Glycated proteins in nutrition: Friend or foe?

Experimental Gerontology xxx (xxxx) xxx–xxx

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Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero

Review

Glycated proteins in nutrition: Friend or foe? ⁎

Katarína Šebekováa, , Katarína Brouder Šebekováb a b

Institute of Molecular Biomedicine, Medical Faculty, Comenius University, Bratislava, Slovakia Intensive Care Unit, John Radcliffe Hospital, Oxford, United Kingdom of Great Britain and Northern Ireland

A R T I C LE I N FO

A B S T R A C T

Keywords: Dietary advanced glycation end products Skin autofluorescence Beneficial health effects Negative health effects Cardiometabolic risk

Advanced glycation end products (AGEs) are formed in in vivo, and accumulate in tissues and body fluids during ageing. Endogenous AGE-modified proteins show altered structure and function, and may interact with receptor for AGEs (RAGE) resulting in production of reactive oxygen species, inflammatory, atherogenic and diabetogenic responses. AGEs are also formed in thermally processed foods. Studies in rodents document that dietary AGEs are partially absorbed into circulation, and accumulate in different tissues. Knowledge on the health effects of high dietary intake of AGEs is incomplete and contradictory. In this overview we discuss the data from experimental and clinical studies, either those supporting the assumption that restriction of dietary AGEs associated with health benefits, or data suggesting that dietary intake of AGEs associates with positive health outcomes. We polemicize whether the effects of exaggerated intake or restriction of highly thermally processed foods might be straightforward interpreted as the effects of AGEs-rich vs. AGEs-restricted diets. We also underline the lack of studies, and thus a poor knowledge, on the effects of different single chemically defined AGEs administration, concurrent intake of different dietary AGEs, of load with dietary AGEs corresponding to the habitual diet in humans, and on those of dietary AGEs in vulnerable populations, such as infants and particularly elderly.

1. Introduction

2. Formation of advanced glycation end-products

Humans are the only species on our planet dependent on fire for food preparation. During evolution, cooking allowed humans to gain maximal benefits from limited food resources and switch the energy supply to increasingly energy-demanding brain. Thus, the attraction to smell and taste of cooked food as well as to fat and sugar-rich foods is encoded in our brains as heritage from our Paleolithic ancestors. Over the recent decades we have faced virtually unlimited food availability and thus consumption of calorie-dense diets exceeding the actual energy demands. As well as being rich in sugar, fat, and salt, Western type of diet and particularly “fast food” is usually processed under temperatures of- > 100 °C. This yields to formation of advanced glycation end-products (AGEs). In current industrial processing of foods, high temperatures are implemented to impart desirable properties such as long shelf-life, sterility, and attractive taste and aroma.

AGEs are formed by the Maillard reaction (Maillard, 1912), in foods during thermal processing, ultra-high temperature processing, pasteurization, sterilization or irradiation, during their storage; and in vivo (Sun et al., 2016; Chen and Smith, 2015; Sun et al., 2015; MilkovskaStamenova and Hoffmann, 2017; Visentin et al., 2010; Brownlee et al., 1984). Classical Maillard reaction is initiated by non-enzymatic reaction between aldehyde groups of reducing sugars and amino moieties of proteins, phospholipids or nucleic acids. Initially formed products are Schiff bases which spontaneously rearrange into more stable Amadori products, while both remain reversible. Series of further parallel and, or sequential reactions (such as oxidation, reduction, dehydration, degradation, fragmentation, condensation, isomerization, cyclation, etc.) occur to form late-stage, irreversible AGEs (Hellwig and Henle, 2014; Henning and Glomb, 2016). Alternatively, formation of AGEs might be initiated by α-dicarbonyls (such as glyoxal - GO, methylglyoxal - MGO,

Abbreviations: AGEs, advanced glycation end products; BMI, body mass index; CEL, Nε-carboxyethyllysine; CML, Nε-carboxymethyllysine; CRP, C-reactive protein; Exclude dAGEs, dietary advanced glycation end products; dCML, dietary Nε-carboxymethyllysine; DG, 3-deoxyglucosone; GC, gas chromatography; GO, glyoxal; GOLD, GO-glyoxal-derived lysine dimer; GST, glutathione-S-transferase; HDL, high density lipoprotein; HPLC, high performance liquid chromatography; IL6, interleukine-6; MGO, methylglyoxal; MG-H1, methylglyoxal-derived imidazolone; MOLD, methylglyoxal-derived lysine dimer; MS/MS, tandem mass spectrometry detection; RAGE, receptor for advanced glycation end products; SAF, skin autofluorescence; STZ, streptozotocin; TNF-α, tumor necrosis factor-α; UPLC, ultraperformance liquid chromatography; VCAM-1, vascular adhesion molecule-1 ⁎ Corresponding author at: Institute of Molecular Biomedicine, Medical Faculty, Comenius University, Sasinkova 4, 811 05 Bratislava, Slovakia. E-mail address: [email protected] (K. Šebeková). https://doi.org/10.1016/j.exger.2018.11.012 Received 22 February 2018; Received in revised form 20 September 2018; Accepted 16 November 2018 0531-5565/ © 2018 Elsevier Inc. All rights reserved.

Please cite this article as: Sebekova, K., Experimental Gerontology, https://doi.org/10.1016/j.exger.2018.11.012

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express the results as a ratio of protein-bound AGE-adduct to total protein, or as a ratio of AGE-modified lysine or arginine adducts to total content of respective amino acids. Chromatographic methods - high performance liquid chromatography (HPLC), ultra-performance liquid chromatography (UPLC), or GC are separation methods of choice to determine chemically defined AGEs. HPLC methods with fluorometric detection are suitable for analysis of AGEs with intrinsic fluorescence – such as pentosidine (Forster et al., 2005), or non-fluorescent compounds after derivatization (e.g. ortho-phthaldialdehyde-derivatized CML) (Drusch et al., 1999). UPLC (Scheijen et al., 2016; Hull et al., 2012; Assar et al., 2009) and LC (Bechtold et al., 2009) coupled to tandem mass spectrometry (MS/MS) in the multiple reaction monitoring mode with stable isotope dilution or standard addition represent “a gold standard” for quantification of chemically defined AGE-adducts. Arginine and lysine are main targets of AGE-modification in proteins. CML, CEL, GO- or MGO-lysine dimers (GOLD and MOLD, respectively) represent the most frequently analyzed adducts to lysine, while GO-, MGO- and 3DG-derived hydroimidazolones (G-H1, MG-H1, and 3DG-H, respectively) represent arginine derivatives. The proportion of arginine and lysine varies in different proteins; thus, it is desirable to analyze adducts to both amino acids simultaneously. As CML is a most abundant glycated amino acid derivative in thermally processed foods, it is most often used as a marker of glycation load in foods (Birlouez-Aragon et al., 2004). However, owing to its route of formation in foods and biological systems, CML can be classified both as AGE and advanced lipoxidation end product (Poulsen et al., 2013). Advanced lipoxidation products represent different non-enzymatically generated irreversible adducts and crosslinks, formed by reaction between reactive carbonyls (generated during lipid peroxidation and the lipid metabolism) with proteins or deoxyribonucleic acids (Pamplona, 2011). In the AGEpathway, CML is formed e.g. by reaction of glucose and lysine, oxidation of fructosyl-lysine, or from ascorbate; while the reaction of glyoxal with lysine to form CML might represent both, the glycoxidation and the lipoxidation path (Hull et al., 2012; Ahmed et al., 1986; Fu et al., 1996; Glomb and Monnier, 1995; Wells-Knecht et al., 1995; Wolff and Dean, 1987). Except for the abovementioned highly selective analytical approaches, immunochemical techniques, e.g. enzyme-linked immunosorbent assays (ELISA), are also used to quantify AGEs content in foods. However, some antibodies, such as the anti-CML monoclonal antibody 4G9 or anti-MG monoclonal antibody 3D11 (Goldberg et al., 2004; Uribarri et al., 2010) show low specificity in complex food matrices and their employment may lead to unreliable results (Scheijen et al., 2016; Poulsen et al., 2013; Charissou et al., 2007).

or 3-deoxyglucosone - 3-DG), which are much more potent glycating agents than reducing sugars (Yaylayan and Huyghuesdespointes, 1994). Several metabolic pathways lead to production of α-dicarbonyls: they are formed at all stages of the Maillard reaction, during auto-oxidation of monosaccharides, lipid peroxidation, conversion of triosephosphates, the catabolism of ketone bodies and threonine; or in the polyol pathway (Thornalley et al., 1999). Thus, due to a plethora of potential metabolic pathways, highly heterogenous and largely chemically uncharacterized compounds represent AGE family. Even chemically defined AGEs display diverse chemical-physical properties. E.g., Nε-carboxymethyllysine (CML), Nε-carboxyethyllysine (CEL), and pyrraline do not present intrinsic fluorescence and do not cross-link with other proteins; vesperlysine and pentosidine are fluorescent and form cross-links; while lysine dimers formed by GO, MGO or 3-DG yield non-fluorescent imidazolium cross-links (Schalkwijk and Miyata, 2012; Soboleva et al., 2017). In some strongly heated foods (such as roasted coffee or bakery products), melanoidins - brown-to-black high molecular weight polymers of a heterogenous and largely unknown structure - represent final products of the Maillard reaction (Morales et al., 2012; Wang et al., 2011). Interestingly, prof. Louis-Camille Maillard never isolated a chemically defined product of “his” reaction; and discussed the role of the reaction in relation to plant and human physiology and pathology, but not in relation to reactions in foods (Hellwig and Henle, 2014). 3. Advanced glycation end-products in foods In living organisms, AGEs are formed physiologically. Thus, certain amounts of AGEs are present in raw foods of animal (Sun et al., 2016; Chen and Smith, 2015) and of plant (Bilova et al., 2016; Bechtold et al., 2009) origin, and even bacteria contain AGEs (Mironova et al., 2001). The Maillard reaction and lipid peroxidation are considered the main sources of AGEs in meat and milk (Han et al., 2013); while autooxidation of monosaccharides, high fructose and ascorbic acid levels, and environmental stress (such as drought or excessive light) contribute to their formation in plants (Bilova et al., 2016; Bechtold et al., 2009; Bilova et al., 2017; Paudel et al., 2016). 3.1. Quantification of advanced glycation end-products in foods 3.1.1. Methods Despite that stand-alone fluorescence detectors give no indication about the nature of specific fluorophores, measurement of the fluorescence of advanced Maillard products and soluble tryptophan (FAST index) has been recently proposed as an indicator of the nutritional damage imposed by heat-processing at industrial scale (BirlouezAragon et al., 2001). There are no commercially available kits, or commonly accepted standard methods to quantify specific AGEs in foods. Thus, their accurate quantification in foods is technically demanding, requires sophisticated instrumentation, and trained personnel. It is also complicated by structural diversity of AGEs, poor identification of chemically defined AGEs, limited availability of standards, and a lack of reference material. Determination of food AGE content requires preanalytical steps, such as mixing, grinding, fat-extraction, lyophilisation, etc. Ultrafiltration of samples is necessary for analyses of free-AGE adducts, while exhaustive degradation of proteins using acidic, alkalic, or enzyme hydrolysis must precede determination of protein-bound AGEadducts (Soboleva et al., 2017). The choice of the hydrolytic method depends on the targets of the analysis: in harsh acidic milieu several compounds, such as hydroimidazolones and pyrallines, are instable; while despite the application of proteolytic enzyme cocktails containing endo- and exo-proteases, in some highly cross-linked AGEs cleaving sites might be blocked (Soboleva et al., 2017; Thornalley, 2005). For gas chromatography (GC), volatile derivatives are needed. Concentration of proteins, or that of selected amino acids is to be determined to

3.1.2. Advanced glycation end products in raw foods The amounts and hence the ratio of individual AGE-adducts vary in different foods. Free pentosidine has been detected both in regular cola and diet cola drink, while the regular beverage contained also free CML, MG-H1, GOLD and MOLD (Ahmed et al., 2005). In fruits, vegetables, butter, oils, and some beverages (such as wine, fruit juices, and cola), amounts of protein-bound CML, CEL or MG-H1 are negligible or even under the detection limit of UPLC–MS/MS method (Scheijen et al., 2016; Ahmed et al., 2005). In raw meat, the amounts of free- and protein-bound AGE adducts vary for different animal species, strains, different meat cuts, and meats of different suppliers (Sun et al., 2016). E.g., raw pork contains about 50% less free CML and CEL compared to beef. In chicken meat, levels of free CML are about the same as in beef, while those of free CEL are in average 11-fold higher. Free CML and CEL adducts account for about 7% and 11%, respectively, of total CML and CEL adducts in beef and pork; while in chicken, proportion of free adducts reached 13% and 62%, respectively (Sun et al., 2016). Similarly, proportion of AGE-adducts differs in raw cow milk (Ahmed et al., 2005). Concentrations of free CML and CEL are about 32

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appetite hormone responses, or subsequent food intake (Poulsen et al., 2014). On the other hand, the preference of “fast-foods” by young generation might be potentiated also by the attractive taste and odor of the Maillard substances. Some Maillard reaction products, such as 5-hydroxymethylfurfural, acrylamide (formed particularly in potatoes, breakfast cereals, but also in infant formulas) or heterocyclic aromatic amines (originating mainly from creatine, thus present in well-done meat or fish) are potentially toxic (Mehta and Deeth, 2016; Capuano and Fogliano, 2011; Felton et al., 2007; Birlouez-Aragon et al., 2010a). These heat-generated compounds are potentially carcinogenic to humans or might be metabolised to potentially carcinogenic compounds. Generally, their formation during thermal processing cannot be dissected from that of AGEs, thus virtually all thermally processed foods containing dAGEs comprise also these heat-generated compounds. In studies focusing on health effects of dAGEs, food content of 5-hydroxymethylfurfural, acrylamide or heterocyclic aromatic amines is generally not quantified. In a single study focusing on this issue, 3-fold reduction in dietary CML (dCML) content achieved by mild vs. high heat-treatment of foods, associated with 5-fold reduction in dietary acrylamide and even with 45-fold reduction of 5-hydroxymethylfurfural (Pouillart et al., 2008). In nutritional studies, positive health effects of restriction of dAGEs, or negative effects of high AGE diets are simplistically attributed to dAGEs. Potential additive or synergic negative health effects of other heat-derived compounds to those of dAGEs are generally not considered and remain unknown.

fold higher compared with those of MG-H1; while the levels of proteinbound adducts are about 2-fold lower for CML compared with CEL or MG-H1 (Ahmed et al., 2005). 3.1.3. Advanced glycation end-products in processed foods Thermal treatment of foods may increase their digestibility, nutritive value, and prolong their shelf-life. Dietary AGEs (dAGEs) render heated foods attractive color, aroma and taste. On the other hand, AGEmodification of essential amino acids, particularly that of lysine, may decrease nutritional value of proteins since cross-linked proteins are less digestible. Thus, heat-induced rise in proportion of protein-bound AGEs has a nutritional impact, as proteolytic degradation in gastrointestinal tract is a prerequisite for potential absorption of peptides (Finot and Magnenat, 1981). During thermal processing, brownish AGEs are formed within minutes or hours, particularly on food surfaces. The rate and extend of the Maillard reaction are influenced by concentration and by type of reactants. High temperature, longer duration of heating, alkaline pH, low water content and presence of metal ions increase the reaction rate (Lund and Ray, 2017). Thus, foods prepared from the same ingredients by dry heating such as grilling, roasting, baking, or frying, contain much higher amounts of AGEs compared with those prepared by boiling or steaming. With heating time and heating temperature, particularly the amounts of protein-bound AGE-adducts increase. Sterilization (121 °C/10 min) did not affect significantly the amounts of free CML or CEL in beef, pork or chicken meat, while both protein-bound adducts increased approximately 3-fold (Sun et al., 2016). In ground beef, protein-bound CML content increased by 50% and that of CEL by 72% after 60 min of pasteurization at 65 °C, while heating at 100 °C resulted in 361% and 301% increase, respectively. High correlation between protein-bound CML and CEL suggested that these lysine derivatives increase during heating in parallel (Sun et al., 2015). Validated databases on AGE content of foods affirm that content of protein-bound AGE adducts significantly differs in various food items. E.g., in bread products, some fish, meat and pastry products, amounts of CEL and MG-H1 might substantially exceed those of CML. Nuts and breads contain high amounts of HG-H1; while cheese and milk products contain similar amounts of all three AGE-adducts. Validated databases also report a similar rise in AGE-adducts using different culinary techniques (Sun et al., 2015; Scheijen et al., 2016; Hull et al., 2012; Charissou et al., 2007; Delatour et al., 2009). Thermal processing results in accumulation of AGEs mainly on food surfaces. Frying of meat leads to approximately 10-fold increase of CML in the outer layer, while in the middle layer the increase is usually insignificant (Chen and Smith, 2015). Bread crusts contain 8- to 12-fold higher amounts of CML compared with bread crumbs (Assar et al., 2009). Processing of the meat in direct contact with a heat source, such as frying or broiling, may increase the surface accumulation of CML by 25% to 60% compared with baking, when the meat is cooked indirectly by hot air. When frying, multiple flipping of the meat may reduce CML formation by about 40% compared with single turning (Chen and Smith, 2015). In food industry, there is a strong interest in modulation of Maillard reaction, to affect functionality of food, and to enhance the formation of desirable flavour compounds (van Boekel, 2006; Newton et al., 2012). Attractive taste of aroma-containing dAGEs might drive food overconsumption and contribute to the addictive qualities of highly thermally processed foods (Vlassara and Uribarri, 2014; Kellow and Coughlan, 2015). Study in rats suggests that 3-weeks-long administration of sensory-stimulating aroma-containing dAGEs (e.g. AGE-rich diet in form of bread crusts) affects orexigenic and anorexigenic hormone levels and the expression of their central receptors; central reward, appetite regulation and energy homeostasis at the level of the hypothalamus, while the effects of aroma-extracted bread crusts are negligible (Sebekova et al., 2012). However, in healthy overweight individuals intake of a single high-AGE meal did not affect hunger,

3.1.4. Databases on the content of advanced glycation end products in foods The first published database on AGEs content in foods (Goldberg et al., 2004), used ELISA with a monoclonal antibody to quantify CML. This database has been later extended to cover AGE content of 456 food items, and in selected foods, also total MG content using anti-MG monoclonal antibody has been reported (Uribarri et al., 2010). In these databases, the amounts of CML are expressed semiquantitatively (as kU per food weight or beverage volume, or per serving). Thus, a straightforward comparison with data obtained by validated chromatographic methods, reporting AGE amounts in foods quantitatively (e.g. as mmol/ mol amino acid, mg/kg protein, or mg/kg of food) (Scheijen et al., 2016; Hull et al., 2012; Assar et al., 2009), is impossible. In comparison with data obtained later by validated methods, ELISA-derived databases substantially overestimate CML content in oils, butter, margarines or fatty foods, and underestimate it in starchy ones, such as biscuits or grocery products (Goldberg et al., 2004; Uribarri et al., 2010). The scientific community considers this database as incorrect, due to flawed methodology of food sample preparation, insufficient characterization of CML-antibody and its cross-reactivity with other epitopes in food matrices (Poulsen et al., 2013; Delgado-Andrade and Fogliano, 2018). Despite this fact, ELISA database is widely used: most of clinical studies on dAGEs have been performed by the group authoring this database, and since being published as first, it has been also employed by other groups (Jochemsen et al., 2009; Semba et al., 2014). Even though in healthy subjects daily dCML intake estimated using ELISA database correlated directly with plasma CML concentrations measured using the same monoclonal antibody (Uribarri et al., 2005; Uribarri et al., 2007), published data using this database are to be interpreted with caution. Results on significant association between any biological marker and dietary intake of AGEs calculated from food records or diaries using ELISA database are dubious: food records remain unpublished, thus even a rough estimation what the quantification of dAGEs intake reflects, is impossible. Such data and the conclusions drawn from them should be critically addressed. The Japanese database reported glucose-, fructose-, glyceraldehyde-, and CML-derived AGEs content using competitive ELISA involving immunoaffinity-purified specific antibodies in 1650 commonly consumed Japanese foods and beverages, in units per bottle or serving (Takeuchi et al., 2015). Comparative data using validated methods are not available. 3

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2008)), following oral administration of free CML at doses of 200, 500 or 1000 mg/kg, decreased appetite and a mild reduction in body weight was observed. Nephrotoxic and hepatotoxic effects manifested as increased relative organ weights associated with lipomealopin deposition, congestion, inflammatory cell infiltration, decline in antioxidant enzyme activities (e.g. superoxide dismutase and glutathione peroxidase), a rise in malondialdehyde levels; and increased plasma urea, creatinine, uric acid levels and liver enzyme activities (Liu et al., 2016). Tissue CML levels were not determined in this study. Oral administration of free CML in dose of 60 mg/kg/day to rats for 12 weeks confirmed a significant accumulation of protein-bound CML in the kidneys (+107% over the controls), in the heart, the liver and in the lung (+41% to +85%) (Li et al., 2015). Even this lower dose of free CML turned out to be hepatotoxic and nephrotoxic. After intravenous application of radiolabelled free pentosidine to healthy rats, the radioactive load also accumulated mainly in the kidneys but transitory rise has been detected in plasma and liver proteins (Miyata et al., 1998). These data suggest that exogenous free AGE-adducts may bind rapidly and ad interim to tissue or plasma proteins. The nature of this binding remains unclear. Alternatively, it cannot be excluded that absorbed free dietary CML (Li et al., 2015) might have induced in certain tissues de novo production of CML. The potential mechanism of de novo formation remains unclear, as free AGEs do not interact with RAGE (Kislinger et al., 1999; Xie et al., 2008), thus are unlikely to induce RAGE-dependent microinflammation or production of reactive oxygen species, which could perpetuate formation of CML (Li et al., 2015). Experimental data suggest that administration of free CML in pharmacological dosage results in organ accumulation of CML, promoting organ dysfunction via induction of inflammation and oxidative stress. However, the physiological impact of these observations remains questionable. If human exposure to tested substance is known, in subacute toxicity studies approximately corresponding dose to that, and 10-fold lower and 10-fold higher dose is generally tested; otherwise generally 0.1%, 1.0% and 10% of LD50 is administered. Even if we consider the highest oral load of protein-bound CML estimated in humans, e.g. 1.5 mg/kg/day in infants consuming formulas with high CML content (Klenovics et al., 2013), dietary load with free CML in tens or hundreds of mg/kg/day cannot be achieved in humans. It is assumed that amino acid transporters are not able to transport glycated amino acids, and that free AGE-adducts cross intestinal barrier by simple diffusion and are quickly excreted via urine (Grunwald et al., 2006). In the study of Li et al. (Li et al., 2015), renal excretion of CML was not determined. After intravenous administration of free radiolabelled pentosidine, > 80% of the radioactivity was recovered in the urine but only about 20% appeared as intact pentosidine (Miyata et al., 1998), indicating that after glomerular filtration, pentosidine undergoes a degradation or modification process. This suggests that except for a key role of the kidney in disposal of AGE-peptides, the endo-lysosomal apparatus of the proximal convoluted tubule might participate in catabolism of some free AGE-adducts (Gugliucci and Bendayan, 1996). A limited recovery of radioactivity in faeces after intravenous load of free pentosidine (Miyata et al., 1998) might reflect hepatobiliary transfer of pentosidine or its residues. It remains to be elucidated whether other AGE-adducts are subject to such transport.

Data using validated methods show a good agreement in AGE content of different foods (Scheijen et al., 2016; Hull et al., 2012; Charissou et al., 2007). Data on content of AGEs in foods and beverages, determined using selective analytical methods for individual reaction products by several research groups, are publicly accessible at the web page of the Technical University of Dresden, Germany (AGE database, n.d.). 3.2. Dietary exposure to advanced glycation end-products Data on daily oral AGEs load either come from clinical studies employing a direct measurement in AGE content of ingested foods, or from studies estimating the intake based on food frequency questionnaires using dAGE databases. Studies employing GS-MS/MS or LC-MS/MS methods to determine CML content in consumed diets, show that dCML load depends on CML content of food, and decreases with increasing body weight of the subject ingesting the food. In exclusively breast-fed 3-to-6-month old toddlers, estimated daily intake of dCML is < 4 μg/kg body weight/day; it rises to 270-to-330 μg/kg/day in peers fed by infant formulas with low CML content, and reaches even 1300-to-1500 μg/kg/day in infants consuming formulas with high CML content (Klenovics et al., 2013). Correspondingly, infant formulas-fed toddlers presented higher total plasma CML concentration and higher urinary CML excretion compared with breast-milk fed infants (Klenovics et al., 2013; Sebekova et al., 2008). In 11-to-14 year old boys, oral exposure to diet low in AGEs reached about 94 μg CML/kg/day, while the exposure increased to 197 μg/kg/day under consumption of AGE-rich diet (Delgado-Andrade et al., 2012). In young adults, daily oral load of CML was estimated to be 34 μg/kg/day on low-AGE diet, and 83 μg/kg/day under consumption of AGE-rich diet (Delgado-Andrade et al., 2012; Birlouez-Aragon et al., 2010b). In these studies, daily intake of protein-bound CML on AGE-rich diets reached 11.3 mg/day (Delgado-Andrade et al., 2012) and 5.4 mg/day (Birlouez-Aragon et al., 2010b). In the Australian study on young-to-middle-aged individuals (de Courten et al., 2016), protein bound CML, CEL and MG-H1 content in consumed diets was measured by GS-MS/MS method (Scheijen et al., 2016). On diet low in AGEs, mean daily intake reached 3.2 mg of CML, 2.0 mg of CEL, and 18.3 mg of MG-H1. On high-AGE diet, CML and CEL intake was approximately 1.3-fold higher, and that of MG-H1 1.6-fold higher. Intakes of dAGEs corresponded with those reported in the Dutch study on middle-aged population, e.g. 3.1 mg/day, 2.3 mg/day and 21.7 mg/day, respectively (Scheijen et al., 2018). In this study, intake was calculated using a dietary AGE database (Scheijen et al., 2016). Moreover, intake of three protein-bound AGEs showed strong interrelationship. The daily oral exposure per kg of body weight has not been reported in the latter two studies (de Courten et al., 2016; Scheijen et al., 2018). Thus, exact data on dietary exposure to AGEs (e.g. per kg body weight per day) are limited to that on CML. This might be of relevance due to relatively comprehensive data on pathophysiological effects of CML, but they cannot be considered as universal information of dietary AGEs load. With the exception of infants, who in human milk substitutes consume extraordinary high amounts of CML (Klenovics et al., 2013), in well-controlled clinical studies – in which prepared foods were provided, food consumption was controlled, and CML content was measured by validated methods – difference in exposure to CML under consumption of AGE-rich vs. AGE-poor diet reached the factor of about 3 (Birlouez-Aragon et al., 2010b; Seiquer et al., 2006).

3.3.2. Bioavailability of AGE-peptides in experimental animals Current knowledge indicates that glycated peptides do not have specific transporters in gastrointestinal tract, and that their bioavailability is crucially dependent on their structure. Some glycated dipeptides, such as CML-, CEL-, and MG-H1-adducts which are proteolytically released from dAGEs during digestion, may reach bloodstream via intestinal dipeptide transporter PEPT1 (Hellwig et al., 2011). It is anticipated that similarly to free AGE-adducts, neither AGE-peptides interact with RAGE (Kislinger et al., 1999; Xie et al., 2008). Current data indicate that affinity of tissue proteins to trap distinct AGE-peptides differs. In rats consuming casein-linked lysinoalanine

3.3. Bioavailability of dietary advanced glycation end-products 3.3.1. Bioavailability of free AGE-adducts in experimental animals In acute oral toxicity test performed according to the OECD Test Guidelines 420 (OECD, 2002), the median lethal dose (LD50) of free CML in mice was estimated to be > 5000 mg/kg (Liu et al., 2016). In the sub-acute 28 days toxicity study (OECD Test Guidelines 407 (OECD, 4

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melanoidins indigestible by digestive enzymes, might be partially degraded by intestinal microbiota (Morales et al., 2012; Erbersdobler et al., 1970; Qu et al., 2017).

(LAL), casein-linked FL or casein-linked CML for10 days, about 6% of ingested LAL, 5% of FL, and 29% of CML were recovered in urine and 14%, 1%, and 22%, respectively, in faeces (Somoza et al., 2006). Tissue content of LAL, FL and CML increased compared with the baseline 2.5fold-, 1.4-fold- and 1.2-fold, respectively, in the liver; 13-fold, 33-fold and > 700-fold, respectively, in the kidney; and plasma levels were elevated 3.2-fold, 2.6-fold, and up to 20-fold, respectively. Thus, magnitudes of rise of LAL, FL and CML in plasma and tissues profoundly varied (Somoza et al., 2006). High renal excretion of CML, and its accumulation in the kidneys and in the liver correspond with the data of Bergmann et al. (Bergmann et al., 2001). They used [18F]fluorobenzoylated CML and CEL as model substances for AGE-modified dipeptides which might be released during the digestion process and could be resorbed afterwards. Intravenously administered [18F]-labelled CML and CEL to rats showed quick first-pass effect in the liver, not connected with any metabolisation or enterohepatic circulation, followed by a rapid accumulation in the kidneys and by virtually complete urinary excretion (Bergmann et al., 2001). In a different study, 3 months-long administration of bread crusts-enriched diet (10%/90%, wt/wt, 4 μg CML/g protein, e.g. 1.8-fold higher compared with the control diet) to weanling rats resulted in accumulation of CML in the heart and in the tail tendons (about 2-fold compared with the controls), but not in the bones (Roncero-Ramos et al., 2013). Serum protein-bound CML levels remained unaffected; while 15% of ingested CML were recovered in urine and about 41% in faeces. Administration of heated chow containing approximately 10-fold higher CML content compared with the low-AGEs diet to female rats for 6 months, resulted in about 2.3-fold elevation of serum AGE levels, and immunohistochemically documented increased accumulation of AGEs in the theca interna cells of the ovarian tissue (Diamanti-Kandarakis et al., 2007). However, neither of these experimental studies answered the question whether the observed increase in AGE tissue content and, or, plasma levels reflected accumulation of absorbed dAGEs. As neither chromatographic, nor immunohistochemical detection allow for distinguishing between AGEs of endogenous dietary origin, accumulation in vivo might have reflected induction of endogenous formation of AGEs by nutritional components, or by nutritional components-induced reactive specimen. Recently, Tessier et al. definitely proved that dAGEs accumulate in tissues (Tessier et al., 2016). Using radiolabelling, they could discriminate between endogenous native (12C2-CML) and dietary CML (13C2-CML). They administered a control diet or a diet enriched with CML-modified bovine serum albumin (BSA) to Wild-type C57BL/6 mice and those knocked-out for the receptor for AGEs (RAGE−/−). After 30 days, amounts of native CML were rather similar in 4 animal groups, ranging roughly from 42 μg of 12C2-CML/g of dry matter in kidneys to < 1 μg/g in fat. Accumulation of dCML was not RAGE-dependent. The highest amounts were observed in kidneys, confirming the former findings that kidney plays a key role in elimination of AGE-peptides (Gugliucci and Bendayan, 1996; Bergmann et al., 2001); and that the extraction of AGEs by the liver is negligible (Ahmed et al., 2004) and not connected with any metabolisation or enterohepatic circulation (Bergmann et al., 2001). In contrast to acute i.v. administration of fluorinated CML or CEL (Bergmann et al., 2001), chronic oral administration of BSA-CML resulted in a strong accumulation of CML in the intestine, colon, and lungs. This study showed that dCML accumulates in reproductive organs of males (testes), and, importantly, gave a first evidence on accumulation in brains, suggesting that CML-peptides cross the blood-brain barrier (Tessier et al., 2016). The missing accumulation of dCML in fat tissue is a surprising finding, as low levels of circulating CML in obese in comparison to lean subjects (Sebekova et al., 2009; Semba et al., 2011) have been explained by trapping of lyophilic AGEs into fat tissue (Semba et al., 2011; Gaens et al., 2013). It remains unclear whether this discrepancy might potentially reflect interspecies differences in handling of CML-adducts. It is assumed that non-transportable Amadori products, dAGEs and

3.3.3. Human studies Experimental data from the 1950's, showing that the heating of amino acid-sugar mixtures increases their oral toxicity, suggested that dAGEs might be absorbed into circulation (Krug et al., 1959). Almost 40 years later, Koschinsky et al. postulated that dAGEs in humans are absorbed into circulation and eliminated via urine (Koschinsky et al., 1997). Using immunochemical detection, they concluded that about 10% of dAGEs passes into circulation, and 30% thereof is excreted via kidney. Moreover, they invented the term “glycotoxins” for dAGEs (Koschinsky et al., 1997). Using reversed-phase HPLC, Forster et al. showed that in healthy humans up to 90% of urinary FL and free pyrraline are of dietary origin, while a significant part of urinary pentosidine most likely originates from endogenous sources, e.g. protein turnover or in vivo formation (Forster et al., 2005). Their data also indicated different resorption and metabolic transit of dAGEs: whereas urinary recovery of ingested protein-bound pyrraline and free pentosidine reached up to 64% and 80%, respectively, the urinary recovery of protein-bound pentosidine was minimal. In adolescent boys, total (urinary plus faecal) recovery of dCML reached 47%-to-49% (DelgadoAndrade et al., 2012). Of theoretically absorbed dCML, urinary excretion in rats reached about 37% (Somoza et al., 2006), and 23%-to-32% in humans (Delgado-Andrade et al., 2012). This roughly corresponds with the estimate of Koschinsky et al. (Koschinsky et al., 1997). The recent large Dutch study involving middle-aged and elderly subjects showed that higher dietary intake of protein-bound CML, CEL and MG-H1 estimated from a food frequency questionnaire using a validated dAGE database (Scheijen et al., 2016), was associated (after adjustment for different confounders) with higher respective free plasma and urinary AGE levels, but not with protein-bound plasma AGEs (Scheijen et al., 2018). Based on the observation of a tight relationship between maternal plasma CML and MGO levels at delivery and of those in plasma of their newborns, Mericq et al. (2010) suggested that AGEs are maternally transferred. Whether AGEs are transplacentally transferred remains unclear, but it is highly possible. The metabolic transit of dietary AGE-adducts seems to depend on their individual chemical structure and binding to proteins, which presumably affect their microbial degradation, their absorption mechanisms and their metabolisation. For ethical reasons, it is highly unlikely that we will be able to obtain data on tissue accumulation of dietary AGEs and their exact metabolic transit in humans. Thus, we have to rely on experimental data obtained from rodents, despite these cannot be straightforwardly translated into humans. Experimental data suggest that both dietary free AGE adducts as well as AGE peptides which escape rapid renal elimination may - due to their high affinity to various tissue proteins - accumulate in different tissues. Data from rodents are generally obtained by feeding of nonphysiologically high doses of model substances over a relatively short time period. It remains unclear how the organism would handle a long-term oral load with mildly elevated dosage of dAGEs, and thus whether it would lead to a similar pattern of tissue accumulation as observed under dietary overload. Different accumulation might not be excluded, since the rate of elimination of dCML excreted in urine seems to be limited or saturated: after consumption of the AGEs-rich diet, a percentage of the ingested CML excreted via urine is lower than the proportion excreted after consumption of the AGEs-low diet (Delgado-Andrade et al., 2012). Moreover, generally single AGE-modified model substances are administered in experimental settings. This enables for their tracking but does not make possible to elucidate concurrent effects of natural load with diverse dAGEs. Despite information on general accumulation of dAGEs in different tissues, data on localization within different cell types or tissue structures remain unknown, and studies describing tissue 5

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1997; Celecova et al., 2013). Although the total interference of lowmolecular-weight fluorophores naturally occurring in plasma under physiological conditions with plasma fluorescence is low (up to 1%) (Munch et al., 1997), the interference of non-AGE-modified proteins cannot be excluded. In non-diabetic subjects with normal renal function (Sebekova et al., 2014) or type 2 diabetic patients with impaired renal function (Wagner et al., 2001), AGE-associated fluorescence of plasma showed a direct significant relationship with protein-bound CML. Quantification of chemically defined AGEs and their precursors in biological fluids and tissues is currently the domain of research (Ashraf et al., 2015; Wrobel et al., 2018). The most common approach to determine AGEs in body fluids is based on the ELISA. Commercial kits for determination of protein-bound CML, CEL, pentosidine or MGO-glycated albumin are available from different suppliers. However, different specificity and possible cross-reactivity of antibodies may hamper direct comparison of the results from different studies. As in foods, chromatographic analysis coupled with tandem MS is a “gold standard” to quantify free and protein bound AGE-adducts in body fluids (Scheijen et al., 2018; Ahmed et al., 2004).

accumulation patterns do not provide data on associated metabolic consequences (Somoza et al., 2006; Tessier et al., 2016). Furthermore, it is not known for how long dAGE adducts trapped into tissue remain accumulated. 4. Advanced glycation end products in human body Maillard reaction in foods and in vivo leads to formation of the same AGE-compounds, such as CML, CEL, pentosidine, MG-H1, etc. (Poulsen et al., 2013; Brings et al., 2017). A discovery of glycated hemoglobin (Kunkel and Wallenius, 1955), nowadays known as HbA1c, gave the first evidence of in vivo ongoing Maillard reaction. In humans, AGEs are formed slowly (within weeks or months), particularly on long-lived proteins. Under physiological conditions, Maillard reaction takes place in a closed system, under almost constant low temperature (around 37 °C), almost neutral pH (around 7.40), and under mildly fluctuating concentrations of substrates (saccharides and proteins). Moreover, glycating potential of glucose in vivo is rather low, since only about 5% of its amount is in opened-chain (carbonyl) configuration, capable to glycate (Bunn and Higgins, 1981). On the other hand, α-dicarbonyls are potent propagators of AGEs formation. Thus, endogenous formation of AGEs is accelerated under conditions of chronic hyperglycemia and enhanced oxidative- and carbonyl-stress, while decreased renal function results in retention of AGEs (Goh and Cooper, 2008; Miyata et al., 2000; Heidland et al., 2001). In healthy subjects, AGEs naturally accumulate in body fluids (Uribarri et al., 2007) and tissues (Koetsier et al., 2010; Klenovics et al., 2014) during ageing. Over the period of 5 to 6 decades of ageing, AGEassociated fluorescence of plasma and protein-bound CML levels rise by a factor of approximately two (Sebekova et al., 2001a), while skin autofluorescence (SAF, used in clinical practice as a proxy measure of accumulation of fluorescent AGEs in tissues) increases with age by about 0.022 to 0.024 arbitrary units per year (Koetsier et al., 2010; Klenovics et al., 2014).

4.2. Impact of dAGEs on plasma and urinary AGE levels and skin autofluorescence Using chromatographic methods, amounts of daily ingested dAGEs with conventional diets were estimated to 25–75 mg, thus exceeding at least 10-fold the total amount of AGEs in human body. It had been concluded that the major proportion of AGEs measured in urine is of dietary origin (Henle, 2003). The large Dutch study on older subjects demonstrated that higher intake of dAGEs (calculated using the validated database on CML, CEL and MG-H1 content in foods) (Scheijen et al., 2016) associated with higher levels of free CML, CEL and MG-H1 in plasma and urine; while no significant relationship between the intake and plasma proteinbound AGE adducts has been revealed (Scheijen et al., 2018). In clinical trials comparing the outcomes of consumption of AGErich vs. AGE-restricted diet, generally isocaloric diets, differing only in AGE content were administered to probands. Diets were either centrally prepared and provided as ready-to-eat or provided as packed food portions with detailed instructions for storage and preparation (method, temperature, and duration). In long-term trials participants usually got instruction on choice of food items and their thermal processing. AGE content (usually that of CML) of the diets was either directly measured or calculated from available databases. In randomized clinical trials lasting at least 2 weeks, with cross-over or parallel design (Delgado-Andrade et al., 2012; Birlouez-Aragon et al., 2010b; de Courten et al., 2016; Seiquer et al., 2006; Baye et al., 2017; Seiquer et al., 2014; Seiquer et al., 2008; Mark et al., 2014), which studied the effects of AGEs-rich diet vs. AGE-restricted diets in nondiabetic subjects with normal renal function, intake of dCML measured using chromatography-tandem mass spectrometry methods differed 1.2 to about 3-fold. Higher dAGEs intake associated with higher plasma CML concentration and, or, higher urinary CML excretion (DelgadoAndrade et al., 2012; Birlouez-Aragon et al., 2010b); or dAGEs restriction resulted in lower plasma and, or, urinary CML levels (Mark et al., 2014). Similarly, a study using ELISA database to calculate dAGEs load in overweight men documented that 2.2-fold lower oral intake (in kU AGE/day) associated with lower plasma CML levels (MaciasCervantes et al., 2015); while 4.3-higher intake of dAGEs in overweight and obese males associated with a decline in plasma, but a rise in urinary CML excretion (Harcourt et al., 2011). However, some cross-sectional studies seem to cast doubt on whether consumption of foods considered high in AGEs is a major determinant of either serum or urinary AGE levels. Clinically healthy older subjects presented with higher plasma CML levels compared with younger peers - males by about 16%, females by about 43%; while daily

4.1. Quantification of advanced glycation in vivo Determination of HbA1c, which represents an Amadori product, is widely used in clinical practice to estimate glycemic control over the previous period of approximately 8 to 12 weeks. Another clinically available method is measurement of skin autofluorescence (Mulder et al., 2006). This noninvasive measurement reflects the accumulation of glycemic-, oxidative-, and carbonyl-stress derived AGEs (Koetsier et al., 2010; Klenovics et al., 2014; Mulder et al., 2006; Meerwaldt et al., 2005). SAF correlates significantly with collagen-linked fluorescence and specific skin AGE levels, such as pentosidine, CML and CEL, obtained from skin biopsies of healthy subjects, patients with diabetes and renal failure (Mulder et al., 2006), and highly correlates with AGE accumulation within other organs, such as in the heart (Hofmann et al., 2015). In general population, smokers, sedentary subjects, those with inadequate sleep, high mental stress level, not eating breakfast, and consuming sugary foods present higher SAF (Koetsier et al., 2010; Klenovics et al., 2014; Yue et al., 2011; M.S. Ahmad et al., 2017; Isami et al., 2018; van Waateringe et al., 2016). Compared with healthy subjects, SAF levels are significantly higher in subjects presenting cardiometabolic risk factors (Koetsier et al., 2010; Klenovics et al., 2014; Yue et al., 2011). Accumulating evidence suggests the clinical utility of measurement of SAF for evaluating cardiovascular risks in diabetes, chronic renal failure, and in other high-risk patients (Mulder et al., 2006; Yamagishi et al., 2015). Most commonly, AGEs are analyzed in body fluids, such as serum or plasma, saliva, urine, synovial fluid or cerebrospinal liquor. Direct fluorometric measurement of AGEs in body fluids at excitation wavelengths in the range of 350–390 nm and emission wavelengths of 440–470 nm provides information on bulk accumulation of fluorescent AGEs, but not on quantity of individual compounds (Munch et al., 6

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enzymes display altered catalytic activity (Aljahdali and Carbonero, 2017; Gao et al., 2007). AGE-modification of structural proteins or glycosaminoglycans associates with increased vascular, aortic and cartilage stiffness; and it affects all renal structures in diabetic and nondiabetic renal disease, altering mechanochemical functioning of tissues with significant implications also in several age-related diseases, such as cardiovascular disease, diabetes, renal failure and osteoporosis (Jensen et al., 2005; Daroux et al., 2010; Sims et al., 1996; Moshtagh et al., 2018; Aronson, 2003). AGE-modification of functional proteins might play a role in development of diabetes and its complications. Glycated hormones are less effective, e.g. proportion of glycated insulin is in type 2 diabetic patients up to 2.4-fold higher compared with healthy controls (Hunter et al., 2003). AGE-modification decreases antibacterial activity of lysozyme and lactoferrin, thereby increasing susceptibility to bacterial infections (Li et al., 1995), and decreased biological activity of AGE-modified platelet-derived growth factor might contribute to the chronic deficiencies in wound healing in diabetic patients (Nass et al., 2010). AGE-modification of apolipoprotein-B in low density lipoprotein (LDL) cholesterol significantly impairs LDLreceptor-mediated clearance mechanisms and may thus contribute to atherogenic dyslipidemia and atherogenesis, particularly in patients with diabetes or renal insufficiency (Bucala, 1997; Bucala et al., 1994). RAGE is a cell-surface multiligand pattern-recognition receptor belonging to immunoglobulin superfamily (Bierhaus et al., 2005; Schmidt et al., 2000). AGE-RAGE interaction initiates downstream cell-signaling pathways, leading to production of reactive oxygen species as well as of different cytokines, growth factors, and adhesive molecules, which finally promote oxidative stress, inflammation, and induce atherogenic and diabetogenic responses (Bierhaus et al., 2005; Schmidt et al., 2000; Uribarri et al., 2015; Bastos and Gugliucci, 2015; Lin et al., 2009). Thus, AGEs play a pathophysiological role in different diseases and their complications, such as diabetes, obesity, metabolic syndrome; cardiovascular, inflammatory, and neurological diseases, chronic renal insufficiency, polycystic ovarian syndrome, erectile dysfunction, osteoporosis, food allergies, and some cancers (Kellow and Coughlan, 2015; Goh and Cooper, 2008; Heidland et al., 2001; S. Ahmad et al., 2018; Munch et al., 2012; Van Puyvelde et al., 2014; Merhi, 2014; Neves, 2013; Sanguineti et al., 2014; Toda et al., 2014). As the prevalence of chronic degenerative and neurodegenerative diseases rises with increasing age, it is widely disputed whether dAGEs restriction should be recommended as one of nonpharmacological treatment approaches.

intake of dAGEs estimated from 3-day food records using ELISA database (Goldberg et al., 2004) was lower in older than in younger individuals (by about 30% and 7%, respectively) (Uribarri et al., 2007). Thus, question on accuracy of estimated dAGEs intake arises. In another large study on adults of wide age-range, no significant relationship between serum CML and intake of fast food has been revealed, while urinary CML excretion corrected for urinary creatinine showed even negative correlation with intake of fast foods (Semba et al., 2012). Neither serum CML, nor urinary CML correlated significantly with intake of AGE-rich foods such as fried chicken, French fries, sausage or crispy snacks, except for a significant negative correlation between fried chicken and serum CML. However, serum CML levels correlated positively with intake of soy, fruit juice, breakfast cereal, non-fat milk, whole grains, fruit, non-starchy vegetables and legumes; while urinary CML was positively correlated with intake of starchy vegetables, whole grains, sweets, nuts/seeds and chicken (Semba et al., 2012). In the light of recently published validated databases on CML content in foods (Scheijen et al., 2016; Hull et al., 2012), showing that breakfast cereals, whole grain products, some sweets, nuts and seeds – particularly if roasted – contain high amounts of CML, these data are less contradictory. Information obtained from validated databases (Scheijen et al., 2016; Hull et al., 2012) also elucidates our former seemingly paradoxical observation that vegetarians present with higher circulating CML levels and higher AGE-associated fluorescence of plasma compared with omnivores (Sebekova et al., 2001b). Thus, except for a Western-type diets and fast food, other food items rich in AGEs might significantly contribute to plasma and urinary AGE levels. This should be considered in studies on populations preferentially consuming diets prepared according to traditional recipes. The impact of dAGEs to SAF is equivocal. Intake of a single meal with a medium AGEs content according to the ELISA database (Goldberg et al., 2004), associated with a significant increase in SAF 2 h thereafter, by approximately 9% in healthy subjects and by about 12% in diabetic patients (Stirban et al., 2008). On the other hand, 4-weeks long consumption of diets differing in daily CML intake about 2.3-fold did not affect SAF significantly (Mark et al., 2014); and dAGEs intake calculated from three-day food diaries using the ELISA database (Goldberg et al., 2004), did not correlate with SAF in elderly subjects (Jochemsen et al., 2009). During the first 6 months of life, formula-fed infants present significantly higher SAF in comparison with their breastmilk-fed peers (by about 40% in 1-to-3-month-olds and 31% in 4-to-6month-olds). After the introduction of diversified diet this difference gradually diminishes: formula-fed infants still present higher SAF at 1 and 2 year of age (by 17% and 13%; respectively), but significance is not reached (Sebekova et al., 2010). High SAF of infant-formulas-fed babies might associate with high dAGEs load, since e.g. CML content of formulas is 1-to-2 orders of magnitude higher than that of human breast milk (Delatour et al., 2009; Sebekova et al., 2008; Dittrich et al., 2006). In comparison, in well controlled randomized clinical trials dCML load differed < 3-fold between an AGE-rich vs. AGE-poor diet (DelgadoAndrade et al., 2012; Birlouez-Aragon et al., 2010b). Thus, habitual variation of dAGEs load from balanced diversified diet prepared by traditional culinary recipes is probably too low to impact significantly accumulation of AGEs on skin collagen of healthy subjects. Whether in humans a strict long-term consumption of a Western-type diet and food items rich in AGEs imposes a dAGEs load reflected by rise in tissue AGEs, and thus SAF, remains unclear.

5. Health effects of dietary AGEs 5.1. Evidence not supporting negative health effects of high dAGEs load 5.1.1. Studies in experimental animals Experimental studies in rats indicate that ingestion of heated foods may exert positive metabolic effects. Streptozotocin (STZ)-induced diabetic rats administered a diet containing 20% of glycated proteins (glycated casein and glycated soy protein, 1:1) for 11 weeks, presented lower glycemia compared to control STZ-rats fed with intact proteins, while HbA1C and glucosuria were similar in both groups (Chuyen et al., 2005). Both groups of rats showed similar lipid peroxidation status in serum, liver, and kidney; and presented similar superoxide dismutase and glutathione-S-transferase (GST) activity in serum and liver. Moreover, no significant between-groups differences in degree of cataract formation and concentration of glucose, fructose, sorbitol, and lipid peroxides in the lenses were observed. FL was detected in the hepatic portal vein, artery, and femoral vein only in rats fed glycated proteins (Chuyen et al., 2005). The same group also showed that healthy Wistar rats administered glycated casein for two months, presented higher antioxidative status compared with controls fed with intact casein (Chuyen et al., 1990). Induction of chemopreventive, biotransformation phase II GST enzyme was observed in kidneys of Wistar rats administered either a

4.3. Health effects of AGE accumulation In vivo, accumulated AGEs might exert negative health effects either directly (receptor-independent effects) or indirectly (effects mediated via RAGE). AGE-modified proteins display altered physical and chemical properties. E.g., AGE- modified and particularly cross-linked proteins are less susceptible to proteolytic degradation, and AGE-modified 7

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survival rates (Schwedler et al., 2002). The authors suggested that high plasma AGE levels could reflect a better nutritional status, thus be of dietary origin. Patients suffering from non-small cell lung carcinoma presenting high AGE-associated fluorescence of plasma had a later reoccurrence of the tumor after curative surgery and a higher survival rate compared with patients with low AGE-associated fluorescence (Bartling et al., 2011). Mechanisms remain unclear but the effect of dAGEs intake might not be excluded. Melanoidins which are abundant particularly in coffee and cocoa beans, bakery products, or soy sauce may act as dietary fiber, may exert health-promoting effects via their anti-oxidant and anti-inflammatory, anti-microbial, anti-glycative and prebiotic effects, via induction of chemopreventive enzymes, and via the stimulation of growth of healthbeneficial bacteria in gut (Morales et al., 2012; Mesias and DelgadoAndrade, 2017; Tagliazucchi and Bellesia, 2015).

casein-linked CML in pharmacological doses (110 and 300 mg CML/ kg body weight/day), or a diet supplemented with bread crusts (25% w/w; representing an intake of 11 mg CML/kg body weight/day) for 10 days (Faist et al., 2002). In the same animal model, effective induction of renal GST had been demonstrated after administration of a diet with 5-fold lower bread crust-enrichment of the chow for 15 days (Somoza et al., 2005). Moreover, total antioxidant capacity of plasma was significantly higher, and concentration of lipid peroxidation products quantified as thiobarbituric acid reactive substances was significantly lower compared with control animals. In female athymic mice, consumption of AGE-rich diet (standard diet enriched with 15% of bread crusts) attenuated the tumor growth of H358 lung cancer cells. Mice on AGE-rich diet developed less frequently large tumors (by about 30%) than mice consuming an AGE-poor diet, the volume and weight of tumors were reduced significantly, whereas the tumor vascularization was not influenced (Bartling et al., 2011). These data suggest antitumorigenic effects of dAGEs. In a model of steatohepatosis in rat, melanoidins administered in drinking water effectively reduced accumulation of fat and collagen, liver inflammation, systemic and liver oxidative stress, and expression and concentrations of proteins and cytokines related to inflammation (Vitaglione et al., 2010).

5.2. Effects of AGEs-rich and AGEs-restricted diets in humans Cardiovascular disease (CVD) accounts for 45% of all deaths in Europe and of all behavioral risk factors, dietary factors make the largest contribution to the risk of CVD mortality and CVD disability-adjusted life years (European Cardiovascular Disease Statistics 2017, 2017). Metabolic syndrome is a cluster of metabolic risk factors, e.g. central obesity, elevated blood pressure, atherogenic dyslipidemia and impaired glucose homeostasis, that come together in a single individual and increase the chance of developing type 2 diabetes, CVD and other chronic degenerative diseases (Papakonstantinou et al., 2013). Metabolic syndrome also associates with dysregulation of adipokines, with low-grade inflammation, and imbalance in oxidative status (FernandezSanchez et al., 2011). Due to potential glycotoxic effects of dAGEs, herein we focus on the results obtained in controlled interventional nutritional trials comparing the effects of AGEs-restricted and AGEsrich diets on metabolic markers associated with metabolic syndrome. Studies in healthy subjects, those with overweight, obesity, metabolic syndrome or type 2 diabetes, with intervention lasting for at least 2 weeks were considered. As the terminology of definition of AGEs-restricted and AGEs-rich diets in different articles varies, we considered as AGEs-restricted diets those referred to as a low AGE diet (Semba et al., 2014; Uribarri et al., 2005; Baye et al., 2017; Mark et al., 2014; MaciasCervantes et al., 2015; Harcourt et al., 2011; Vlassara et al., 2002; Vlassara et al., 2009; Uribarri et al., 2014; Uribarri et al., 2011; Vlassara et al., 2016; de Courten et al., 2016), a steam diet (Birlouez-Aragon et al., 2010b), and a white diet (Delgado-Andrade et al., 2012; Seiquer et al., 2014; Seiquer et al., 2008); while those termed an AGE-rich or a high-AGE diet (Semba et al., 2014; Baye et al., 2017; Mark et al., 2014; Harcourt et al., 2011; Vlassara et al., 2002; de Courten et al., 2016), a brown diet (Birlouez-Aragon et al., 2010b; Seiquer et al., 2014; Seiquer et al., 2008), a regular diet (Vlassara et al., 2009; Uribarri et al., 2014), and a standard diet (Birlouez-Aragon et al., 2010b) are referred to as an AGEs-rich diet. Data from randomized clinical trials on the effects of dAGEs load on obesity-related anthropometric parameters are inconsistent. In overweight females, 4 weeks-long administration of isocaloric but AGEs-rich or AGEs-restricted diet, resulted in a significant decline in body weight, body mass index (BMI), and waist circumference (Mark et al., 2014). It has not been indicated whether dietary energy intake during the study differed from the habitual energy intake before the trial. In older obese subjects with metabolic syndrome, 12 months-long consumption of energy-restricted diets differing significantly in dAGE content resulted in a reduction of waist circumference and visceral abdominal fat surface, without changes in body weight, BMI or total body fat percentage compared with baseline in the arm on AGEs-rich diet; while in subjects consuming AGEs-restricted diet, body weight, waist circumference, the surface of subcutaneous as well as visceral body fat declined, without significant change in BMI or total body fat percentage (Vlassara et al.,

5.1.2. Human studies In humans, increased levels of circulating AGEs are not inevitably associated with worse health status. Vegetarians present more favorable cardiometabolic profile than omnivores: they are more insulin sensitive, present lower blood pressure, more favorable lipid profile, lower levels of atherogenic risk factors, higher levels of factors with antiatherogenic effect, and better antioxidant status (Key et al., 2006; McEvoy et al., 2012; Sabate, 2003). Despite these facts, they present compared with omnivores significantly higher plasma CML levels and AGE-associated fluorescence of plasma (Sebekova et al., 2001b). High plasma AGE levels in vegetarians are with high probability of dietary origin: dark, whole meal, currant bread; knäckebröd, rusks, biscuits and cereal products; nuts and seeds (particularly roasted); dry-heat processed snacks containing seeds, nuts, dried berries and soft fruits; dried cereals; fried or marinated tofu, dark chocolate; fruit juices, drinks containing high amounts of reducing carbohydrates and/or soybean flour; represent items with high AGE content, and they are more frequently consumed by vegetarians than by omnivores. It has been anticipated that in vegetarians, high levels of natural antioxidants may ameliorate or antagonize negative effects of high load of dAGEs (Sebekova et al., 2001b). These data also evidence that lower calories intake (as typical for vegetarian vs. omnivorous diets) may not necessarily be associated with lower dAGEs intake. Similar association of higher circulating AGEs with better cardiovascular health status has been recently reported in the study on elderly lifelong endurance athletes (Maessen et al., 2017). Physically exercising subjects presented higher circulating CML and CEL levels compared with their sedentary counterparts, both AGEs correlated positively with oxygen uptake (a measure of cardiorespiratory fitness) and CML showed an inverse relationship with body mass index, pulse wave velocity, fasting insulinemia, and homeostasis model assessment of insulin resistance (HOMA-IR) (Maessen et al., 2017). Mechanisms leading to higher plasma AGE concentrations in lifelong endurance athletes remain unclear, but it cannot be excluded that they, at least partially, reflect dietary intake. Data from ICARE study on infants do not indicate associations between infant formula feeding-associated exaggerated dAGEs intake and insulin resistance or inflammatory status (Klenovics et al., 2013). However, it is to be mentioned that the effects of high dAGEs load in early infancy on health status in later life have not been studied. The study in 312 patients on renal replacement therapy with hemodialysis, showed that patients with low C-reactive protein and high CML levels or high AGE-associated fluorescence of plasma had the best 8

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higher energy intake. The same group reported no significant changes in BMI, insulin sensitivity, leptin and adiponectin levels in healthy individuals subjected for 4 months to isocaloric diet with either high- or low-AGEs content (Uribarri et al., 2014). Effects of dAGE load on inflammatory markers are controversial. In healthy older subjects, neither AGEs-rich, nor AGEs-restricted diet had significant impact on inflammatory mediators (e.g. C-reactive protein – CRP, interleukine-6 – IL6, tumor necrosis factor-α - TNF-α receptors I and II, vascular adhesion molecule-1 – VCAM) after 6 weeks of intervention (Semba et al., 2014). In a 2-weeks long cross-over study, 8isoprostanes and VCAM levels decreased after consumption of AGEsrestricted diet, while decline in CRP was observed only in the study with parallel setting, in subjects consuming AGEs-restricted diet for 6weeks (Vlassara et al., 2009). Studies in overweight subjects reported no significant changes in inflammatory markers (e.g. IL6, CRP, TNF-α, monocyte chemoattractant protein-1) regardless of dietary intervention (Baye et al., 2017; Harcourt et al., 2011). In diabetic patients, 2-weeks long administration of diet either rich or restricted in dAGES in a crossover design did not affect C-reactive protein levels significantly, while in the 6 weeks-long trial with a parallel design, levels of C-reactive protein decreased from baseline after consumption of AGEs-restricted diet and increased after consumption of AGEs-rich diet (Vlassara et al., 2002). Regarding oxidative status markers, plasma lipid peroxidation products (measured as malondialdehyde levels or thiobarbituric acid reactive substances), reduced glutathione concentration, antioxidant power of plasma and activities of antioxidant enzymes in erythrocytes were not affected significantly by either diet in healthy adolescents or young adults; while concentrations of antioxidant vitamins – C and E – decreased under consumption of AGEs-rich diet (Birlouez-Aragon et al., 2010b; Seiquer et al., 2008). However, the ability of plasma to suppress lipid peroxidation, was significantly higher when the adolescents consumed the AGEs-rich diet (Seiquer et al., 2008). In healthy subjects, overweight patients with metabolic syndrome and type 2 diabetic subjects, intervention with AGEs-restricted diet associated with a decline in 8-isoprostane levels (Vlassara et al., 2009; Uribarri et al., 2011; Vlassara et al., 2016), while an increase has been reported after intake of AGEs-rich diet (Uribarri et al., 2011; Vlassara et al., 2016). Two studies in which concentrations of soluble RAGE and endogenous secretory RAGE in response to dietary intervention were determined, reported no significant changes either after AGEs-restricted or AGEs-rich diet consumption (Semba et al., 2014; Harcourt et al., 2011). These findings might reflect the fact that neither free AGEs, nor AGE-peptides interact with RAGE and suggest that dietary AGEs are not determinants of circulating RAGE levels. Taken together, dAGEs load per se probably does not affect significantly obesity-associated anthropometric variables, blood pressure and lipid profile in humans. Available data suggest that restriction of dAGEs load might associate with better insulin sensitivity. However, fatness, insulin sensitivity, adipokines, inflammatory markers and those of oxidative status are interrelated. These outcomes are seldom reported concurrently, single reports yield dissimilar outcomes, and data are not subjected to multivariate analyses and corrected for confounders. Thus, available data do not allow drawing unequivocal conclusions on the impact of dAGEs on insulin sensitivity and associated markers. However, potential effect of dAGEs on insulin sensitivity should not be neglected. Free AGEs and AGE-peptides accumulate in liver and muscle – at least in rodents (Miyata et al., 1998; Tessier et al., 2016). Data on accumulation in fat are contradictory – CML was shown to accumulate particularly in the visceral fat in humans (Gaens et al., 2014), but has not been observed in mice (Tessier et al., 2016). The liver, skeletal muscle, and adipocytes manifest resistance to insulin, features characteristic to type 2 diabetic subjects, and also commonly observed in nondiabetic subjects displaying overweight, obesity or metabolic syndrome (DeFronzo and Ferrannini, 1991). Mechanisms by which modification of target tissues by dAGEs potentially affects insulin

2016). However, dietary energy intake in subjects on AGEs-restricted diet was significantly lower compared with their peers on AGEs-rich diet. In obese males consuming calories- and AGEs-restricted diet for 3 months, intervention resulted in decline in body weight, BMI and waist circumference (Macias-Cervantes et al., 2015). In other studies that reported anthropometric data, no significant differences were observed, regardless of dAGEs load (de Courten et al., 2016; Seiquer et al., 2014; Harcourt et al., 2011; Vlassara et al., 2002; Uribarri et al., 2014). Regarding the other components of metabolic syndrome, e.g. atherogenic lipid profile and elevated blood pressure, in healthy young subjects, 4-weeks-long consumption of AGE-rich diet associated with a rise in cholesterol and triacylglycerol levels (Birlouez-Aragon et al., 2010b), but in this study AGE-rich diet also contained higher proportion of fats. In older healthy subjects, triacylglycerols increased and HDL-cholesterol levels declined after 12-months-long consumption of energy restricted AGEs-rich diet, while in the arm on AGEs-restricted diet, HDL-cholesterol levels increased (Vlassara et al., 2016). Several studies did not report any significant effect of either diet on lipid profile (Baye et al., 2017; Seiquer et al., 2014; Mark et al., 2014; MaciasCervantes et al., 2015; Vlassara et al., 2002; Vlassara et al., 2009; Uribarri et al., 2014). Moreover, liver function – as monitored by plasma activity of liver enzymes and total bilirubin levels – showed no significant changes under either diet (Seiquer et al., 2014). Data on blood pressure effects of dietary interventions with AGEs-restricted or AGEs-rich diets are reported seldom, but concordantly describe no significant effects (Baye et al., 2017; Macias-Cervantes et al., 2015; Vlassara et al., 2002; Vlassara et al., 2009; Vlassara et al., 2016). Although not explicitly indicated, subjects with elevated blood pressure were probably included only in one study (Macias-Cervantes et al., 2015). Except for obesity, insulin resistance is a central feature of metabolic syndrome. In overweight subjects or patients with type 2 diabetes, intake of an AGEs-restricted diet improved insulin sensitivity (Mark et al., 2014; Uribarri et al., 2011; Vlassara et al., 2016; de Courten et al., 2016), while an AGEs-rich diet associated in healthy or overweight subjects, and patients with diabetes with increased fasting plasma insulin and, or, decreased insulin sensitivity (Birlouez-Aragon et al., 2010b; Mark et al., 2014; Uribarri et al., 2011; Vlassara et al., 2016). However, two studies in older healthy subjects did not report significant effect of either diet on insulin sensitivity (Uribarri et al., 2014; Vlassara et al., 2016). Unfortunately, other studies either quoted only fasting glucose concentrations, which remained unaffected by either diet and were within the normal range or did not report data on glucose homeostasis (Semba et al., 2014; Macias-Cervantes et al., 2015; Harcourt et al., 2011). Normal fasting glucose concentrations are not indicative regarding incipient glucose homeostasis imbalance, since normoglycemia might be maintained on the account of increased insulin, denoting insulin resistance. Visceral adiposity is an independent negative predictor of adiponectinemia and a positive predictor of leptinemia (Yatagai et al., 2003; de Castro et al., 2015). Except for insulin, glucose homeostasis is regulated also by adipokines. In humans, reduction of adiponectin has been associated with insulin resistance, dyslipidemia, and atherosclerosis (Yadav et al., 2013). Leptin also increases insulin sensitivity, by decreasing adiposity and lipotoxicity, but also via insulin-independent action, both centrally (mainly in hypothalamus) and peripherally (in liver and skeletal muscle) (Paz-Filho et al., 2012). Only two studies reported simultaneously anthropometric data, those on insulin sensitivity and adipokines (Uribarri et al., 2014; Vlassara et al., 2016). Reduction in visceral fat area after 12 months of calories- and AGEs-restricted diet intake in obese subjects with metabolic syndrome associated, as expected, with improved insulin sensitivity, decline in leptin, and a rise in adiponectin concentrations (Vlassara et al., 2016). In the AGEs-rich arm, reduction of visceral fat area after intervention associated with increase in insulin resistance, rise in leptinemia and decline in adiponectin levels. However, AGEs-rich diet also imposed 9

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is a status of enhanced oxidative stress and microinflammation (Tilg and Moschen, 2006; McMurray et al., 2016), and often associates with deliberately flawed food intake behavior. Thus, it would be assumed that exaggerated formation of endogenous AGEs and increased intake of dAGEs in obese subjects would be reflected by elevated levels of circulating and tissue AGEs. Surprisingly, obese individuals present lower circulating FL and CML concentrations, lower AGEs-associated fluorescence of plasma, and lower levels of glycated albumin (Sebekova et al., 2009; Semba et al., 2011; Gaens et al., 2013; Nishimura et al., 2006). Low plasma CML levels have been attributed to accumulation of lipophilic CML in enlarged fat tissue (Semba et al., 2011; Gaens et al., 2013). Obesity-associated hyperfiltration could also contribute via enhanced urinary elimination of AGEs-modified peptides (Sebekova et al., 2009). However, recent experimental data in mice suggest that dCML does not accumulate in fat (Tessier et al., 2016). Association between undernutrition or malnutrition and circulating AGE levels remains unclear. On one hand, dAGEs are main contributors to plasma AGE levels. Thus, undernutrition and malnutrition should be accompanied with low circulating AGE levels. However, if undernutrition or malnutrition is caused by diseases inducing oxidative stress and inflammation, their association with elevated circulating AGE levels might be foreseen.

sensitivity require aimed research. Interpretation of the outcomes of randomized controlled trials on consumption of diets with different load of dietary AGEs is complicated. The first set of issues is related to the diet being administered. Only in few studies dCML content has been quantified using validated chromatographic methods coupled to MS/MS (Klenovics et al., 2013; Delgado-Andrade et al., 2012; Birlouez-Aragon et al., 2010b; Seiquer et al., 2006; Seiquer et al., 2014; Seiquer et al., 2008; Mark et al., 2014), in the remaining ones, dCML was either quantified using ELISA method, or calculated from available ELISA databases (Goldberg et al., 2004; Uribarri et al., 2010). In studies using ELISA methods, the real dCML load is uncertain. So far, the outcomes were reported only in relation to dCML load, thus the impact of the exposure to dietary CEL, MG-H1 or other dAGEs remains unknown. Diets rich in AGEs are often more calorie-dense compared with AGEs-restricted diets, and even if isocaloric diets are administered, AGE-rich ones generally contain higher amounts of fats (Birlouez-Aragon et al., 2010b; Seiquer et al., 2008; Mark et al., 2014). AGE-rich diets are prepared using higher temperatures, thus they almost certainly contain higher amounts of other potentially toxic heat-derived compounds (Capuano and Fogliano, 2011; Felton et al., 2007; Pouillart et al., 2008). Higher employed temperatures may lead to higher partial destruction of different thermo-labile essential nutrients (Birlouez-Aragon et al., 2010a; Seiquer et al., 2008). Thus, the outcomes measured can be hardly attributed solely to differences in dAGE content. Moreover, the dAGEs load between AGEsrich and AGEs-restricted diets varies between different studies, and the age and health status of probands differs, thus might potentially affect the outcomes. The other problems stem from a lack of consensus on standard protocols and Standard operating procedures in nutritional studies. Thus, it remains unclear whether essential fundamental data, such as anthropometric measures, blood pressure, or lipid profile, were not followed, or simply were not reported, even as supplementary data. Changes in special markers (e.g. adipokines, markers of inflammation or oxidative status, etc.) observed after dietary intervention, can hardly be attributed to the diet without considering alterations in elementary data – components of metabolic syndrome. Moreover, multivariate analyses, allowing for correction for confounders, are rarely used in statistical analyses of the dAGEs outcomes.

5.5. Dietary AGEs and neurological disorders of elderly Accumulation of AGEs is a normal feature of ageing. Numerous studies suggest that exaggeratedly accumulated AGEs may act as “gerontotoxins”. E.g., a common disorder of later life – decline in memory - associates with elevated systemic or brain levels of AGEs. In non-demented elderly individuals higher serum MGO concentrations associated with poorer memory, executive function, and lower brain grey matter volume (Srikanth et al., 2013). In similar populations, a faster rate of cognitive decline associated with higher circulating MGO concentrations, or higher urinary excretion of pentosidine at baseline (Beeri et al., 2011; Yaffe et al., 2011). Post-mortem study in elderly patients with cerebrovascular disease and cognitive dysfunction but only minimal Alzheimer pathology showed that immunostaining for CML in vessels and neurons in the cortex directly correlated with severity of cognitive impairment (Southern et al., 2007). Study of West et al. suggests that dAGEs could contribute to cognitive impairment, as in initially non-demented elderly subjects higher intake of dAGEs (estimated using ELISA database) associated with a faster rate of decline in memory over time (West et al., 2014). Neurodegenerative diseases such as Alzheimer's and Parkinson's disease associate with significantly accelerated accumulation of AGEs in brain tissue and in cerebrospinal fluid (Munch et al., 2012; Salahuddin et al., 2014). In the model of Alzheimer's disease (Tg2576 mice), AGErich diet worsened the spatial and learning memory (Lubitz et al., 2016). High intake of dAGEs was reflected by elevation of serum MGO and CML, increase in AGE-immunostaining in insoluble amyloid-β fraction from hippocampus, and hippocampal amyloid-β correlated significantly with urinary MGO. These negative effects were not observed in the Tg2576 mice administered diet low in AGEs (Lubitz et al., 2016).

5.3. Consequences of a life-long consumption of AGE-rich diet in animal models Exposition of type 1 diabetic NOD mice to low-AGE vs. nutritionally similar high-AGE diet with about 5-fold higher dCML content, postponed and suppressed the manifestation of diabetes in the founder (F0) generation, as well as the F1 and F2 offspring (Peppa et al., 2003). While 76% of the founder mice fed the low-AGEs diet were alive up to 56 weeks, none of the AGEs-rich diet fed mice survived after 44 weeks, including diabetic mice treated with insulin (Peppa et al., 2003). While a life-long calorie restriction (of about 40% calories/day) significantly prolonged the life-span in mice, survival of animals consuming similarly calorie-restricted but AGEs-rich diet tended to be shorter compared with that of mice consuming a regular diet (Cai et al., 2008). In comparison with a standard diet, consumption of calorie-restricted AGEs-rich diet imposed about 70% higher daily dCML load. In both studies, ELISA method was used to determine dCML content.

6. Is it rationale to recommend and feasible to accomplish selective reduction of dAGEs intake?

5.4. Increased cardiometabolic risk in presence of low circulating AGEs Since dAGEs have been labelled as “glycotoxins” decades ago, they are often referred to as substances exerting negative health effects, presumed to provoke oxidative stress and inflammation reactions in the body (Koschinsky et al., 1997). The Maillard reaction decreases proteins digestibility, and thus consumption of a diet rich in AGEs negatively affects protein availability (Mehta and Deeth, 2016; Seiquer et al., 2006). However, it is highly improbable that habitual consumption AGEs-rich diet would result in clinically manifested

Even subjects presenting low circulating AGE levels might manifest cardiometabolic risk factors. Epidemics of obesity recorded in recent decades worldwide are, among others, linked to virtually unlimited food availability (Cuschieri and Mamo, 2016). Obesity predisposes to manifestation of metabolic syndrome, which, in turn, represents a risk factor for development of type 2 diabetes, cardiovascular and other chronic degenerative diseases (Papakonstantinou et al., 2013). Obesity 10

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rodents (Peppa et al., 2003; Cai et al., 2008), question arises whether accelerated brain maturation is a forerunner of accelerated ageing. DAGEs load and concurrently that of other heat-derived neo-formed contaminants may be easily and effectively reduced using culinary techniques requiring lower heating temperatures, with higher moisture and preferably acidic pH, with minimized direct contact of food with a heat source (Chen and Smith, 2015; Lund and Ray, 2017). Thermallyinduced dietary losses of vitamins and other bioactive substances (Birlouez-Aragon et al., 2010b) might be compensated with a sufficient intake of fruits and raw vegetables. High levels of natural antioxidants might potentially ameliorate negative health effects of high dAGEs load (Sebekova et al., 2001b). In vitro studies also suggest that natural products might be promising anti- or de-glycating agents: plants-derived antioxidants and phytochemicals in fresh fruits and vegetables, fruit and vegetable seed extracts and herbs might exert protective role, acting (among others) as anti-glycating agents and mitigating the negative health effects of endogenous or exogenous AGEs (SadowskaBartosz and Bartosz, 2015; Ahmad and Farhan, 2016; Mesias et al., 2013; Sompong and Adisakwattana, 2015). At industrial scale, changing food production processes, technologies and formulation strategies to avoid excessive generation of compounds arising during heating should be achieved while keeping appealing characteristics of the products.

malnutrition. At present, no study clearly supports the assumption that dAGEs exert negative health effects. This discrepancy might partially stem from the fact that in studies on the health effects of foods processed under high vs. low temperature, the effects are generally referred to as associated with AGE-rich vs. AGE-poor diet intake. However, chemical characteristics of AGEs is insufficient, heating of foods leads to formation of numerous neo-formed substances and might result in degradation of different bioactive health promoting moieties (Capuano and Fogliano, 2011; Felton et al., 2007; Birlouez-Aragon et al., 2010b). Thus, dAGEs per se are probably not responsible for negative health effects of ingested thermally treated foods, as these effects might reflect the additive effects of concurrent dietary load with several potentially toxic compounds - ineffective if ingested separately, in under-threshold concentrations. Moreover, health-promoting effects of the final products of the Maillard reaction – melanoidins – has been documented (Morales et al., 2012; Delgado-Andrade and Fogliano, 2018; Tagliazucchi and Bellesia, 2015; Mesias and Delgado-Andrade, 2017). These questions could be elucidated in long-term studies focused on administration of single AGE-compounds, and their co-administration with different other thermal neo-formed contaminants. Health promoting effects of AGE-rich diets have been documented in experimental studies in rodents (Chuyen et al., 2005; Chuyen et al., 1990; Faist et al., 2002; Somoza et al., 2005; Bartling et al., 2011). In certain groups of healthy humans, high plasma AGE levels associate with low cardiometabolic risk (Klenovics et al., 2013; Sebekova et al., 2001b; Maessen et al., 2017), and in some patients' groups even with better prognosis (Bartling et al., 2011; Schwedler et al., 2002); and low circulating AGE levels might confer increased cardiometabolic risk (Sebekova et al., 2009; Semba et al., 2011; Gaens et al., 2013). Based on the current data, hard evidence to recommend dAGE restriction as a general health promoting nonpharmacological intervention is lacking. Moreover, in habitually consumed heat-treated food, the selective reduction of AGEs formation is hardly feasible. Nevertheless, diets prepared using culinary methods requiring less heating may have considerable health impact in patients suffering from diseases in which AGEs play a pathogenetic role, such as diabetes and its complications, renal insufficiency, certain neurodegenerative or inflammatory diseases, etc. Kellow and Coughlan (2015), Goh and Cooper (2008), Miyata et al. (2000), Heidland et al. (2001), Munch et al. (2012), and Toda et al. (2014). Recent data indicate that even pregnant women might benefit from the restriction of the intake of highly thermally processed foods. Frequent consumption of fried food pre-conceptionally and during pregnancy associated with a significantly greater risk of gestational diabetes mellitus (GDM) (Bao et al., 2014; Osorio-Yanez et al., 2017). Mothers presenting GDM have substantially increased risk of developing type 2 diabetes in later in life; and the risk of obesity, the metabolic syndrome, type 2 diabetes, impaired insulin sensitivity and secretion in offspring of mothers with GDM are 2-to-8-fold those in offspring of mothers without GDM (Damm et al., 2016). At the time of diagnosis of GDM (e.g. at 24–30th week of gestation), mothers with GDM have significantly (by about 38%) higher protein- and BMI-normalised CML levels compared to healthy pregnant controls (Bartakova et al., 2016). Consequences of prenatal challenge with highly thermally processed foods (rich in dAGES) or those of GDM-associated high maternal CML plasma concentrations on child health remain unknown. However, offspring of mice consuming during pregnancy a bread crustsenriched diet with about 60% higher CML content, manifest some physiological reflexes earlier than their peers from dams on standard chow. Young adult male offspring of dams consuming CML-rich diet were heavier and less insulin sensitive compared with their control counterparts. These effects were manifested in absence of maternal obesity and GDM, without a direct consumption of CML-rich diet by offspring (Csongova et al., 2018). Earlier manifestation of neurological reflexes might indicate accelerated brain maturation. As a life-long consumption of AGEs-rich diet associates with shorter life-span in

7. Summary and perspectives Recent decades brought considerable progress into analysis of dAGEs and understanding of their bioavailability and biological effects. Regarding human studies, we learned that dAGEs and are major contributors to the body's AGE pool. Current data do not allow clear distinguishing of the association between low or high circulating AGE levels, or AGEs-rich or restricted diets intake, regarding positive or negative health outcomes. Experimental studies in rodents documented that after digestion of AGE-modified proteins, free AGE-adducts and AGE-peptides are partially absorbed into circulation, and despite their rapid excretion via urine, they, at least ad interim, accumulate in the body. The pattern of organ accumulation of CML after sub-acute exposure of mice to dietary protein-bound CML has been described in detail (Tessier et al., 2016). This breakthrough discovery brought, as expected, several questions. Physical-chemical nature of tissue binding of AGEs absorbed from diet is not known, and the background of clearly different affinity of dCML to different tissue proteins remains unclear. It is not known, whether trapped dCML remains stacked in tissues for ad interim, or whether the accumulation is of a prolonged duration, and in which tissue structures or cell types dCML accumulates. The study with labelled CML (Tessier et al., 2016), tracking the fate of dCML in organism, did not linked organ accumulation to specific biological effects, such as those on glucose homeostasis, lipid profile, inflammatory and oxidative status, adipokines, adhesion molecules, etc. Lacking cause-and-effect information contributes to uncertainty on real harmful effects of dAGEs per se. If the assumptions on undesirable effects of accumulation of dAGEs within the tissues are confirmed, the question arises by what mechanisms they are caused, since it is assumed that absorbed dAGEs do not bind to tissue RAGEs. Thus, analysis of the expression of genes and proteins of different potentially affected metabolic pathways is of importance. Moreover, still unknown duration of tissue binding should be considered. Whether other dAGEs, such as e.g. arginine adducts abundant in foods, would display similar distribution pattern to that observed under consumption of dCML, and whether their organ accumulation could be linked to specific biological effects, remains unclear. We neither know, how would concurrent administration of proteins modified with different defined dAGEs accumulate in vivo, as both free adducts and AGE-peptides of different chemical structure might either display completely different affinity to different tissue proteins or behave competitively. Thus, we do not know whether the effects of 11

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References

simultaneous accumulation of different dAGEs would induce different biological effects. Since renal elimination of AGEs seems to be a saturable process (Delgado-Andrade et al., 2012), described patterns of dCML accumulation in organs after sub-chronic administration of dCML in pharmacological dosage might not reflect organ accumulation pattern resulting from real-time long-term, low-dose exposure. As heatprocessing of foods gives rise to different potentially toxic compounds, studies on the effects of co-administration of dAGEs with other potentially toxic compounds, in pathophysiologically relevant dosages, would be extremely important. To elucidate these questions and to confirm specific biological effects of dAGEs accumulated within the body, feeding experiments with well-defined free and protein-bound AGEs, dosed in amounts realistically approximating human exposure, are needed. Synthesis of well-defined or even labelled free-, peptides-, or protein-bound AGEs is currently possible, but production in large scale needed for prolonged feeding experiments might still be complicated. Moreover, long-term animal studies are time consuming and costly, and additional - not negligible - financial demands concern reliable quantification of AGEs in biological matrices, currently available only in few laboratories worldwide. Despite that results obtained in rodents cannot be straightforwardly translated into humans, well designed experimental trials with reliable analytical methods to quantify AGEs as well as biological markers, are extremely important to estimate potential impact and pathophysiological consequences of oral load with dAGEs in humans. Considering the continuously increasing consumption of Western type of diets and “fast foods” worldwide, targeted research is required to elucidate the impact of habitual intake of dAGEs, as well as dAGEs restriction, particularly in vulnerable populations, such as children, adolescents, seniors, and patients suffering from diseases in which AGEs play a pathogenetic role. Particularly, complex reporting of findings (e.g. including data not affected significantly but in relation to endpoints), and complex analyses of outcomes corrected for several confounders, are needed to distinguish whether potential effects of dAGEs consumption are independent contributors to the end-points. Thus, findings in clinical studies on effects of dAGEs load are to be evaluated complexly and discussed critically. Based on recent data, research should tackle the potential consequences of pre- and peri-natal exposure to dAGEs on susceptibility to develop non-communicable and neurodegenerative diseases in later life, also regarding potential sex differences in adverse metabolic responses to maternal AGE-rich diet. Another field requiring attention are potential differences in health effects of high dAGEs load in young vs. old subjects; as well as appetiteenhancing effects of flavourful dAGEs, which might promote food overconsumption and contribute to the addictive qualities of highly processed foods. Taken together, it still remains unclear whether habitual dAGEs load per se exerts negative health effects in humans.

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Funding This review was elaborated in frames of the project supported by the grant from Ministry of Education, Science, Research and Sport of the Slovak Republic (VEGA 1/0062/2016).

Author contributions KŠ made the literature search and prepared the manuscript. KBŠ participated in the edition of the final version of the manuscript.

Conflicts of interest The authors declare no conflict of interest. 12

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