Toxic AGEs (TAGE) Cause Lifestyle-Related Diseases

Abstract

Advanced glycation end-products (AGEs) play a role in the onset/progression of lifestyle-related diseases (LSRD), suggesting that the suppression of AGE-induced effects can be exploited to prevent and treat LSRD. However, AGEs have a variety of structures with different biological effects. Glyceraldehyde (GA) is an intermediate of glucose, and fructose metabolism and GA-derived AGEs (GA-AGEs) have been associated with LSRD, leading to the concept of toxic AGEs (TAGE). Elevated blood TAGE levels have been implicated in the onset/progression of LSRD; therefore, the measurement of TAGE levels may enable disease prediction at an early stage. Moreover, recent studies have revealed the structures and degradation pathways of TAGE. Herein, we provide an overview of the research on TAGE. The TAGE theory provides novel insights into LSRD and is expected to elucidate new targets for many diseases.

Keywords: TAGE degradation pathway; TAGE structures; advanced glycation end-products (AGEs); lifestyle-related diseases (LSRD); toxic AGEs (TAGE).

Figure 1

Glycation reaction (Maillard reaction).

Figure 2

Overview of the various AGE production pathways in the body and major AGE structures. G-6-P, glucose-6-phosphate; F-6-P, fructose-6-phosphate; F-1,6-BP, fructose-1,6-bisphosphate; GA-3-P, glyceraldehyde-3-phosphate; F-1-P, fructose-1-phosphate; GO, glyoxal; GO-AGEs, glyoxal-derived AGEs; Glycol-AGEs, glycolaldehyde-derived AGEs; CML, N^ε-(carboxymethyl)lysine; Glu-AGEs, glucose-derived AGEs; 3-DG, 3-deoxyglucosone; 3-DG-AGEs, 3-deoxyglucosone-derived AGEs; MGO, methylglyoxal; MGO-AGEs, methylglyoxal-derived AGEs; GA, glyceraldehyde; GA-AGEs, glyceraldehyde-derived AGEs; Fru-AGEs, fructose-derived AGEs; G-H, GO-derived hydroimidazolone; GOLD, GO-lysine dimer; 3-DG-H, 3-DG-derived hydroimidazolone; DOLD, 3-DG-lysine dimer; MG-H1, MGO-derived hydroimidazolone 1; ArgP, argpyrimidine; CEL, N^ε-(carboxyethyl)lysine; MOLD, MGO-lysine dimer; TAGE, toxic AGEs; GLAP, glyceraldehyde-derived pyridinium; PPG, pyrrolopyridinium lysine dimer derived from glyceraldehyde.

Figure 3

Overview of the known GA-AGE and TAGE formation pathways. GA, glyceraldehyde; P-NH₂, a free amino residue of a protein; GLAP, glyceraldehyde-derived pyridinium; PPG, pyrrolopyridinium lysine dimer derived from glyceraldehyde; TAGE, toxic AGEs.

Figure 4

Estimated TAGE structures. (A) Dimer structure, 1,4-di(5-amino-5-carboxypentyl)-2,5-dihydroxymethyl-1,4-dihydropyrazine; Trimer structure, 1,4-di(5-amino-5-carboxypentyl)-5-(5-amino-5-carboxy-pentylaminomethyl)-2-hydroxymethyl-1,4-dihydropyrazine. (B) Left, Coomassie brilliant blue (CBB) staining; Right, Western blot analysis using an anti-TAGE antibody.

Figure 5

TAGE theory in LSRD. Habitual intake of sugar/HFCS and dietary AGEs causes excessive production of intracellular GA by activating the Glu/Fru metabolic pathway. GA binds to intracellular proteins to generate and accumulate TAGE, a type of GA-AGEs, which causes cell damage and cell death due to a decrease in proteostasis. As a result, TAGE leak out of cells and contribute to the onset/progression of LSRD, coupled with the action of the RAGE. Furthermore, since fluctuations in the blood TAGE levels are strongly correlated with the onset/progression of LSRD, including pre-disease states, it is expected that the onset of diseases can be predicted. This insight may support the prevention of LSRD and the extension of a healthy lifespan. SSB, sugar-sweetened beverages; HFCS, high-fructose corn syrup; AGEs, advanced glycation end-products; GA, glyceraldehyde; TAGE, toxic AGEs; RAGE, receptor for AGEs; ROS, reactive oxygen species; LSRD, lifestyle-related diseases; P-NH₂, free amino residue of protein.

Figure 6

Overview of the TAGE degradation pathway. GA, glyceraldehyde; TAGE, toxic AGEs; Ubi, ubiquitin; CHK1, checkpoint kinase 1; SPRTN, Spartan protease; p62, p62/SQSTM1.