Effects of Toxic AGEs (TAGE) on Human Health

Abstract

The habitual and excessive consumption of sugar (i.e., sucrose and high-fructose corn syrup, HFCS) is associated with the onset and progression of lifestyle-related diseases (LSRD). Advanced glycation end-products (AGEs) have recently been the focus of research on the factors contributing to LSRD. Approaches that inhibit the effects of AGEs may be used to prevent and/or treat LSRD; however, since the structures of AGEs vary depending on the type of reducing sugars or carbonyl compounds to which they respond, difficulties are associated with verifying that AGEs are an etiological factor. Cytotoxic AGEs derived from glyceraldehyde, a triose intermediate in the metabolism of glucose and fructose, have been implicated in LSRD and are called toxic AGEs (TAGE). A dietary imbalance (the habitual and excessive intake of sucrose, HFCS, or dietary AGEs) promotes the generation/accumulation of TAGE in vivo. Elevated circulating levels of TAGE have been detected in non-diabetics and diabetics, indicating a strong relationship between the generation/accumulation of TAGE in vivo and the onset and progression of LSRD. We herein outline current findings on "TAGE as a new target" for human health.

Keywords: advanced glycation end-products (AGEs); healthy life expectancy; human health; lifestyle-related diseases (LSRD); toxic AGEs (TAGE).

Figure 1

TAGE as a new target for human health. AD: Alzheimer’s disease; CRC: colorectal cancer; CVD: cardiovascular disease; DM: diabetes mellitus; NASH: non-alcoholic steatohepatitis; NBNC-HCC: non-B or non-C (NBNC)-hepatocellular carcinoma; TAGE: toxic advanced glycation end-products.

Figure 2

Routes for the production of advanced glycation end-products (AGEs) in the human body. DHA-P: dihydroxyacetone-phosphate; HbA1c: hemoglobin A1c; GO-AGEs: glyoxal (GO)-derived AGEs; Glycol-AGEs: glycolaldehyde-derived AGEs; CML: Nε-(carboxymethyl)lysine; Glu-AGEs: glucose-derived AGEs; MGO-AGEs: methylglyoxal (MGO)-derived AGEs; 3-DG-AGEs: 3-deoxyglucosone (3-DG)-derived AGEs; GA-AGEs: glyceraldehyde (GA)-derived AGEs; Fru-AGEs: fructose-derived AGEs; GOLD: GO-lysine dimer; G-H1: GO-derived hydroimidazolone 1; GA-pyridine: glycolaldehyde-derived pyridine; DOLD: 3-DG-lysine dimer; CEL: Nε-(carboxyethyl)lysine; MOLD: MGO-lysine dimer; MG-H1: MGO-derived hydroimidazolone 1; GLAP: glyceraldehyde-derived pyridinium; TAGE: toxic AGEs; P-NH₂: free amino residue of a protein.

Figure 3

The onset and progression of lifestyle-related diseases (LSRD) are associated with the habitual excessive intake of sugars and/or dietary AGEs. TAGE are produced from the metabolite of glucose, the main component of rice, bread, and noodles, as well as the metabolites of sugars (sucrose and HFCS) added to beverages and processed foods. Fluctuations in TAGE levels in the human body are closely associated with dietary habits. The chronic intake of excessive amounts of SSB, processed foods, and/or rice/bread/noodles, which is characteristic of the modern daily diet, increases the cellular levels of the sugar metabolite glyceraldehyde (GA), which promotes the production of TAGE from intracellular proteins. Elevated levels of TAGE damage cells, which results in the leakage of TAGE into the circulation, thereby increasing circulating TAGE levels. Moreover, the habitual and excessive consumption of excessive dietary AGEs (mainly Glu-/Fru-AGEs) promotes the accumulation of TAGE and up-regulates the expression of RAGE, resulting in TAGE-RAGE interactions. Activation of the TAGE-RAGE axis leads to the production of ROS, which up-regulate the expression of RAGE and promote the generation of TAGE, which have been implicated in the onset and progression of LSRD. 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.