**2. Glycation stress**

Glycation stress is a general concept of biological stress caused by a series of glycation reactions, including AGEs formation, AGEs accumulation, glycationassociated dysfunction of proteins and cellular signaling, inflammation, oxidation, and/or tissue damage (**Figure 1**).

Protein glycation is a complex series of sequential reactions collectively called the Maillard reaction, which is named after the French chemist Louis Camilli Maillard. The Maillard reaction is divided into three stages, early (the formation of reversible Schiff base and rearrangement to Amadori products), intermediate (the formation of unstable AGEs precursors), and late (the formation of irreversible AGEs products). At the early stage, the carbonyl group of the reducing sugar reacts with the α-amino group at the N-terminal of protein or the ε-amino group of lysine or arginine residue, resulting in a formation of Schiff-base intermediates, followed by a rearrangement to Amadori products, relatively stable ketoamine. Amadori products in the living body include hemoglobin A1c and glycoalbumin. At the intermediate stage, the reaction proceeds and produces highly reactive dicarbonyl intermediates such as 3-deoxyglucosone and methylglyoxal. These intermediates are up to 20,000 times more reactive than glucose in glycation reactions [18]. At the late stage, the intermediates undergo complex reactions such as oxidation, dehydration, condensation, and cleavage to form stable AGEs, with a variety of physicochemical characteristics such as brown color, fluorescence, and cross-linking. Glycation of protein is a post-translational modification that progresses non-enzymatically, unlike enzymatic glycosylation, phosphorylation, acetylation, and glycosylation. Among more than 20 types of AGEs identified in vivo, methylglyoxal-derived hydroimidazolone (MG-H1) and Nε-carboxymethyllysine (CML) are likely the most abundant [19, 20].

Intracellular protein glycation can cause changes in the protein structure due to covalent cross-linking, resulting in the formation of protein misfolding and aggregation [21]. Although these unfunctional proteins are usually degraded through

**Figure 1.** *Conceptual diagram of glycation stress.*

*The Effect of Glycation Stress on Skeletal Muscle DOI: http://dx.doi.org/10.5772/intechopen.97769*

ubiquitin-proteasome system, AGEs-modified protein is the lack of free lysine residue needed for ubiquitin conjugation, preventing protein ubiquitination and subsequent its degradation by proteasome [22]. In addition, enzymes present in the ubiquitin-proteasome system and lysosomal proteolytic system are also undergone glycation [23]. Thus, intracellular glycation disrupts proteostasis, inducing cell apoptosis, and thereby increasing the risk of disorders.

On the other hand, extracellular AGEs stimulate several signaling pathways by a series of cell surface receptors. The most studied of which is receptor for AGEs (RAGE), a multi-ligand member of the immunoglobulin superfamily [24]. The activation of AGEs-RAGE axis causes the onset of several diseases, including diabetic complications, cardiovascular disease, Alzheimer's disease, and osteoporosis, by inducing inflammation and the production of reactive oxygen species [25–28]. RAGE is widely expressed in various cells and organs, can be upregulated under pathological conditions where AGEs are increased, and participate in those aging-related pathophysiologies [29]. On the other hand, other groups of cellsurface receptors of AGEs with opposite functions to RAGE, including AGE-R1/ Oligosaccharyltransferase 48 KDa Subunit, AGE-R2/protein kinase C substrate 80 K-H, and AGE-R3/galectin-3, and scavenger receptor families act as regulators of endocytosis and clearance of AGEs [30, 31]. These receptors can suppress AGEs-RAGE interaction, but their expressions and functions are impaired during aging and under higher levels of oxidative stress [30]. There is an inverse relationship between AGE-R1 expression and AGEs toxicity [30].

## **3. Dietary AGEs**

AGEs are not only produced endogenously; we ingested them from diet. AGEs content of food depends on the content of protein, fat, and sugar and the types of processing and cooking methods, predominantly on the temperature and duration of preparation [32]. High temperatures during various processes like baking, roasting, frying and grilling promote glycation in food. Scheijen et al. [33] analyzed the content of CML, Nε-carboxyethyllysine (CEL), MG-H1 in the protein fraction of the 190 food items by UPLC-MS/MS, and they showed that CML and CEL were contained in <7 mg/100 g in high-content foods such as fried bacon, chocolate, and peanut butter. The content of MG-H1 was higher compared to those of CML and CEL, and it was <65 mg/100 g in high-content foods such as black pudding, peanut butter, cereals, and biscuit.

Proteins are digested into amino acids and small peptide in the gastrointestinal tract. Therefore, dietary AGEs are expected to be absorbed in the circulation mostly in the form of free AGEs and AGEs-modified peptides. The amount of AGEs absorbed in the circulation was estimated to be 10% in healthy people; 1/3 of the absorbed AGEs are excreted in urine within 48 hours and 2/3 remained in the body [34]. For healthy people, a daily AGEs intake of around 9,000–23,000 kU/day was determined [32]; one AGE Unit was defined as the amount of antibody-reactive material that was equivalent to that in 1 μg of an AGEs-BSA standard. The AGEs content of major meals [35] is listed in **Table 1**.

A cross-sectional study revealed that higher levels of dietary AGEs were associated with higher levels of free plasma and urinary AGEs [36]. In addition, a tracer study using 13C2-CML found that dietary CML was accumulated in kidney, ileum, colon, lung, brain, testis, heart muscle, skeletal muscle, and liver, but not in fat [37], suggesting the contribution of dietary AGEs to tissue dysfunction and development of diseases. In fact, a meta-analysis of 13 randomized controlled trials showed a decrease in metabolic parameters including body weight, insulin resistance, total


#### **Table 1.**

*AGEs content in meals.*

cholesterol, low-density lipoprotein, and leptin and an increase in adiponectin levels after consumption of low AGEs diets compared to high AGEs diets [38, 39]. This study indicates that the restriction of AGEs from food can be effective in reducing the incidence of chronic metabolic diseases and promoting health.
