Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : January 28, 2020
Accepted : February 21, 2020
Published online : March 31, 2020
doi:10.24659/gsr.7.1_70

Review article

Glycative stress and anti-aging: 15. Regulation of Glycative stress.
3. Reduction of AGEs intake from food.
Masayuki Yagi, Yoshikazu Yonei
Anti-Aging Medical Research Center and Glycative Stress Research Center,
Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan

Abstract

Lifestyle and dietary habits aimed at the reduction of glycative stress are called anti-glycation. Specific measures for antiglycation include reduction of postprandial glucose elevation, inhibition of glycative reaction, decomposition and excretionof advanced glycation end products (AGEs) produced and reducing the intake of AGEs in the diet. Since food contains
nutrients such as proteins, lipids and carbohydrates, glycation proceeds during cooking, processing and storage. Melanoidins
are dark brown substances in food having physiological functions such as imparting brown color to food and having an antioxidant effect (so-called “good AGEs”). On the other hand, heterocyclic amine, and acrylamide in food are substances thatare involved in mutagenicity and carcinogenicity (so-called “bad AGEs”). Most AGEs ingested from food, are excreted in theurine. However, it is reported that AGEs contained in ingested food may accumulate in the body of patients with chronic renal
failure caused by impaired renal function. In healthy persons, about 7% of the AGEs contained in ingested food may remainin the body. To suppress the effects of AGEs in food on the body, we can consider selecting a cooking method that produces
fewer AGEs and the reduction of AGEs absorption in the body. Although various analytical methods have been reported formeasuring AGEs in food, there are few examples where pretreatment methods of samples have been studied in detail. It isnecessary to verify the effects of ingested AGEs in food, the accuracy of AGEs measurement, health condition, and eating
habits of the person ingesting the food.

KEY WORDS: advanced glycation end products (AGEs), food, melanoidin, absorption, excretion.
Conflict of Interest Statement

The authors claim no conflict of interest in this study.

2. AGEs in Food1. Introduction:
Reduction of Glycative Stress

Lifestyle and dietary habits aimed at the reduction ofglycative stress are called anti-glycation 1), and include thereduction of postprandial glucose, inhibition of glycation,
decomposition and excretion of advanced glycation end
products (AGEs) produced, and reducing the intake of AGEs
in the diet. This paper describes AGEs contained in food,their absorption and excretion mechanisms and the possibilityof reducing the consumption of AGEs.

Food contains nutrients such as proteins, lipids, andcarbohydrates. Also, substances contained in food include
reducing sugars, carbonyl compounds, amino acids, andproteins which are contained in large quantities. For thisreason, the glycation in food proceeds during cooking,processing, and storage. The glycation of food is generally
known as the browning reaction. Various model reaction
systems and reaction mechanisms using food have been
investigated, and brown substances have been separated andContact Address: Professor Masayuki Yagi, PhD
Anti-Aging Medical Research Center and Glycative Stress Research Center,
Faculty of Life and Medical Sciences, Doshisha University
1-3, Tatara Miyakodani, Kyotanabe, Kyoto, 610-0394 Japan

Tel / Fax: +81-774 -65-6394 e-mail: myagi@mail.doshisha.ac.jp
Co-author: Yonei Y, yyonei@mail.doshisha.ac.jp_ 70 _

Glycative Stress Research 2020; 7 (1) : 70-74(c) Society for Glycative Stress ResearchGlycative Stress Research

identified for the browning reaction of foods 2).
The glycation of food starts when reducing sugars
generated by the decomposition of monosaccharides such as
glucose and fructose are used as raw materials and seasonings,
and disaccharides such as sucrose, oligosaccharides, andcarbohydrates react non-enzymatically with amino acids andproteins to generate N-glucoside ( Fig. 1 ) 3).
Next, N-fructoside is produced by Amadori rearrangement,
and further carbonyl compounds such as ozone and furfuralare formed by dehydration and deamination reactions. The
carbonyl compounds that are produced react again with amino
compounds as an intermediate of the glycative reaction,
producing melanoidins, which are brown substances, bycondensation and polymerization. Melanoidins are not puresubstance, and their accurate quantification is difficult since
their structure and degree of polymerization differ dependingon the amino compounds from which the melanoidins
are generated and the reaction conditions 4). In addition toimparting brown color to food 5), melanoidins are substanceswith various physiological functions, such as anti-oxidanteffect 6), cholesterol inhibition effect 7) and α-glucosidase
inhibition effect 8).
In addition to melanoidins, cooked and processed foods
contain various substances such as N ε-carboxymethyllysine (CML), pyrraline, pentosidine, and glycative reaction
intermediates 9-11). Many of these are produced during theprocess of cooking food. This means that we ingest AGEs
every day through food. There are several commercial
beverages, and foods that contain a variety of AGEs 12). Some
AGEs in the diet are likely to be involved in the generationof reactive oxygen in the living body and the worsening ofchronic diseases such as diabetic complications 13). For thisreason, the dietary habit of the intake of food containing avariety of AGEs every day may contribute to the onset ofdiseases.
In experiments using mice, the intake of a high AGEs
diet was reported to be involved in a shortening of thelifetime 14). Food cooked at high temperatures is known toproduce heterocyclic amine 15), and acrylamide 16), which areanalogs of AGEs involved in mutagenicity and carcinogenicity.

Fig. 1. General scheme of the Maillard reaction (glycation) occurring in food.
The figure is adapted from Reference 3).

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Reduction of AGEs intake from foodIn this way, it is hypothesized that carbonyl compounds andAGEs contained in food are associated with various diseases
and are called "glycotoxins" 17).
On the other hand, it has been pointed out that thecoincidence between the period of human evolution when
the intake of AGEs increased with the use of fire 500,000
to 800,000 years ago and the period when brain capacity
increased dramatically was not by chance. In recent years,
Yamamoto et al. have discovered that AGEs increase
receptors for AGEs (RAGE) in the endothelium of brain
capillaries and that RAGE helps oxytocin pass throughthe blood-brain barrier (BBB) by binding with oxytocin 18).
Oxytocin is a hormone that affects the emotions of thebrain. Studies with animals have shown that a deficiency ofoxytocin in the brain can reduce the survival rate of offspring
due to abandonment, and it is also called the "love hormone."How diets with extremely low AGEs affect RAGE expression
in the BBB is a topic of great interest.

3. Absorption and Excretion AGEs in Food
There are several reports on the relationship between
AGEs we ingest from food and their excretion. When sevenhealthy men and women restricted the intake of foods highin AGEs such as roasted food, bread, beer, and coffee forthree days, pyrraline levels in the urine decreased during
the period of restricted intake of food high in AGEs ascompared to the unrestricted period. As a result, it was foundthat AGEs in the ingested food were excreted in urine 19). We
investigated the ingestion of AGEs in patients with end-stage
renal disease (ESRD), and the results showed a correlation

between the amount of AGEs in the food ingested and serum
CML level, and also among serum CML, the amount ofmethylglyoxal and Blood Urea Nitrogen (BUN). In persons
with impaired renal function, there is a possibility that AGEs
contained in ingested food will be stored in the body 20).
Therefore, reducing AGEs in the diet for patients with renal
failure is considered to be necessary for disease management.
A study was conducted in which diabetic patients andhealthy persons ingested a high AGEs meal cooked byheating egg whites after adding fructose and a low AGEs
meal cooked with heat using only egg whites, and AGEs inthe blood and urine after ingesting each of the test foods
was measured. After 48 hours following the intake of thetest meal, the amount of AGEs absorbed in the blood wasestimated to be 30% in diabetic patients with nephropathy,
and 10% in healthy persons (Fig. 2) 17). In the healthy persons,it was estimated that 1/3 of 10% of the AGEs absorbed inthe blood was excreted in urine within 48 hours, and 2 /3
(approximately 7%) remained in the body. The effect ofAGEs contained in food can be significant when the renal
function is impaired.

4. Inhibiting the Production andAbsorption of AGEs in Food

To suppress the effects of AGEs in food on the body, wecan consider selecting a cooking method that produces fewer
AGEs and inhibition of AGEs absorption in the body.
The amount of AGEs contained in various cooked
foods was higher in foods rich in fat (lipids) and meat(protein) than in foods rich in carbohydrates 21). Even when

Fig. 2. Schematic representation of the fate of diet-derived AGEs.

Cooked foods contain sugar-derived protein or lipid glycation intermediates that may include either non-reactive products orglycotoxins. The “non-reactive products” are presumable readily excreted in the urine, while the “glycotoxins” may reattach onto
serum or tissue components to form new AGEs with eventual pathological consequences. The figure is adapted from Reference 17).

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the same ingredients are cooked by boiling, AGEs wereless likely to be produced than by frying or roasting 22). The
cooking method in which meat is soaked in lemon juice orvinegar before roasting was able to inhibit the production ofAGEs that are formed by half. It has also been shown thatplant polyphenols, vitamins, and phenolic acid compounds
contained in food may inhibit the production of AGEs
produced during cooking 23, 24).
Kremezine is known as a drug that inhibits the absorptionof dietary AGEs in the body. Kremezine is a spherical carbonadsorbent obtained by oxidizing and reducing spherical finegrained, porous carbon derived from petroleum hydrocarbons
at a high temperature. It is an oral drug used to improve
symptoms and delay the start of dialysis for chronic renal
failure by adsorbing uremic toxins in the digestive tract andexcreting it with stool. In a study conducted on patients withdiabetic nephropathy who were administered Kremezine
at a dose of 6 g/day for three months, a decrease in blood
CML was observed 25). Activated carbon having the sameadsorption capacity as Kremezine could function as an AGEs
adsorption and excretion material.

with food safety and taste, such as improved preservation,enhanced absorption of nutrients and adding a brown colorand flavor to the food. Therefore, the effects of AGEs in foodon the body need to be evaluated comprehensively. In healthy
persons, about 7% of the AGEs contained in ingested food
may remain in the body. However, it is necessary to take into
account the effect of adsorption and excretion due to dietaryfiber contained in side dishes ingested at the same time,on residual AGEs. Various analytical methods have beenreported for measuring AGEs in food 26). There are many
types of proteins contained in food, which are impossible tobe denatured by cooking and are impossible to extract. The
coexisting lipids also interfere with various measurement
methods. The Kjeldahl method is used for measuring theamount of protein in nutrition science, which quantifies
the amount of nitrogen in food and converts to obtain theamount of protein 27). However, the pretreatment method ofAGEs in the diet has been examined only by a few reports.
The amount of AGEs produced in food can also be reduced
through the selection of ingredients and cooking methods.
The effects of AGEs in food need to be considered based on
the health condition and overall dietary habits of the person
ingesting the food.

5. Issues with AGEs in Food
Glycation (maillard reaction) products in food include
substances with physiological functions such as melanoidins(so-called “good AGEs”) and substances such as AGEs andacrolein that may damage cells and tissues (so-called “ badAGEs” ). Cooking food with heat has advantages associatedConflict of Interest Statement
The authors claim no conflict of interest in this study.

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