The "endogenous" Maillard reaction, that is, the formation of Maillard reaction products in vivo, commonly known as the "glycation" reaction, is recognized today as one of many non-enzymatic modifications of proteins that not only contribute to the aging of the body's proteins, but may also have an important regulatory role in both physiological responses and pathological processes . A major outcome of the studies on glycation was the recognition that oxidative reactions, and by inference, oxidative stress and ROS, catalyze the chemical modification of proteins by Maillard reactions in vivo. Reactive carbonyl species formed upon oxidation of carbohydrates, as well as lipids and amino acids were identified as intermediates in the formation of irreversible, advanced glycoxidation end products (AGEs) and advanced lipoxidation end products (ALEs) acting on proteins (see Box 10.4).
The first stage of the classical Maillard reaction is the formation of a Schiff base and Amadori adducts between reducing sugars and free amino groups in proteins (see Box 2.3). The Amadori adduct formed from glucose in vivo undergoes non-oxidative rearrangement and hydrolysis reactions, releasing 1- and 3-deoxygluco-sones (1DG, 3DG), hence preserving the carbon skeleton of the sugar. Schiff base and Amadori adduct also undergo facile oxidation, however, especially in the presence of transition metal ions, and subsequently fragment to yield shorter chain sugars and reactive intermediates, such as glyoxal (GO) and methylglyoxal (MGO). Interestingly, both glucosone (GLO) and GO are also produced by peroxynitrite-mediated oxidation of glucose.
These reactive dicarbonyl compounds, described as intermediates formed during the second stage of the Maillard reaction, react with lysine and arginine (and other amino acid) residues in proteins to produce a wide range of protein-bound AGEs and crosslinks during the third and final stage of the classical scheme of the reaction.
In addition to the multiplicity of AGE structures, it is now acknowledged that there are multiple pathways for formation of AGEs from reducing sugars: some proceed from the Amadori compound, while others proceed from the Schiffbase or by direct autoxidation of carbohydrates (autoxidative glycosylation). Some AGEs, such as the fluorescent vesperlysines and crosslines, retain the intact carbon structure of glucose and thus they appear to be directly derived from glucose. In contrast, formation of pentosidine, another AGE from glucose, requires oxidative cleavage and loss of one carbon atom; analysis of the valency of carbon atoms indicates that formation of pentosidine from pentoses also requires oxidation. In contrast, formation of pyrraline and crosslines from glucose seems to be a non-oxidative process. Other AGEs, such as N-e-(carboxymethyl)lysine (CML) and N-e-(carboxyethyl)lysine (CEL), require oxidative fragmentation of the carbon skeleton of glucose, but may also be formed from other hexoses, pentoses, glycolytic intermediates or ascorbic acid.
The term "glycoxidation product" was originally introduced to characterize products formed by sequential glycation and oxidation reactions. There is also increasing evidence  that lipids are as important as carbohydrates in the chemical modification of tissue proteins and the development of pathology. The chemical modification of proteins is, in both cases, primarily the result of carbonylamine chemistry or, in a broader sense, the reaction of nucleophilic groups on proteins (e.g. the side-chains of lysine, arginine, histidine and cysteine) with electrophilic carbohydrates, lipids and their derivatives (e.g. hydroxyaldehydes, dicarbonyls, hydroxyalkenals and epoxides). Thus, Maillard type reactions may be seen as uncatalyzed chemical reactions of proteins with substrates and intermediates in metabolism that, in addition to direct oxidative damage, also affect the physico-chemical and biological properties of target proteins.
Reactive carbonyl species also react with DNA , causing mutations both in nDNA and mtDNA [120, 121], and inhibit complex I, increasing free radical leakage . Moreover, hyperglycemia stimulates inflammatory processes  through the activation ofspecific receptors for AGE products called RAGE (receptors for advanced glycoxidation end products).
Different phenomena relate AGE products to aging: (1) pentosidine concentration in the skin is negatively correlated with MLSP in mammals ; (2) AGE products accumulate in the extracellular matrix during aging ; (3) dietary restriction reduces glycation in rodents [124-126]; (4) sugar-enriched diets decrease rodent longevity ; and (5) AGE products are linked to different age-related diseases such as Parkinson's disease, cataracts, diabetes, atherosclerosis and Alzheimer's disease .
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