Perspective of Advanced Glycation End Products on Human Health

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A perspective of advanced glycation endproducts (AGEs) on human health Jer-An Lin, Chi-Hao Wu, and Gow-Chin Yen J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.7b05943 • Publication Date (Web): 08 Feb 2018 Downloaded from http://pubs.acs.org on February 10, 2018

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Journal of Agricultural and Food Chemistry

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A perspective of advanced glycation endproducts (AGEs) on human

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health

3 , ,

Jer-An Lin§,∇, Chi-Hao Wu‡,∇, and Gow-Chin Yen† § *

4 5 6

†

Department of Food Science and Biotechnology, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan

7 8

‡

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University, 162, Section 1, Heping E. Rd., Taipei City 106, Taiwan

Department of Human Development and Family Studies, National Taiwan Normal

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§

11

Road, Taichung 40227, Taiwan

Graduate Institute of Food Safety, National Chung Hsing University, 145 Xingda

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∇

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*Author to whom correspondence should be addressed.

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Tel: 886-4-2287-9755, Fax: 886-4-2285-4378,

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E-Mail: [email protected]

These authors contributed equally to this work.

17 18 19

Keywords: AGEs, cancer, diabetes, cardiovascular disease, microbiota

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1

ACS Paragon Plus Environment


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Abstract

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In the last 20 years, the effects of advanced glycation endproducts (AGEs) on health

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have received increasing attention. High AGE levels in the body correlate with the

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progression of many diseases, such as diabetes, cardiovascular disease, and some

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cancers. However, whether AGEs are a cause of these diseases or represent

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accompanying symptoms of these diseases still needs to be elucidated by more

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comprehensive research. Recently, many researchers have begun to investigate the

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effects of AGE intake-induced variations of gut microbiota on disease progression,

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which will further explain the impact of AGEs on health and open a new chapter in

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AGE research.

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INTRODUCTION

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In 1912, French chemist Louis-Camille Maillard found in his study of food that

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reducing sugar molecules reacted chemically with the lysine side chains and

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N-terminal amine groups on proteins and amino acids, leading to browning [1]; this

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chemical reaction is the origin of the reaction known as the “Maillard reaction”. In

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today's dietary patterns, the characteristics of most foods (especially heat-processed

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foods), such as aroma and color, are closely related to Maillard reaction products

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because Maillard reaction substrates exist widely in foods. Common dietary

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components, such as biscuits, bread, tea, coffee, fried and barbecued food, and fast

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food products, are quite typical Maillard reaction-related foods.

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Early studies of the Maillard reaction focused primarily on the reduced

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nutritional value of proteins and amino acids due to sugar modification and the

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chemistry of Maillard flavor generation. As glycated hemoglobin is found in the blood

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of diabetic patients [2], the effects of the Maillard reaction on the organism began to

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receive attention. The endproducts of the Maillard reaction in organisms are the

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so-called advanced glycation endproducts (AGEs). However, disagreements exist

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regarding the types of compounds covered by AGEs. Generally, AGEs do not cover

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all Maillard reaction products [3]. Compounds discussed in most of the AGE studies

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are mainly substances produced from Amadori products via rearrangement and a

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series of chemical reactions, and products from interaction reactions between the

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degradation and fragmentation products of reducing sugars (such as glucose and

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fructose) and free lysine/arginine or protein lysine/arginine residues [4]. Of these

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compounds, N-ɛ-carboxymethyllysine (CML) was the first AGE discovered [5] and is

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also a well-studied AGE marker. Therefore, many studies use CML as the AGE

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marker. However, different AGEs not only have different chemical characteristics but 3



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also have different physiological effects (such as the ability to induce macrophage

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endocytosis) [6].

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Given that AGEs and their protein adducts accumulate in various lesions,

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investigations of the relationship between AGEs and diseases have recently gained

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attention, and this research boom culminated in the discovery of the receptor for

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AGEs (RAGE). Numerous studies suggest that RAGE acts as a bridge between AGEs

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and diseases. AGE protein adducts can generate large amounts of reactive oxygen

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species (ROS) by activating RAGE on cells. This AGE-RAGE-ROS loop leads to the

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activation of inflammatory cells and the release of RAGE ligands with different

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physiological effects, such as S100 proteins or HMGB1, to change immune

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homeostasis, resulting in tissue damage and lesion formation [7]. This AGE-RAGE

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axis is even related to the development of cancer [8]. In addition, AGE protein

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adducts also stimulate the activation of different cellular signaling pathways through

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RAGE, affecting cell physiology [9,10]. AGEs also cause cross-linking, leading to

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stiffness in tissues, such as tendons, intervertebral discs, skin, arteries, and vaginal

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tissues [11].

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As the pathological role of AGEs is clarified, scholars have begun to explore

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whether prolonged ingestion of large amounts of dietary AGEs promotes the onset of

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diseases or disease deterioration. A recent book edited by Jaime Uribarri details the

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role of dietary AGEs in disease and health over the past two decades [12]. Although

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there is no standardized analytical method for AGEs, the consumption of foods rich in

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AGEs can indeed increase the content of AGEs in vivo [13,14] and change in vivo

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redox and immune homeostasis to affect disease development [12]. Dietary exposure

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to AGEs in humans has been reported to be approximately 100-300 µmol/day or

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16,000 AGE kU/day [4]. However, increases in AGEs in vivo are not necessarily 4


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directly derived from AGEs in the diet, but may result from the intestinal digestion of

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food [15,16]. Given that AGE-induced oxidative stress and chronic inflammation are

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involved in many disease processes, the physiological mechanisms that reduce AGE

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production, inhibit AGE function, or clear AGEs, as well as dietary factors [17,18]

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and pharmacological drugs [19] with these biochemical features, have been

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investigated intensively in the last decade. Most of these substances have multiple

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biochemical properties, such as anti-glycation and anti-oxidation, which increase the

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difficulty in clarifying the major mechanisms by which these substances affect AGEs

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and impact their applicability.

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In the following sections, AGE chemistry, analysis and experimental models will

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be introduced. Furthermore, current knowledge on the homeostasis of AGEs in the

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body and the effects of AGEs on human health will be elaborated.

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FUNDAMENTAL KNOWLEDGE OF AGEs

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AGE Chemistry

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The entire process wherein glycosamine condensates and forms melanoidins

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after a series of complex chemical reactions is known as the Maillard reaction [3].

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Amadori products generated during the initial reaction are rearranged and chemically

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modified via oxidization or non-oxidization reactions to produce AGEs (Figure 1A)

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[4,18]. In addition, reducing sugars participating in the Maillard reaction and the early

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and mid-Maillard reaction products undergo autoxidation and/or lysis and degradation

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to produce the highly reactive precursors of AGEs. Among them, the most widely

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investigated are dicarbonyls, including glyoxal (GO), methylglyoxal (MG), and

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3-deoxyglucosone (3-DG). These precursors react with amino group-bearing

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substances (mainly lysine and arginine groups) to produce AGEs (Figure 1A) [4,17]. 5



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However, AGE precursors, such as dicarbonyls, are not only produced by the Maillard

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reaction. Other biochemical reactions, such as lipid oxidation, protein degradation,

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and glycolysis, also represent sources of AGE precursors in foods or organisms [8].

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Therefore, AGEs are not derived exclusively from the Maillard reaction. The main

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synthesis pathways of AGEs in vivo and in food, as well as AGE precursors and

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common AGE types, are summarized in Figure 1.

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AGE Analysis

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AGE analysis mainly consists of two categories. One is analyte preparation, i.e.,

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the isolation of AGEs from samples through steps of extraction, hydrolysis, and

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purification. According to the different extraction methods, free AGEs and

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protein/peptide-bound AGEs can be obtained [20]. The second category is

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measurement of the AGE samples by immunochemical or instrumental methods.

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Analyte preparation for these two methods is totally different. In general, analyte

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preparation is less complicated for immunochemical methods than for instrumental

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analysis.

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The most common method for AGE immunochemical analysis is enzyme-linked

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immunosorbent assay (ELISA). Previously, various types of polyclonal/monoclonal

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antibodies to a protein-bound AGE epitope(s) were published for application in

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ELISA, of which the protein-bound AGEs commonly used for antibody generation

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include AGE-bovine serum albumin (BSA), AGE-keyhole limpet hemocyanin (KLH),

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AGE-collagen, and AGE-ribonuclease (RNase) [21]. In the AGE ELISA, commonly

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used antibodies include the 6D12 [22] and 4G9 (6C7) monoclonal antibodies [12,15]

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that specifically react with CML protein adducts, and the 3D11 mAb monoclonal

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antibody [12] that specifically reacts with MG-modified protein. To date, 6


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approximately 300 types of AGE ELISA commercial kits are available that are

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suitable for the detection of protein/peptide-bound AGE accumulation in humans,

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mice, rats, rabbits, guinea pigs, and other species. Despite the simplicity and speed of

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ELISA analysis, the actual concentration of AGEs in the test samples cannot be

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measured by ELISA (ELISA results are typically represented in arbitrary units), and

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numerous doubts exist about the accuracy of using ELISA to detect AGEs in food.

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Given that the matrix of food is complex, the validity of the antibodies used in ELISA

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must be confirmed in different food matrices before AGE measurements. However,

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most of the AGEs ELISA kits do not perform the test to confirm the validity of

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antibodies. Therefore, the values of some food AGE content databases established

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using ELISA are still being questioned by many scholars in the AGE field [4,18].

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However, recent studies have confirmed the consistency of the results of

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immunochemical and instrumental analyses of dietary AGEs [23].

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The objective of the instrumental analysis is to separate the target by

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chromatography

and

further

determine

the

target

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light/ultraviolet/fluorescence detector or mass analyzer [20]. Key factors influencing

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the instrumental analysis of AGE results include sample pretreatment steps (including

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the type of extraction solution used; inorganic salts/organic salts, pH, etc.), hydrolysis

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methods (acid/base or enzyme), reaction temperature, reaction time, environmental

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gas (aerobic/anaerobic), and shaking intensity during the reaction. All of these factors

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affect the result of subsequent analysis and detection. AGEs with different chemical

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structures have different sensitivities to acid, alkali, temperature, and enzyme

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reactions. Therefore, when analyzing AGEs with different characteristics, each type of

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AGE must have an internal standard to calibrate the effect of sample pre-treatment on

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the analysis results to obtain objective and accurate results. However, at present, no 7


using

a

visible


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standard procedure is available for sample pretreatment for the analysis of AGEs in

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vivo and in food. As a result, it is difficult to discuss and compare the AGE values

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listed in many studies, despite the use of similar AGE analysis methods.

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In recent years, the rapid determination of in vivo AGEs using AGE fluorescence

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has attracted considerable attention due to the correlation between the accumulation

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of AGEs in vivo and the degree of aging as well as many chronic metabolic diseases

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[24]. Related technologies have been used in the development of medical testing

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equipment, such as AGE Reader (Diagnoptics Technologies BV), which can be used

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for risk assessment of aging and cardiovascular disease- and diabetes-related diseases.

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Common Experimental Models in AGE Studies

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Common AGE research can be divided into two categories. One category

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involves the analysis of AGEs in food [20] and the assessment of factors and

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mechanisms that affect AGE production in food [18], the bioavailability of AGEs in

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the diet, and the effects of AGE intake on health [4]. The other category involves

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analyzing AGEs in vivo [5,11,21,22], exploring the possible pathogenesis of AGEs in

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vivo [6-10] and in vivo AGE generation, metabolism, and clearance mechanisms

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[4,10,12], and investigating the association of AGEs with disease progression [4,10,12]

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and methods to reduce the physiological impacts of AGEs [17,19]. Among the above

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types of studies on AGEs, the largest number of studies focus on the physiological

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effects of AGEs in vivo and related inhibition methods [8,10,12], of which the most

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common research model involves investigating the biochemical characteristics of

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AGE-BSA and the inhibition of the physiological effects of AGE-BSA.

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Albumin is the most abundant protein in the blood, with a half-life of

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approximately 21 days, and is therefore the most prominent target for glycation in the 8


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circulatory system [25]. Glycated albumin can be phagocytosed by macrophages and

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neutralized by free RAGE, thus reducing cell and tissue stimulation. However, if the

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glycated albumin content is too high in the body, it may affect the immune balance

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and burst oxidative stress, resulting in tissue inflammatory damage. This phenomenon

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is common in people with diabetes. Therefore, glycated albumin is an important

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pathogenic factor in many diabetic complications, as it can affect most of the cells and

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tissues in the body through the circulatory system. Due to the above reasons, many

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studies have been designed with the main axis of AGE-BSA biochemical

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characteristics, and these types of studies have also become the most common

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experimental model in AGE studies. Related studies have included an analysis of the

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biochemical characteristics of BSA modified by different glycation agents

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(RAGE-binding ability, amount of different AGE residues, fluorescence intensity, and

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browning degree), effects of AGE-BSA on the physiological properties of different

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cells and tissues, blockade of AGE-BSA-induced responses, and means for

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elimination of AGE-BSA (including inactivation of AGE precursors). However, due

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to the different methods of AGE-BSA preparation in different laboratories, it is

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difficult to systematically discuss and compare relevant studies. In addition, most

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studies do not provide AGE-BSA chemical analysis results, and the experimental

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analysis data regarding the presence of free AGEs or microbial contaminants, such as

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lipopolysaccharides (LPS), greatly reduce the reference value of AGE-BSA studies.

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Of note, in recent years, the effects of high glycation stress caused by the specific

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metabolic mode of cancer cells and AGE

accumulation in the

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microenvironment on the development of cancer have received considerable attention

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[8]. Of these studies, the most basic physiological studies on cancer cells explored the

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effects of AGE-BSA or AGE precursors. Numerous studies have used both high and 9


tumor


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low heat-processed foods to design high or low AGE diets and to explore the

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association of AGEs in the diet with disease development [4,12]. Given that the

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source of food-derived AGEs in the body is digested food, it is not useful to link the

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AGE content of the food to the physiological effects caused by ingestion of the food.

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In addition, heat processing not only produces AGEs but also produces numerous

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highly reactive substances, such as heterocyclic amines (HCAs). Therefore, the results

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of the relevant research cannot be entirely attributed to the role of AGEs in food.

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AGE HOMOEOSTASIS

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Source of Body AGEs

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AGE accumulation in the body can be derived from two main sources: the

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glycation of proteins in the body and dietary uptake. Key factors affecting protein

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glycation in vivo include oxidative stress and the types of glycation agents and

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proteins. Glycation agents include glucose, fructose, and dicarbonyl/carbonyl

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compounds with higher activities, of which the former has less reactivity compared

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with the latter. Most scholars agree that dicarbonyl/carbonyl compounds are the main

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precursors of AGEs. These highly active AGE precursors may result from protein

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degradation, glycolysis, lipid oxidation, glucose autoxidation, and other free-radical

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induced molecular lysis reactions (Figure 1A). Oxidative stress promotes the

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production of highly reactive glycation agents, such as MG and GO, to further

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enhance the rate of protein glycation in the body [17-19]. Oxidative stress is thus

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often considered an important promoter of the accumulation of large amounts of

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glycated proteins in the body. In addition, free AGEs in the diet can enter the

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circulatory system directly from the intestine through simple diffusion, whereas

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peptide-bound AGEs can enter the body via transporter proteins [26]. Glycation may 10


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lead proteins to be resistant to digestive enzymes. This not only affects the nutritional

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value of the protein but may cause changes in intestinal microbiota due to glycated

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protein with high molecular weight that is difficult to digest and absorb, thus

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accumulating in the stool [3,15,26].

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Mechanisms Involved in Circulating AGE Homeostasis

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As shown in Figure 2, the amount of AGEs observed in the body is the

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consequence of a dynamic equilibrium among various reactions. Most of the

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low-molecular-weight food-derived AGEs are excreted via the kidneys, whereas

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food-derived AGEs with high molecular weight that cannot be metabolized and

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absorbed into the body are excreted in stool [3,4,13,14,16]. In addition,

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monosaccharides (especially fructose and glucose) and fatty acids derived from foods

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are important sources of glycation compounds in the body. Many monosaccharides

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are glycation compounds, and many biochemical reactions involving fatty acids and

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monosaccharides, including cell metabolism, glucose autoxidation, and lipid

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peroxidation can produce glycation compounds. These glycation compounds can react

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with plasma proteins and tissue proteins to generate plasma and tissue AGEs, which

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are important sources of AGEs in the circulation system. However, most of these

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AGEs can be removed by the urinary system [3,4,13,14,16] or via endocytosis of

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hepatocytes and macrophages [4, 27]. The rest of the circulating AGEs in the body

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may accumulate in the organs and tissues (mainly the liver, kidney, and bladder).

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Given the limited metabolic capacity of organisms, the amount of AGEs that

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accumulate in organs and tissues increases with increasing age. Of note, dietary

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patterns, digestive system status, and intestinal bacteria are important factors that

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influence the content of food-derived AGEs and glycation compounds in the body 11



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[3,15,16,18,26]. The interactions between these factors are complex, and more studies

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are needed to help clarify the relationship between dietary AGEs and disease.

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AGEs: A THREAT OR BENEFIT TO HUMAN HEALTH?

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The Physiological Role of AGEs

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The physiological effects of AGEs can be simply divided into two categories. (1)

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AGEs promote protein cross-linking and can act as bridging molecules of different

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peptide chains in proteins to promote protein aggregation or tissue stiffness, causing

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proteins and tissues to lose their original function. This aspect of the physiological

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role of AGEs is often discussed in cardiovascular disease associated with diabetes and

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chronic kidney disease, aging, skin diseases, and neurodegenerative diseases. (2)

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Protein-bound AGEs can activate cell membrane receptors, such as RAGE,

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oligosaccharyl transferase complex protein 48 (OST-48, generally known as AGER1),

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80 KH protein (AGER2), and galectin-3 (AGER3), to directly promote ROS

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generation and affect cell physiology. Given the positive correlation between RAGE

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activation and numerous diseases, there is a wealth of research regarding the

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interaction of AGEs with RAGE and its role in disease [7-9]. However, not all AGE

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protein adducts can bind to RAGE and activate specific cellular pathways [28]. Only

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CML or N-ɛ-carboxyethyllysine (CEL) protein adducts bind to RAGE and cause the

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activation of specific cellular signaling pathways [29].

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Effects of AGEs on Human Health

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As shown in Figure 3, through the physiological functions described above, in

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vivo AGEs enhance oxidative stress, affect immune balance, promote chronic

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inflammation, cause tissue damage, change the functional properties of tissue proteins, 12


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promote protein aggregation, and further induce the occurrence of numerous diseases

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or accelerate disease progression [7-12,30]. However, the differences in physiological

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effects induced by free AGEs and protein-bound AGEs have not yet been completely

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elucidated. The relationship of AGE structures and their bioactivities, the number of

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AGE residues, and the structures of glycated proteins with the biological activity of

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AGE protein adducts has not been clarified. Therefore, to clearly understand the

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effects of in vivo AGEs on disease and health, more research is needed to establish the

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relationship of AGE physicochemical properties with AGE disease bioactivity.

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Melanoidins, a group of Maillard reaction products, may involve AGEs and AGE

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protein adducts [3,4]. Numerous studies confirm that melanoidins in food may have

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potential beneficial effects on health because melanoidins have potential tumor

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growth inhibition and anti-mutation, antioxidative and intestinal microflora regulatory

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effects [31]. However, most studies do not clarify the impact of molecular weight,

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molecular structure or AGE residue content in the mode of action of melanoidins.

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Therefore, these studies will not be helpful to clarify the physiological characteristics

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of AGEs. The integration of the above discussion leads to the inference that AGEs

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have the potential to endanger health, but this needs to be verified in more detailed

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studies.

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FUTURE PERSPECTIVES

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Numerous studies have demonstrated the association of in vivo AGE protein adducts

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with disease and health. Despite the potential of AGEs to highly endanger health and

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advance the disease process, numerous controversies exist regarding the physiological

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impact of AGEs because the relationship between the physicochemical properties and

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biological activities of AGEs remains unclear. Furthermore, most AGE study designs 13



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did not explore or compare the biochemical and structural characteristics of free

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AGEs and AGE protein adducts and their contribution to the metabolic uptake and

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physiological effects of AGEs. Instead, these studies exclusively focused on

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evaluating the effects of carbohydrate-modified protein (such as AGE-BSA,

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AGE-HSA, AGE-casein, and fructose-modified egg whites) or Maillard reaction

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product-rich food (such as bread crust and heat-processed foods) on diseases via in

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vivo and in vitro experiments. Given that related studies have not fully elucidated the

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physiological roles of AGEs, designing a better experimental platform to explore the

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relationship between AGEs and diseases is a direction that scholars in relevant fields

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should focus on. Different scholars also have different opinions on the types of

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compounds covered by AGEs. Therefore, the conclusions drawn by different studies

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are not necessarily based on the same substance. In the future, scholars in

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AGE-related fields should unify the definition of AGEs and establish a standard

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experimental platform to evaluate the physicochemical properties and biological

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activities of AGEs to break through the bottleneck of AGE research at this stage and

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clarify the physiological role of AGEs. Regarding the design of relevant experimental

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platforms, standard AGE preparation, precise AGE analysis, digestion and intestinal

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microbial effects, and adjusting nutrition loss and concerning effects of non-AGE

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products derived from heat processing in test samples should be considered. Of note,

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many scholars have recently started to explore the interaction among dietary AGEs,

327

microbiota, immuno-modulation, circulating AGEs, and the extent of disease, which

328

will further explain the impact of AGEs on health and open a new chapter in AGE

329

research.

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Conflict of interest statement 14


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The authors have declared no conflicts of interest.

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Figure Legends

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Figure 1. (A) AGE chemistry. (B) AGE precursors and common AGEs with different

438

characteristics. GO, glyoxal; MG, methylglyoxal; 3-DG, 3-deoxyglucosone; GOLD,

439

glyoxal-lysine

dimer;

MOLD,

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N-ɛ-carboxymethyllysine;

CEL,

441

Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine.

442

Figure 2. Scheme of circulating AGE homeostasis. *Glycation compounds mainly

443

include monosaccharides, dicarbonyl and carbonyl compounds. #Biological/chemical

444

reactions in vivo include metabolic reactions, glucose autoxidation, lipid peroxidation,

445

and possibly other free radical-induced fragmentation/degradation of organic

446

compounds.

447

Figure 3. AGE-induced biological effects and correlated diseases [7-12,30].

methylglyoxal-lysine

dimer;

N-ɛ-carboxyethyllysine;

21


CML, MG-H1,


Figure 1.

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Figure 2.

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Figure 3.

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Table of Contents Graphic

AGE-induced biological effects, such as chronic inflammation and oxidative stress, may play important roles in the onset and progression of many diseases, including cancer, metabolic disease, and renal disease.

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Perspective of Advanced Glycation End Products on Human Health

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