RAGE, and all activate the NFkB pathway. Involvement in BSE of glycation products and activation of prion proteins are also suggested by other authors.75,76
Atherosclerosis and cardiovascular diseases. Oxidative stress (lipid peroxidation) and protein glycation have repeatedly been associated with extensive arteriosclerosis. A recent study reports significant increases in both chemical AGEs (carboxymethyl lysine) and fluorescent AGEs (spectrofluorimetry) in 42 patients with atherosclerosis when compared with 21 healthy controls (p
Cancers. The influence of AGEs/ALEs on the pathogenesis of malignant tumors and their ability to grow is not extensively studied. However, it is reported that the sRAGE receptor, highly expressed in healthy lung tissues and especially at the site of alveolar epithelium, is significantly down-regulated in lung carcinomas,8 and the RAGE expression is reported to be elevated in human pancreatic cells with high metastatic ability and decreased in tumor cells with low metastatic ability.84 High RAGE expression is also reported in colonic and prostatic86 cancers. Little information is available about other types of cancers, including breast cancer, but it has recently been suggested that inhibition of AGE-RAGE interaction might have a potential as a molecular target for both cancer prevention and therapy.84,86
Cataract and other eye disorders. AGEs/ALEs accumulate with age in all ocular tissues, including lacrimal glands, and trigger pathogenic events, especially in diabetic patients, in all parts of the eye.87
DM. More than 2000 publications listed in PubMed (ie, almost half of all DM papers listed) deal with AGEs/AGEs and their role in DM. Several excellent reviews have recently been published.88-90 Overconsumption of fat and carbohydrates, not only of glucose but also other carbohydrates such as lactose and fructose, contribute especially in diabetic patients to a significant accumulation of AGEs/ALEs in the tissues. Consumption of high-fructose corn syrup in the United States exceeds that of sucrose and is suggested to be the major contributor not only to obesity and hepatic steatosis but especially to T2DM and to severe complications of both types 1 and 2 DM.91 The feeding of dairy cows have in recent years, similar to human foods, undergone significant changes from mainly foragebased feeds to significant amounts of starch-rich and fast-absorbed carbohydrates: corn, maize grains, barley, molasses, and dextrose, feeds that induce insulin resistance in cows and, if the cows are allowed to live long enough, will lead to manifest DM. Insulin resistance is also observed in calves when intensively fed milk and lactose.92 Endocrine disorders. Many if not most of the signs and symptoms of aging, as well as age-associated diseases, are identical to manifestations seen in hormone deficiencies and in premature aging, which is strongly associated with multiple hormone deficiencies. Most consequences of aging such as excessive free radical formation, imbalanced apoptosis system, tissue accumulation of waste products, failure of repair systems, deficient immune system, poor gene polymorphisms, and premature telomere shortening are also associated, if not caused, by hormone deficiencies.93 Up- regulation of putative pathologic pathways, accumulation of AGEs, activation of the renin-angiotensin system, oxidative stress, and increased expression of growth factors and cytokines are all associated with aging. However, little information either in health or disease, is available about content of AGEs/ALEs in endocrine organs: the pituitary gland, thyroids, parathyroids, adrenals, ovaries, and testes. Increased serum AGE levels and activation of RAGE are reported in women with polycystic ovary syndrome.94
Activation of the renin-angiotensin system, known to have a pivotal role in ChDs such as DM and chronic renal disease, contributes to enhanced pathogenic mechanisms: increased oxidative stress, increased general inflammation, increased serum levels of free fatty acids, increased glycotoxicity and lipotoxicity, and advanced glycation and lipoxidation.95-97
Gastrointestinal disorders. It is likely that digestive tract disorders such as liver cirrhosis and liver steatosis, as well as inflammatory bowel disorders, are associated with elevated AGEs/ ALEs. A recent study reports a 14- to 16-fold increase of glyoxal- derived adducts in portal and hepatic venous plasma of cirrhotic patients compared with healthy controls.98 Plasma AGE levels were also measured in 51 patients with liver cirrhosis, 5 patients after liver transplantation, and 19 healthy controls.99 Patients with liver cirrhosis demonstrated significantly increased AGE levels, almost to the same extent as seen in patients with end-stage renal disease. A dramatic improvement was observed in patients after liver transplantation, although the AGE levels did not return to those seen in healthy controls, and the preoperative decrease in renal function did persist. One hundred ten patients with chronic liver disease (CLD) were recently studied and compared with 124 healthy controls. Serum levels of AGE (CML) were significantly affected by the stage of liver cirrhosis and closely associated with liver function capacity, and AGE (CML) level was reported to positively correlate with levels of hyaluronic acid (HA; r = 0.639; ?
Pulmonary disorders. Lack of homeostasis in oxidant/antioxidant balance is obvious in a variety of airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, and idiopathic pulmonary fibrosis. Interaction of AGEs/ ALEs and RAGE plays a large role, if not a dominating one, in the pathogenesis of these pulmonary diseases, and depletion of antioxidants, particularly GSH, in lung epithelial lining is suggested to play a key role in these disorders.103-105
Rheumatoid arthritis and other skeletomuscular disorders. A very strong expression of RAGE, and some of the highest levels of AGEs in the body are found in tissues with slow turnover, such as tendons, bone, cartilage, skin, and amyloid plaques. Changes, frequently associated with change in color from white to yellow-brown, include increased fluorescence, increased expression of proinflammatory cytokines, matrix metalloproteinases (MMP), especially MMP-I and – 9. These manifestations are likely responsible for the observed increased tissue stiffness and brittleness in structures such as intervertebral discs, bones tendons, cartilages, synovial membranes, and skeletal muscles and will most likely constitute a major pathogenic factor in diseases such as osteoarthritis,106,107 rupture of intervertebral discs,108 Achilles tendons109 and eventually menisci, and are involved also in rheumatoid diseases110-112 such as rheumatoid arthritis (RA) and fibromyalgia. A significant increase in glycation of myosin occurs with age,113 which most likely contributes to age-associated muscular disorders. Observations in subjects with osteoporosis of significantly elevated levels of pentosidine and CML in serum11 and significantly increased pentosidine in cortical bone115 are of considerable interest. It has also been observed that the remodeling of senescent bone is impaired by AGEs both through stimulation of bone-resorbing cytokines and enhancement of bone resorption by osteoclasts.116 The role of bovine milk in prevention of osteoporosis could be found to discredit what has been claimed for decades, should future studies verify that osteoporosis is more due to interactions of RAGE and AGEs/ALEs than to lack of minerals.
Skin and oral cavity. Skin has a high density of AGE receptors. AGEs/ALEs are known to accumulate in dermal elastin and in collagene also, and are known to interact with dermal fibroblasts, inhibiting their proliferation capacity. A 10-times reduction in proliferation rate is described as normal in humans between the second and seventh decade,117 which might well explain the reduced healing capacity of age-related wounds and especially chronic wounds such as those in the extremities of people with DM. It has also been observed that accumulation of AGEs/ALEs in the skin reflects the AGE/ALE deposition in the rest of the body to such a degree that skin autofluorescence has been suggested as a measure of cumulative metabolic stress and AGEs in the body.118 Skin autofluorescence is suggested to be so exact that it is able to predict progression of retinopathy and nephropathy in DM, as well as mortality in hemodialysis patients.118 RAGE and AGE/ALE-induced apoptosis and enhanced loss of fibroblasts and osteoblasts are also regarded as major pathogenic factors in periodontal pathology, especially in chronic periodontitis.119 A 50% increase in RAGE mRNA is observed in gingiva of diabetic patients compared with controls (p
Urogenital disorders. Nephropathy is common in the modern world and its incidence is fast increasing, much in parallel to the increase in DM. Diabetic nephropathy alone affects today 15%-25% of patients with type 1 DM and as many as 30%-40% of patients with T2DM. Furthermore, it is the single most important cause of end- stage renal failure in the western world.121 The kidney appears as both culprit and target of AGEs/ALEs, and it is well documented that RAGE is significantly activated and levels of AGEs/ALEs are markedly elevated in patients with renal failure. More than 500 papers on PubMed deal with RAGE and AGEs/ALEs in renal diseases. A decrease in renal function and reduced renal clearance are observed much in parallel to increases in circulating AGEs. AGEs are also involved in the structural changes observed in progressing nephropathies such as glomerulosclerosis, interstitial fibrosis, and tubular atrophy122; more detailed information has been published in recent excellent reviews.122-127 Patients with mild chronic uremic renal failure are reported to have plasma glycation free adduct concentrations increased up to 5-fold; patients with end-stage renal disease, as much as 18-fold when receiving peritoneal dialysis and up to 40- fold when receiving hemodialysis.128 Kidney transplantation is reported to improve but does not fully correct the increased levels of AGE/ALE in patients who have been previously dialyzed.129
Dietary Measures to Reduce AGEs/ALEs
The greatest of contributors by far of AGEs/ALEs by food (Table II) seem to be dairy products130 (Figure 1), bread, and meat, not only because they are rich in these substances but also as these foods constitute the bulk of modern food, especially in the western world. Also, plants contribute to accumulation of AGEs/ALEs in the body, especially fruits, which contain larger amounts of fructose, which is highly reactive with proteins. However, consumption of carbohydrates seem mainly, or only, to be of considerable risk when consumed as industrially concentrated products, refined sugar, and high-fructose corn syrup.91
Short list of foods rich in AGEs/ALEs131
Consuming a vegan diet, known to be low in AGEs/ALEs, seems to result in statistically lower systolic and diastolic blood pressure, lower serum total cholesterol, low-density lipoprotein cholesterol, triglycerides, fasting blood glucose, fewer weight problems, and less incidence of ChDs, especially DM and its complications. However, there are also problems with a vegetarian (lactovegetarian and vegan) lifestyle which need to be corrected, among them risk of shortage in vitamin B12 and poor taurine status,132 and for lactovegetarians, higher serum levels of homocysteine. The serum levels of AGEs/ALEs are reported as higher in longtime healthy lactovegetarians than in healthy omnivorous people.133 One explanation could be, as suggested by the authors, a higher intake of fructose, especially because this carbohydrate is significantly more reactive with proteins than sucrose. Another explanation could be a higher consumption of various milk products, especially cheese and milk powder, known to be rich in AGEs/ALEs, meant to substitute meat and fish in the diet. FIGURE 1. Relative furosine content in various milk-based products. A, Milk powder kept for 2 years in room temperature. B, Milk powder kept for 1 year at room temperature. C, DIF with whey plus casein. D, DIF with hydrolyzed whey. E, Milk powder kept for 1 year at 4[degrees]C. F, Fresh milk powder. G, Raw (whole) bovine milk. Reprinted from Baptista JAB, Carvalho RCB. Indirect determination of Amadori compounds in milk-based products by HPLC/ELSD/UV as an index of protein deterioration. Food Res Int. 2004;37:739-747, with permission from Elsevier.
DIF, dietetic infant formulas; UHT, ultraheat treatment.
Several measures have been demonstrated to significantly decrease serum and tissue concentrations of AGEs/ALEs, among which are the following.
Calorie restriction. Evidence from animal studies suggests that restriction in food intake is an effective means to extending median lifespan and preventing ChDs.15 Few studies are, unfortunately, available in primates and almost no studies in humans. Significant benefits of long-term (2-11 years) CL compared with normal western diet were recently reported in a study in healthy humans: blood pressure 102 +- 10/61 +- 7 vs 131 +- 11/83 +- 6 mm Hg, c-reactive protein (CRP) 0.3 +- 0.3 vs 1.9 +- 2.8 mg/L, tumor necrosis factor (TNF)-a 0.8 +- 0.5 vs 1.5 +- 1.0 pg/mL, transforming growth factor (TGF)-ss 29.4 +- 6.9 ng/mL vs 35.4 +-7.1 ng/mL respectively.134 Patients with RA receiving a low-energy diet for 54 days demonstrated a significant reduction in both urinary pentosidine level and RA disease activity.135 However, studies on the effects of CL on AGEs/ALEs are thus far lacking in other groups of ChDs.
Vitamins and antioxidants. Glutathione (7-glutamylcysteinyl glycine [GSH]) is regarded as an important factor for optimal cellular function and defense against oxidative stress. Dietary supply of GSH has been shown to reduce glycation and prevents diabetic complications such as diabetic nephropathy and neuropathy.136 Rich supply of vitamins A, C, E, and particularly B6, B12, and folic acid (Figure 2) is often emphasized in the literature.137 Vitamin D should most likely also be supplemented, especially at higher latitudes. Several thousands of plant-derived chemopreventive agents, polyphenols, and many others, most often yet unexplored, have the potential to reduce the speed of aging and prevent degenerative malfunctions of organs, among them, isothiocyanates in cruciferous vegetables, anthocyanins and hydroxycinnamic acids in cherries, epigallocatechin-3-gallate (EGCG) in green tea, chlorogenic acid and caffeic acid in coffee beans and also tobacco leaves, capsaicin in hot chili peppers, chalcones in apples, eugenol in cloves, gallic acid in rhubarb, hisperitin in citrus fruits, naringenin in citrus fruits, kaempferol in white cabbage, myricetin in berries, rutin and quercetin in apples and onions, resveratrol and other procyanidin dimers in red wine and virgin peanuts, various curcumenoids, the main yellow pigments in turmeric curry foods,138 and daidzein and genistein from the soybean. These compounds have all slightly different functions and seem to complement each other well. Several, most likely the majority, of these substances have a great capacity to inhibit the second phase of the glycation process, eg, the conversion of the Amadori products to AGEs. A significant number of animal studies support health benefits of these antioxidants and AGE/ALE scavengers.139,140 Again, human studies are largely lacking.
FIGURE 2. Involvement of homocysteine, folic acid, and vitamins B6 and B12 influences metabolism and possible mechanisms whereby elevated homocysteine contributes to increased risks of chronic diseases. Reprinted from Mattson MP. Will caloric restriction and folate protect against AD and PD? Neurology. 2003;60:690-695, with permission from Lippincott Williams & Wilkins.137
Taurine, carnitine, carnosine, histidine. Taurine, a sulfonic acid compound, is normally found in high concentrations intracellularly in most animal tissues, and especially in blood cells, retina, and nervous tissues. The highest concentrations are found in neutrophils, where it is suggested to reduce inflammation.141 The richest sources of taurine are seafood, fish, and poultry. Moderate amounts are also found in meat, whereas plants, with the only known exception of some algae, and consequently also vegan diets, are devoid of this amino acid.142 Taurine has strong hypoglycemic effects, observed already in the 1930s.143 It reduces production of AGEs/ALEs and prevents high- fructose-diet-induced collagen abnormalities in animals.144,145 In vitro and animal studies suggest that similar effects are obtained also from supplementing amino acids such as histidine or peptides such as carnitine and carnosine. Again, no human studies have been undertaken.
Pre- and pro-biotics. Plant-derived antioxidants and AGE/ALE scavengers need to be released from the plant fibers during passage through the digestive tract. This process is mainly dependent on microbial enzymes, provided by the flora in the lower gastrointestinal tract. This flora is reported to be severely impaired in about 75% of omnivorous Americans and one-third of vegetarian Americans.146 Lactic acid bacteria (LAB) are also in their own capacity strong oxidation scavengers and effective inhibitors of inflammation. LAB might also have the capacity, before the food is absorbed to eliminate AGE/ALE protein and peptides, as was earlier demonstrated for gluten147 and carcinogens.148 Support for such an assumption derives from an in vitro study, where fructose lysine, the main modified molecule in heated milk,126 is eliminated (deaminated) when incubated with live flora.149
In the past, most studies on lifestyle-associated disease have focused mainly on coronary heart disease, T2DM, and chronic renal disease. Increasing evidence suggests that an “unhealthy” lifestyle is negatively associated with most, if not all, ChDs. Common to the ChDs is a permanent, often silent, exaggerated inflammation, strongly associated with metabolic syndrome and increased deposits in tissues of AGEs/ALEs. ChD patients, including those with obscure etiology and those with inherent genetic disorders (Down syndrome,73,150 cystic fibrosis,151,152 schizophrenia,153,154 and mental depression155-157) might well benefit from reduced AGE/ALE intake. However, more studies are needed. Studies performed in the United States have reported that the incidence of a number of chronic diseases would be greatly reduced if people would follow a “healthy lifestyle.” These estimates suggest that the incidence of coronary artery disease could be reduced by 83%, diabetes mellitus in women could be reduced by 91%, and colon cancer in men by 71%.160 It is likely that controlled intake and cellular production of AGEs/ ALEs constitute important contributions to such a healthy lifestyle.
Exaggerated inflammation is also observed in patients who have complications to acute diseases: sepsis, trauma, and advanced surgical and medical treatments such as transplantations. Complications and sequelae to these events are significantly more common in elderly people and in those with ChDs. Clearly, lifestyle of the individual and inflammation before the trauma will significantly influence outcome.161 Presence of metabolic syndrome has been shown to have a strong negative influence on outcome in acute morbidities and in ICU patients. Future attempts to minimize accumulation of such substances in the body might provide significant benefits in both acute and chronic morbidities. It is important to stress that research in this field is in its infancy, and many more studies are needed, particularly in humans. I wish such studies will be given the highest priority.
1. Maillard LC. Action des acids amine sur des sucres: formation des melanoides per voie methodique. C R Acad Sci. 1912;154: 66-68.
2. Rahbar S. An abnormal hemoglobin in red cells of diabetics. Clin Chem Acta. 1968;22:296-298.
3. Rahbar S. The discovery of glycated haemoglobin: a major event in the study of nonenzymatic chemistry in biological systems. Ann N Y Acad Sci. 2005;1043:9-19.
4. Chavakis T, Bierhaus A, Nawroth PP. RAGE (receptor for advanced glycation end products): a central player in the inflammatory response. Microbes Infect. 2004;6:1219-1225.
5. Ramasamy R, Vannucci SJ, Yan SS, Herold K, Yan SF, Schmidt AM. Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology. 2005;15:16R-28R.
6. Das UN. Metabolic syndrome X: an inflammatory condition? Curr Hypertens Rep. 2004;6:66-73.
7. Black PH. The inflammatory response is an integral part of stress response: implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X. Brain Behau Immun. 2003;17:350-364.
8. Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care. 2004;27:813-823.
9. Libby P. Inflammation in atherosclerosis. Nature. 2003;420:868- 874.
10. Bierhaus A, Humpert PM, Stern DM, Arnold B, Nawroth PP. Advanced glycation end product receptor-mediated cellular dysfunction. Ann N Y Acad Sci. 2005;1043:676-680.
11. Schmidt AM, Yan SD, Yan SF, Stern DM. The multiligand receptor RAGE is a progression factor amplifying immune and inflammatory responses. J Clin Invest. 2001;108:949-955.
12. Bierhaus A, Schiekofer S, Schweninger M, et al. Diabetes- associated sustained activation of the transcription factor nuclear factor-??. Diabetes. 2001;50:2792-2808.
13. Koyama H, Shoji T, Yokoyama H, et al. Plasma level of endogenous secretory RAGE is associated with components of the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vase Biol. 2005;25:2587-2593.
14. Vlassara H. Advanced glycation in health and disease: role of the modern environment. Ann N Y Acad Sci. 2005;1043:452-460. 15. Vlassara H, Cai J, Crandall J, et al. Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc Natl Acad Sci USA. 2002;99:15596-15601. Erratum 2002;763.
16. Peppa M, Uribarri J, Cai W, Lu M, Vlassara H. Glycoxidation and inflammation in renal failure patients. Am J Kidney Dis. 2004;43:690-695.
17. Lin RY, Choudhury W, Cai W, et al. Dietary glycotoxins promote diabetic atherosclerosis in apolipoprotein ?-deficient mice. Atherosclerosis. 2003;168:213-220.
18. Zheng F, He C, Cai W, Hattori M, Steffes M, Vlassara H. Prevention of nephropathy in mice by a diet low in glycoxidation products. Diabetes Metab Res Rev. 2002;18:224-237.
19. Peppa M, Brem H, Ehrlich P, et al. Adverse effects of glycotoxins on wound healing in genetically diabetic mice. Diabetes. 2003; 52:2805-2813.
20. Cai W, He JC, Lu M, et al. Amelioration of insulin resistance, weight gain and markers of oxidant stressing aging mice by dietary glycotoxin restriction: a therapeutic alternative to caloric restriction. Diabetes. 2004;(suppl 2):A343.
21. Uribarri J, Peppa M, Cai W, et al. Restriction of dietary glycotoxins markedly reduces AGE toxins in renal failure patients. JAm Soc Nephrol. 2003;14:728-731.
22. Li SY, Liu Y, Sigmin VK, McCort A, Ren J. High fat diet enhances visceral advanced glycation end products, nuclear O-Glc- Nac modification, p38 mitogen-activated protein kinase activation and apoptosis. Diabetes Obes Metab. 2005;7:448-454.
23. Hartroft WS, Thomas WA. Pathological lesions related to disturbances of fat and cholesterol metabolism in man. JAMA. 1957; 164:1899-1905.
24. Thorpe SR, Baynes JW. Maillard reaction products in tissue proteins: new products and new perspectives. Amino Acids. 2003;25:275-281.
25. Baynes JW, Thorpe SR. Glycoxidation and lipoxidation in atherosclerosis. Free Radie Biol Med. 2000;28:1708-1716.
26. Vamvakas S, Bahner U, Heidland A. Cancer in end-stage renal disease: potential factors involved. Am J Nephrol. 1998;18:89-95.
27. Loske C, Neumann A, Cunningham AM, et al. Cytotoxicity of advanced glycation end products is mediated by oxidative stress. J Neural Transm. 1998;105:1005-1015.
28. Morena M, Cristol JP, Senecal L, Leray-MoraguesH, Krieter D, Canaud B. Oxidative stress in hemodialysis patients: is NADPH oxidase complex the culprit? Kidney Int. 2002;80(suppl):109-114.
29. Descamps-Latscha B, Jungers P, Witko-Sarsat V. Immune system dysregulation in uremia: the role of oxidative stress. Blood Purif. 2002;20:481-484.
30. Zevin D, Malachi T, Gafter U, Friedman J, Levi J. Impaired DNA repair in patients with end-stage renal disease and its improvement with hemodialysis. Miner Electrolyte Metab. 1991; 17:303- 306.
31. Mullarkey CJ, Edelstein D, Brownlee M. Free radical generation by early glycation products: a mechanism for accelerated atherogenesis in diabetes. Biochem Biophys Res Commun. 1990;173: 932- 939.
32. Agalou S, Ahmed N, Dawnay A, Thornalley PJ. Removal of advanced glycation products in clinical renal failure by peritoneal dialysis and haemodialysis. Biochem Soc Trans. 2003;31: 1394-1396.
33. Aronson D. Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes. J Hypertens. 2003;21:3-12.
34. Yamagishi S, Fujimori H, Yonekura H, Yamamoto Y, Yamamoto H. Advanced glycation end products inhibit prostacyclin production and induce plasminogen activator inhibitor- 1 in human microvascular endothelial cells. Diabetologia. 1998;41:1435-1441.
35. Suzuma K, Mandai M, Takagi H, et al. 17-Beta-estradiol increases VEGF receptor-2 and promotes DNA synthesis in retinal microvascular endothelial cells. Invest Ophthalmol Vis Sci. 1999;40:2122-2129.
36. Rautava S, Isolauri E. Cow’s milk allergy in infants with atopic eczema is associated with aberrant production of interleukin- 4 during oral cow’s milk challenge. J Pediatr Gastroenterol Nutr. 2004;39:529-535.
37. Artaud-Wild SM, Connor SL, Sexton G, Connor WE. Differences in coronary mortality can be explained by differences in cholesterol and saturated fat intakes in 40 countries but not in France and Finland: a paradox. Circulation. 1993;88:2771-2779.
38. Moss M, Freed DL. Survival trends, coronary event rates, and the MONICA project: monitoring trends and determinants in cardiovascular disease. Lancet. 1999;354:862-865.
39. Dahl-Jorgensen K, Joner G, Hanssen KF. Relationship between cows’ milk consumption and incidence of IDDM in childhood. Diabetes Care. 1991;14:1081-1083.
40. Gimeno SG, de Souza JM. IDDM and milk consumption: a casecontrol study in Sao Paulo, Brazil. Diabetes Care. 1997;20:1256- 1260.
41. Virtanen SM, Hypponen E, Laara E, et al. Cow’s milk consumption, disease-associated autoantibodies and type 1 diabetes mellitus: a follow-up study in siblings of diabetic children: Childhood Diabetes in Finland Study Group. Diabet Med. 1998;15:730- 738.
42. Park M, Ross GW, Petrovitch H, et al. Consumption of milk and calcium in midlife and the future risk of Parkinson disease. Neurology. 2005;64:1047-1051.
43. Outwater JL, Nicholson A, Barnard N. Dairy products and breast cancer: the IGF-I, estrogen, and bGH hypothesis. Med Hypotheses. 1997;48:453-461.
44. Hjartaker A, Laake P, Lund E. Childhood and adult milk consumption and risk of premenopausal breast cancer in a cohort of 48,844 women: the Norwegian Women and Cancer Study. Int J Cancer. 2001;93:888-893.
45. Ganmaa D, Li XM, Wang J, Qin LQ, Wang PY, Sato A. Incidence and mortality of testicular and prostatic cancers in relation to world dietary practices. Int J Cancer. 2002;98:262-267.
46. Ganmaa D, Li XM, Qin LQ, Wang PY, Takeda M, Sato A. The experience of Japan as a clue to the etiology of testicular and prostatic cancers. Med Hypotheses. 2003;60:724-730.
47. Larsson SC, Bergkvist L, WoIk A. Milk and lactose intakes and ovarian cancer risk in the Swedish Mammography Cohort. Am J Clin Nutr. 2004;80:1353-1357.
48. Genkinger JM, Hunter DJ, Spiegelman D, et al. Dairy products and ovarian cancer: a pooled analysis of 12 cohort studies. Cancer Epidemiol Biomarkers Prev. 2006;15:364-372.
49. Zittermann A, Schleithoff SS, Koerfer R. Putting cardiovascular disease and vitamin D insufficiency into perspective. Br J Nutr. 2005;94:483-492.
50. McCarty MF. Secondary hyperparathyroidism promotes the acute phase response: a rational for supplementing vitamin D in prevention of vascular events in elderly. Med Hypotheses. 2005; 64:1022-1026.
51. Meerwaldt R, Links T, Graaff R, et al. Simple noninvasive measurement of skin autofluorescence. Ann N Y Acad Sci. 2005; 1043:290-298.
52. Soldates G, Cooper ME, Jandeleit-Dahm KA. Advancedglycation end products in insulin-resistant states. Curr Hypertens Rep. 2005;7:96-102.
53. Unno Y, Sakai M, Sakamoto Y, et al. Advanced glycation end products-modified proteins and oxidized LDL mediate downregulation of leptin in mouse adipocytes via CD36. Biochem Biophys Res Commun. 2004;325:151-156.
54. Davis PJ, Smales CM, James DC. How can thermal processing modify the antigenicity of proteins? Allergy. 2001;56(suppl 67): 56- 60.
55. Sancho AI, Rigby NM, Zuidmeer L, et al. The effect of thermal processing on the IgE reactivity of the non-specific lipid transfer protein from apple, Mal d 3. Allergy. 2005;60:1262-1268.
56. Chung SY, Champagne ET. Association of end-product adducts with increased IgE binding of roasted peanuts. J Agrie Food Chem. 2001;49:3911-3916.
57. Franck P, Moneret Vautrin DA, Dousset B, et al. The allergenicity of soybean-based products is modified by food technologies. Int Arch Allergy Immunol. 2002;128:212-219.
58. Tsukahara H, Shibata R, Ohta N, et al. High levels of urinary pentosidine, an advanced glycation end product, in children with acute exacerbation of atopic dermatitis: relationship with oxidative stress. Metabolism. 2003;52:1601-1605.
59. Nicolls MR. The clinical and biological relationship between type II diabetes mellitus and Alzheimer’s disease. Curr Alzheimer Res. 2004;1:47-54.
60. Smith MA, Taneda S, Richey PL, et al. Advanced Maillard reaction end products are associated with Alzheimer pathology. Proc Natl Acad Sci USA. 1994;91:5710-5714.
61. Vitek MP, Bhattacharya K, Gendening JM, et al. Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proc Natl Acad Sci USA. 1994;91:4766-4770.
62. Moreira PI, Smith MA, Zhu X, Nunomora A, Castellani RJ, Perry G. Oxidative stress and neurodegeneration. Ann N Y Acad Sci. 2005;1043:543-552.
63. Lue L-F, Yan SD, Stern DM, Walker DG. Preventing activation of receptor for advance glycation end products in Alzheimer’s disease. Curr Drug Targets CNS Neurol Disord. 2005;4:249-266.
64. Castellani R, Smith MA, Richey PL, Perry G- Glycoxidation and oxidative stress in Parkinson disease and diffuse Lewy body disease. Brain Res. 1996;737:195-200.
65. Dalfo E, Portero-Otin M, Ayala V, Martinez A, Pamplona R, Ferrer I. Evidence of oxidative stress in the neocortex in incidental Lewy body disease. J Neuropathol Exp Neurol. 2005;64: 816- 830.
66. Kikuchi S, Shinpo K, Ogata A, et al. Detection of N- (carboxymethyDlysine (CML) and non-CML advanced glycation end products in the anterior horn of amyotrophic lateral sclerosis spinal cord. Amyotroph Lateral Scler Other Motor Neuron Disord. 2002; 3:63-68.
67. Chou SM, Wang HS, Taniguchi A, Bucala R. Advanced glycation end products in neurofilament conglomeration of motoneurons in familial and sporadic amyotrophic lateral sclerosis. MoI Med. 1998;4:324-332.
68. Kaufmann E, Boehm BO, Sussmuth SD, et al. The advanced glycation end-product N epsilon-(carboxymethyl)lysine level is elevated in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Neurosci Lett. 2004;371:226-229.
69. Ma L, Nicholson LF. Expression of the receptor for advanced glycation end products in Huntington’s disease caudate nucleus. Brain Res. 2004;1018:10-17.
70. Zimmerman GA, Meistrell M, Bloom O, et al. Neurotoxicity of advanced glycation endproducts during focal stroke and neuroprotective effects of aminoguanidine. Proc Natl Acad Sci USA. 1995;92:3744-3748. 71. Gomes R, Sousa Silva M, Quintas A, et al. Argpyrimidine, a methylglyoxal-derived advanced glycation end- product in familial amyloidotic polyneuropathy. Biochem J. 2005;385:339-345.
72. Sasaki N, Takeuchi M, Chowei H, et al. Advanced glycation end products (AGE) and their receptor (RAGE) in the brain of patients with Creutzfeldt-Jacob disease with prion plaques. Neurosci Lett. 2002;326:117-120.
73. Thiel R, Fowkes SW. Can cognitive deterioration associated with Down syndrome be reduced? Med Hypotheses. 2005;64:524-532.
74. Frey J. Bovine spongiform encephalopathy: are the cows mad or full of carbohydrate? Clin Chem Lab Med. 2002;40:101-103.
75. Boratynski J, Gorski A. BSE: a consequence of cattle feeding with glycated molecules host-unknown? Med Hypotheses. 2002; 58:276- 278.
76. Choi YG, Kim JI, Jeon YC, et al. Nonenzymatic glycation at the N terminus of pathogenic prion protein in transmissible spongiform encephalopathies. J Biol Chem. 2004;279:30402-30409.
77. Kalousova M, Zak A, Soukupova J, Stipek S, Malbohan IM, Zima T. Advanced glycation and oxidation products in patients with atherosclerosis [in Czech]. Cas Lek Cesk. 2005;144:385-390.
78. Taki K, Takayama F, Tsuruta Y, Niwa T. Oxidative stress, advanced glycation end product, and coronary artery calcification in hemodialysis patients. Kidney Int. 2006;70:218-224.
79. Tokita Y, Hirayama Y, Sekikawa A, et al. Fructose ingestion enhances atherosclerosis and deposition of advanced glycated end- products in cholesterol-fed rabbits. J Atheroscler Thromb. 2005;12:260-267.
80. Ferretti G, Bacchetti T, Negre-Salvayre A, Salvayre R, Doussett N, Curatola G. Structural modifications of HDL and functional consequences. Atherosclerosis. 2006;184:1-7.
81. de Leeuw K, Kallenberg C, Bijl M. Accelerated atherosclerosis in patients with systemic autoimmune diseases. Ann N Y Acad Sci. 2005;1051:362-371.
82. Ge J, Jia Q, Liang C, et al. Advanced glycosylation end products might promote atherosclerosis through inducing the immune maturation of dendritic cells. Arterioscler Thromb Vase Biol. 2005;25:2157-2163.
83. Bartling B, Hofmann HS, Weigle B, Silber RE, Simm A. Downregulation of the receptor for advanced glycation end-products (RAGE) supports non-small cell lung carcinoma. Carcinogenesis. 2005;26:293-301.
84. Takada M, Hirata K, Ajiki T, Suzuki Y, Kuroda Y. Expression of receptor for advanced glycation end products (RAGE) and MMP-9 in human pancreatic cancer cells. Hepatogastroenterology. 2004;51:928- 930.
85. Yamagishi S, Nakamura K, Inoue H, Kikuchi S, Takeuchi M. Possible participation of advanced glycation end products in the pathogenesis of colorectal cancer in diabetic patients. Med Hypotheses. 2005;64:1208-1210.
86. Ishiguro H, Nakaigawa N, Miyoshi Y, Fujinama K, Kubota Y, Uemura H. Receptor for advanced glycation end products (RAGE) and its ligand, amphoterin are overexpressed and associated with prostate cancer development. Prostate. 2005;64:92-100.
87. Stitt AW. The Maillard reaction in eye diseases. Ann N Y Acad Sci. 2005;1043:582-597.
88. Wada R, Yagihashi S. Role of advanced glycation end products and their receptors in development of diabetic neuropathy. Ann N Y Acad Sci. 2005;1043:598-604.
89. Monnier VM, Sell DR, Genuth S. Glycation products as markers and predictors of the progression of diabetic complications. Ann N Y Acad Sci. 2005;1043:567-581.
90. Yamagishi S, Imaizumi T. Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr Pharm Des. 2005;11:2279-2299.
91. Gaby AR. Adverse effects of dietary fructose. Altern Med Rev. 2005;10:294-306.
92. Hostettler-Allen RL, Tappy L, Blum JW. Insulin resistance, hyperglycemia, and glucosuria in intensively milk-fed calves. J Anim Sci. 1994;72:160-173.
93. Hertoghe T. The “multiple hormone deficiency” theory of aging: is human senescence caused mainly by multiple hormone deficiencies? Ann N Y Acad Sci. 2005;1057:448-465.
94. Diamanti-Kandarakis E, Piperi C, Kalofoutis A, Creatsas G. Increased levels of serum advanced glycation end-products in women with polycystic ovary syndrome. Clin Endocrinol. 2005; 62:37-43.
95. Flyvbjerg A, Khatir DS, Jensen LJ, Dagnaesh-Hansen F, Gronbaek H, Rasch R. The involvement of growth hormone (GH), insulin- like growth factors (IGFs) and vascular endothelial growth factor (VEGF) in diabetic kidney disease. Curr Pharm Des. 2004;10:3385- 3394.
96. Allen TJ, Jandeleit-Dahm KA. Preventing atherosclerosis with angiotensin-converting enzyme inhibitors: emphasis on diabetic atherosclerosis. Curr Drug Targets Cardiovasc Haematol Disord. 2005;5:503-512.
97. Tikellis C, Cooper ME, Thomas MC. Role of the reninangiotensin system in the endocrine pancreas: implications for the development of diabetes. Int J Biochem Cell Biol. 2005;38:737- 751.
98. Ahmed N, Liithen R, Haussinger D, et al. Increased protein glycation in cirrhosis and therapeutic strategies to prevent it. Ann N Y Acad Sci. 2005;1043:718-724.
99. Sebekova K, Kupcova V, Schinzel R, Heidland A. Markedly elevated levels of plasma advanced glycation end products in patients with liver cirrhosis: amelioration by liver transplantation. J Hepatol. 2002;36:66-71.
100. Yagmur E, Tacke F, Weiss C, et al. Elevation of Nepsilon- (carboxymethyl)lysine-modified advanced glycation end products in chronic liver disease is an indicator of liver cirrhosis. Clin Biochem. 2006;39:39-45.
101. Zeng S, Feirt N, Goldstein M, et al. Blockade of receptor for advanced glycation end product (RAGE) attenuates ischemia and reperfusion injury to the liver in mice. Hepatology. 2004; 39:422- 432.
102. Ekong U, Zeng S, Dun H, et al. Blockade of the receptor for advanced glycation end products attenuates acetaminophen-induced hepatotoxicity in mice. J Gastroenterol Hepatol. 2006; 21:682-688.
103. Nadeem A, Raj HG, Chhabra SK. Increased oxidative stress and altered levels of antioxidants in chronic obstructive pulmonary disease. Inflammation. 2005;29:23-32.
104. Hartl D, Starosta V, Maier K, et al. Inhaled glutathione decreases PGE2 and increases lymphocytes in cystic fibrosis lungs. Free Radie Biol Med. 2005;39:463-472.
105. Rahman I, Biswas SK, Kode A. Oxidant and antioxidant balance in the airways and airway diseases. Eur J Pharmacol. 2006;533:222- 239.
106. DeGroot J. The AGE of the matrix: chemistry, consequence and cure. Curr Opin Pharmacol. 2004;4:301-305.
107. Steenvoorden MM, Huizinga TW, Verzyl N, et al. Activation of receptor for advanced glycation end products in osteoarthritis leads to increased stimulation of chondrocytes and synoviocytes. Arthritis Rheum. 2006;54:253-263.
108. Hormel SE, Eyre DR. Collagen in the ageing human intervertebral disc: an increase in covalently bound fluorophores and chromophores. Biochim Biophys Acta. 1991;1078:243-250.
109. Reddy GK. Cross-linking in collagen by nonenzymatic glycation increases the matrix stiffness in rabbit Achilles tendon. Exp Diabet Res. 2004;5:143-153.
110. Hofmann MA, Drury S, Hudson BI, et al. RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response. Genes Immun. 2002;3:117-118.
111. Hein GE, Kohler M, Oelzner P, Stein G, Franke S. The advanced glycation end product pentosidine correlates to IL-6 and other relevant inflammatory markers in rheumatoid arthritis. Rheumatol Int. 2005;26:137-141.
112. Sunahori K, Yamamura M, Yamana J, Takasugi K, Kawashima M, Makino H. Increased expression of receptor for advanced glycation end products by synovial tissue macrophages in rheumatoid arthritis. Arthritis Rheum. 2006;54:97-104.
113. Ramamurthy B, Hook P, Jones AD, Larsson L. Changes in myosin structure and function in response to glycation. FASEB J. 2001;15:2415-2422.
114. Hein G, Wiegand R, Lehmann G, Stein G, Franke S. Advanced glycation end-products pentosidine and N epsilon- carboxymethyllysine are elevated in serum of patients with osteoporosis. Rheumatology. 2003;42:1242-1246.
115. Odetti P, Rossi S, Monacelli F, et al. Advanced glycation end products and bone loss during aging. Ann N Y Acad Sci. 2005; 1043:710-717.
116. Miyata T, Kawai R1 Taketomi S, Sprague SM. Possible involve ment of advanced glycation end-products in bone resorption, Nephrol Dial Transplant. 1996;ll(suppl 5):54-57.
117. Stamatas GN, Estanislao RB, Suero M, et al. Facial skin fluorescence as a marker of the skin’s response to chronic environmental insults and its dependence on age. Br J Dermatol. 2006;154:125-132.
118. Meerwaldt R, Hartog JW, Graaff R, et al. Skin autofluorescence, a measure of cumulative metabolic stress and advanced glycation end products, predicts mortality in hemodialysis patients. JAm Soc Nephrol. 2005;16:3687-3693.
119. Holla LI, Kankova K, Fassmann A, et al. Distribution of the receptor for advanced glycation end products gene polymorphisms in patients with chronic periodontitis: a preliminary study. J Periodontal. 2001;72:1742-1746.
120. Katz J, Bhattacharyya I, Farkhondeh-Kish F, Perez FM, Caudle RM, Heft MW. Expression of the receptor of advanced glycation end products in gingival tissues of type 2 diabetes patients with chronic periodontal disease: a study utilizing immunohistochemistry and RT-PCR. J Clin Periodontal. 2005; 32:40-44.
121. Ostergaard J, Hansen TK Thiel S, Flyvbjerg A. Complement activation and diabetic vascular complications. Clin ChimActa. 2005;361:10-19.
122. Bohlender JM, Franke S, Stein G, Wolf G. Advanced glycation end products and the kidney. Am J Physiol Renal Physiol. 2005;289:F645-F659.
123. Khan ZA, Farhangkhoee H, Chakrabarti S. Towards newer molecular targets for chronic diabetic complications. Curr Vase Pharmacol. 2006;4:45-57.
124. Thomas MC, Forbes JM, Cooper ME. Advanced glycation end products and diabetic nephropathy. Am J Ther. 2005;12:562-572.
125. Kalousova M, Zima T, Tesar V, et al. Advanced glycoxidation end products in chronic diseases-clinical chemistry and genetic background. Mutat Res. 2005;579:37-46. 126. Saito A, Takeda T, Sato K, et al. Significance of proximal tubular metabolism of advanced glycation end products in kidney diseases. Ann N Y Acad Sci. 2005;1043:637-643.
127. Jensen LJ, Ostergaard J, Flyvbjerg A. AGE-RAGE and AGE cross- link interaction: important players in the pathogenesis of diabetic kidney disease. Horm Metab Res. 2005;37(suppl 1):26-34.
128. Agalou S, Ahmed N, Babaei-Jadidi, Dawnay A, Thornalley PJ. Profound mishandling of protein glycation degradation products in uremia and dialysis. J Am Soc Nephrol. 2005;16:1471-1485.
129. Hartog JW, de Vries AP, Lutgers HL, et al. Accumulation of advanced glycation end products, measured as skin autofluorescence, in renal disease. Ann N Y Acad Sci. 2005;1043:299-307.
130. Baptista JAB, Carvalho RCB. Indirect determination of Amadori compounds in milk-based products by HPLC/ELSD/UV as an index of protein deterioration. Food Res Int. 2004;37:739-747.
131. Goldberg T, Cai W, Peppa M, et al. Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc. 2004; 104:1287-1291.
132. McCarty MF. The low- AGE content of low fat vegan diets could benefit diabetics, though concurrent taurine supplementation may be needed to minimize endogenous AGE production. Med Hypotheses. 2005;64:394-398.
133. Sebekova K Krajcoviova-Kudlackova M, Schinzel R, Faist V, Klvanova J, Heidland A. Plasma levels of advanced glycation end products in healthy, long-term vegetarians and subjects on a western mixed diet. Eur J Nutr. 2001;40:275-281.
134. Meyer TE, Kovacs SJ, Ehsani AA, Klein S, Holloszy JO, Fontant L. Long-term caloric restriction ameliorates the decline in diastolic function in humans. J Am Coll Cardiol. 2006;47:398-402.
135. Iwashige K, Kouda K, Kouda M, et al. Calorie restricted diet and urinary pentosidine in patients with rheumatoid arthritis. J Physiol Anthropol Appi Hum Sci. 2004;23:19-24.
136. Osawa T, Kato Y. Protective role of antioxidative food factors in oxidative stress caused by hyperglycemia. Ann N Y Acad Sci. 2005;1043:440-451.
137. Mattson MP. Will caloric restriction and folate protect against AD and PD? Neurology. 2003;60:690-695.
138. Bengmark S. Curcumin: an atoxic antioxidant and natural NFkappaB, COX-2, LOX and iNOS inhibitor: a shield against acute and chronic diseases. JPEN J Parenter Enteral Nutr. 2006;30: 45-51.
139. McCarty MF. Nutraceutical resources for diabetes prevention: an update. Med Hypotheses. 2005;64:151-158.
140. McCarty MF. Potential utility of natural polyphenols for reversing fat-induced insulin resistance. Med Hypotheses. 2005; 64:628-635.
141. McCarty MF. The reported clinical utility of taurine of ischemic disorders may reflect a down-regulation of neutrophil activation and adhesion. Med Hypotheses. 1999;53:290-299.
142. Laidlaw S, Grosvenor M, Kopple JD. The taurine content of common foodstuffs. JPEN J Parenter Enteral Nutr. 1990;14: 183-188.
143. Hansen SH. The role of taurine in diabetes and the development of diabetic complications. Diabetes Metab Res Rev. 2001; 17:330-346.
144. Nandhini AT, Thirunavukkarasu V, Anuradha CV. Stimulation of glucose utilization and inhibition of protein glycation and AGE products by taurine. Acta Physiol Scand. 2004;181: 297-303.
145. Nandhini AT, Thirunavukkarasu V, Anuradha CV. Taurine prevents collagen abnormalities in high fructose-fed rats. Indian J Med Res. 2005;122:171-177.
146. Finegold SM, Sutter VL, Mathisen GE. Normal indigenous intestinal flora. In: Hentges DJ, ed. Human Intestinal Microflora in Health and Disease. London: Academic Press; 1983:3-31.
147. di Cagno R, de Angelis M, Alfonsi G, et al. Pasta made from durum wheat semolina fermented with selected lactobacilli as a tool for a potential decrease of the gluten intolerance. J Agrie Food Chem. 2005;53:4393-4402.
148. Tavan E, Cayuela C, Antoine JM, Cassand P. Antimutagenic activities of various lactic acid bacteria against food mutagens: heterocyclic amines. J Dairy Res. 2002;69:335-341.
149. Erbersdobler H, Gunsser I, Weber G. Abbau von Fructoselysine durch die Darmflora. Zentralbl Veterinarmed A. 1970;A17:573-575.
150. Odetti P, Angelini G, Dapino D, et al. Early glycoxidation damage in brains from Down’s syndrome. Biochem Biophys Res Commun. 1998;243:849-851.
151. Hudson VM. New insights into the pathogenesis of cystic fibrosis: pivotal role of glutathione system dysfunction and implications for therapy. Treat Respir Med. 2004;3:353-363.
152. Foell D, Seeliger S, Vogl T, et al. Expression of S100A12 (ENRAGE) in cystic fibrosis. Thorax. 2003;58:613-617.
153. Altamura AC, Boin F, Maes M. HPA axis and cytokines dysregulation in schizophrenia: potential implications for the antipsychotic treatment. Eur Neuropsychopharmacol. 1999;10:1-4.
154. Muller N, Riedel M, Schwarz MJ. Psychotropic effects of COX- 2 inhibitors: a possible new approach for the treatment of psychiatric disorders. Pharmacopsychiatry. 2004;37:266-269.
155. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24-31.
156. Gundersen Y, Opstad PK, Reistad T, Thrane I, Vaagenes P. Seven days’ around the clock exhaustive physical exertion combined with energy depletion and sleep deprivation primes circulating leukocytes. Eur J Appi Physiol. 2006;97:151-157.
157. Muller N, Schwarz MJ, Dehning S, et al. The cyclooxygenase- 2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, r