Sci. Aging Knowl. Environ., 18 December 2002
Wake Up and Smell the Maillard Reaction
Vincent M. Monnier, and Mark E. Obrenovich
The authors are at the Institute of Pathology at Case Western Reserve University, Cleveland, OH 44120, USA. E-mail: email@example.com (V.M.M.)http://sageke.sciencemag.org/cgi/content/full/sageke;2002/50/pe21
Key Words: Maillard reaction advanced glycation end products glycotoxins inflammation aging diabetes
A recent study by Vlassara et al. (1) might lend new meaning to an ancient discovery: fire. The discovery of fire is thought to have played a major role in the evolution of humans by allowing them, for example, to extract calories from the otherwise toxic seeds of angiosperms (2). The processing of food at high temperature has other benefits, such as a general increase in the safety and shelf-life of stored foods, which is accomplished by the killing of contaminating microorganisms and the inactivation of endogenous proteases. Treatment with high temperatures also increases the palatability of foods by converting carbohydrates, lipids, and proteins into "browned," highly aromatic, and flavorful compounds (Fig. 1). This browning reaction is called the Maillard reaction. It is initiated when reactive sugars and certain oxidized lipids react with proteins, ultimately resulting in the formation of a large number of chemical compounds that enhance food quality (Fig. 2). Normal aging can be regarded as a slow cooking process, in that many of the Maillard products accumulate in long-lived proteins in the body, such as those of the skin, arteries, lenses, joints, and cartilage. Now, Vlassara et al. show that the consumption of foods high in Maillard reaction compounds--so-called advanced glycation end products (AGEs) or glycotoxins--might be responsible for the induction of a low-grade but chronic state of inflammation (1).
Effects of Feeding Foods Rich in Glycotoxins to Diabetic Individuals
The presence of circulating AGE products in the serum of individuals with diabetes and end-stage renal disease has been known for quite some time (3), yet their origin has remained a mystery. To what extent do these products originate from the Maillard reaction in vivo, and to what extent do they derive from processed foods? This is a burning question, as several studies have shown that caloric restriction prolongs life-span in rodents while simultaneously decreasing AGE formation in body tissues (4). These findings raise the possibility that reduced amounts of glycotoxins in the diet might contribute to increased life-span. On the basis of previous experiments from their own laboratory that implicated dietary Maillard products as contributors to plasma AGEs in rodents (5), Vlassara et al. studied how diabetic patients respond to diets containing low or high concentrations of AGE products. Food for the high-AGE diet was obtained by heating the food for a longer period of time and at a higher temperature than the food for the low-AGE diet (1). The researchers first determined how the AGE content of a variety of foods varies after different heat treatments by using an antibody-based assay to measure the relative concentrations of specific Maillard products, and then designed two diets that differed fivefold in AGE content but were similar with respect to nutrient and calorie content.
In the first study described by Vlassara and colleagues, 11 diabetic patients were randomized in a crossover trial, in which each individual was monitored during each of the two treatments: 2 weeks on one diet and 2 weeks on the alternative diet, separated by a 1- to 2-week period. The overall results of this study show that concentrations of AGEs (detected in the serum and urine in soluble form, as well as linked to low-density lipoproteins in the serum) increased 50 to 100% in the high-AGE diet group as compared to the low-AGE group (1). The increase in circulating AGEs by itself would not be of consequence except for the fact that a large body of data has shown that AGEs can have profound biological properties and trigger cells to release inflammatory molecules and growth factors, which might have deleterious effects on the organism. In this respect, the authors found that serum- and leukocyte-associated inflammatory cytokines and factors (such as tumor necrosis factor-, vascular cell adhesion molecule-1, and C-reactive protein, which are all markers of inflammation) were increased in the blood of patients in the high-AGE diet group as compared to those in the low-AGE diet group.
In order to determine whether the observed effects were sustained or were merely an acute response to the change in diet, the researchers also carried out a second study for a longer period of time (6 weeks). This study included six patients on the high-AGE diet and seven patients on the low-AGE diet. Although several homeostatic parameters, such as blood pressure, plasma cholesterol, and lipid profiles, remained unchanged between the two groups after the intervention, here again the diet high in AGEs resulted in higher concentrations of AGEs and inflammatory cytokines in the blood (1).
Significance of Eating Diets Rich in Glycotoxins
This study raises a number of important questions concerning the interface between nutrition, aging, and diabetes. First, considerable evidence shows that the AGE formation that takes place during food preparation also occurs inside the body during the normal aging process (6) and at an accelerated rate in patients with diabetes (7). For example, the AGEs measured in this study accumulate with age at a faster rate in skin collagen from diabetic versus nondiabetic individuals (8). Moreover, when cultured inflammatory cells are exposed to similar AGEs, they respond by releasing inflammatory molecules (9). Thus, chronic exposure of the body to a diet high in AGEs might promote a chronic inflammatory state in arteries, kidney, joints, and brain, and thus contribute to atherosclerosis, glomerulosclerosis, arthritis, and neurodegenerative diseases, respectively, all of which are known to be exacerbated by inflammation. Second, the ability of AGE products to engage cellular receptors, such as RAGE, could also promote tumor growth and metastasis by mechanisms that stimulate cell migration and the release of growth factors and enzymes that digest the extracellular matrix (10). In agreement with this model, some Asian foods rich in browning products, such as soy sauce, and foods that have been found to be rich in AGEs in this study (eggs, meat, and fish) have been associated with an increased risk of colon cancer (11).
Limitations of the Study
In spite of the implied warnings raised by this study, the association between a high AGE content in food and a chronic inflammatory state is preliminary and needs to be confirmed. Caveats include the following points. First, this study was performed with diabetic patients, and extrapolation of the results to healthy people who maintain normal blood glucose concentrations cannot be taken for granted. In the long-term study described above, there was a not only a drop in body weight in the low-AGE group, but also a decrease in glycemia (blood glucose concentration). In contrast, glycemia increased in the high-AGE group. Thus, there was a significant glycemic gap between the groups at the end of the study. Is this effect caused by the fact that the food higher in AGEs was more palatable and this led that group to eat more? Of importance is the fact that elevated glycemia, by itself, can trigger an inflammatory-like state (12). Thus, the increased concentrations of inflammatory mediators present in the high-AGE group might be related to an altered metabolic state. However, elevated glycemia was not observed in the 2-week study, suggesting that the AGEs by themselves caused the increased inflammation.
Also in need of clarification is the role of metal binding by the AGEs present in the food. Carboxymethyl-lysine, one of the major AGEs assayed in this study, has chelation properties and can bind transition metals such as Cu2+ and Zn2+ (13). Iron has also been found to be trapped by AGEs (14). Thus, the question arises as to whether the observed data stem from differences in the absorption and excretion of these transition metals through the gut. Systemic depletion of these metals might result in lower Cu-Zn superoxide dismutase (SOD1) activity, and, therefore, an increase in oxidative stress, which yields a profile of inflammatory molecules similar to the one observed above in the high-AGE group. Data on the status of transition metals in study participants will be needed in future studies of this kind. Another possible confounding factor, which appears to have been ruled out, is the potential destruction of antioxidant and other key vitamins during the prolonged heating of the high-AGE food. The authors were careful to supplement the patients' diet with vitamins.
Should We Be Concerned About Dietary Glycotoxins?
Although some research on glycotoxins has been carried out in the past (15), little is known about the risk of consuming diets rich in such compounds. It is fair to say that a balanced diet is expected to be low in glycotoxins, and that an occasional glycotoxin-rich dinner, such as those eaten on holidays, is unlikely to harm a healthy organism. In this regard, both diets tested above were compatible with the National Cholesterol Education Program and were designed to have the same content of calories, protein, carbohydrate, and fat, but differed fivefold in their AGE content. Hyperlipidemia (elevated blood lipid concentrations), truncal obesity, high blood pressure, and smoking are expected to be far greater health risks than the presence of glycotoxins in the diet. However, in any patient with compromised renal function and a potentially decreased ability to clear glycotoxins, as in diabetic patients, or in older individuals with decreased renal function, the daily consumption of diets rich in glycotoxins might contribute to a chronic inflammatory state. Finally, carcinogenic compounds are also generated during the processing of foods at high temperature (16), a separate issue that requires further research. Thus, although the Maillard reaction that takes place during food processing enhances the quality of our lives, it represents a potential threat, the significance of which we are only beginning to understand.
December 18, 2002
Science of Aging Knowledge Environment. ISSN 1539-6150