Serum Levels of Toxic AGEs (TAGE) May Be a Promising Novel Biomarker for the Onset/Progression of Lifestyle-Related Diseases

Abstract

Advanced glycation end-products (AGEs) generated with aging or in the presence of diabetes mellitus, particularly AGEs derived from the glucose/fructose metabolism intermediate glyceraldehyde (Glycer-AGEs; termed toxic AGEs (TAGE)), were recently shown to be closely involved in the onset/progression of diabetic vascular complications via the receptor for AGEs (RAGE). TAGE also contribute to various diseases, such as cardiovascular disease; nonalcoholic steatohepatitis; cancer; Alzheimer's disease, and; infertility. This suggests the necessity of minimizing the influence of the TAGE-RAGE axis in order to prevent the onset/progression of lifestyle-related diseases (LSRD) and establish therapeutic strategies. Changes in serum TAGE levels are closely associated with LSRD related to overeating, a lack of exercise, or excessive ingestion of sugars/dietary AGEs. We also showed that serum TAGE levels, but not those of hemoglobin A1c, glucose-derived AGEs, or Nε-(carboxymethyl)lysine, have potential as a biomarker for predicting the progression of atherosclerosis and future cardiovascular events. We herein introduce the usefulness of serum TAGE levels as a biomarker for the prevention/early diagnosis of LSRD and the evaluation of the efficacy of treatments; we discuss whether dietary AGE/sugar intake restrictions reduce the generation/accumulation of TAGE, thereby preventing the onset/progression of LSRD.

Keywords: Alzheimer’s disease (AD); advanced glycation end-products (AGEs); biomarker; cancer; cardiovascular disease (CVD); infertility; lifestyle-related diseases (LSRD); nonalcoholic steatohepatitis (NASH); receptor for AGEs (RAGE); toxic AGEs (TAGE).

Figure 1

Alternative routes for the generation of advanced glycation end-products in vivo: Reducing sugars, such as glucose, fructose, and glyceraldehyde, which are known to react non-enzymatically with the amino groups of proteins to form reversible Schiff bases and Amadori products/Heyns products. These early glycation products undergo further complex reactions, such as rearrangement, dehydration, and condensation, to become irreversibly cross-linked, heterogeneous fluorescent derivatives, termed advanced glycation end-products (AGEs). Glu-AGEs: glucose-derived AGEs; Fru-AGEs: fructose-derived AGEs; Glycer-AGEs: glyceraldehyde-derived AGEs; Glycol-AGEs: glycolaldehyde-derived AGEs; MGO-AGEs: methylglyoxal-derived AGEs; GO-AGEs: glyoxal-derived AGEs; 3-DG-AGEs: 3-deoxyglucosone-derived AGEs; CML: Nε-(carboxymethyl)lysine; P-NH2: free amino residue of a protein; AR: aldose reductase; SDH: sorbitol dehydrogenase; FK: fructokinase; HbA1c: hemoglobin A1c; TAGE: toxic AGEs.

Figure 2

Routes for in vivo TAGE generation: The chronic ingestion of excessive amounts of sugar-sweetened beverages (SSB) and commercial food products increases the levels of the sugar metabolite, glyceraldehyde in cells. The glyceraldehyde produced induces the generation of TAGE in intracellular compartments. As a result, TAGE accumulate in cells, cause cell damage, and leak into the blood, and, thus, TAGE levels in circulating fluids may be considered to increase. Furthermore, the chronic ingestion of excessive dietary AGEs (mainly Glu-/Fru-AGEs) increases the enhanced generation/accumulation of TAGE and the expression of RAGE, thereby leading to TAGE-RAGE interactions. Interactions between TAGE and RAGE alter intracellular signaling, gene expression, and the release of pro-inflammatory molecules and also elicit the generation of ROS in numerous types of cells, all of which may contribute to the pathological changes observed in lifestyle-related diseases. TAGE: toxic AGEs; RAGE: receptor for AGEs; ROS: reactive oxygen species; SSB: sugar-sweetened beverages; HFCS: high-fructose corn syrup; AR: aldose reductase; SDH: sorbitol dehydrogenase; FK: fructokinase; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; G-6-P: glucose-6-phosphate; F-6-P: fructose-6-phosphate; F-1,6-DP: fructose-1,6-diphosphate; F-1-P: fructose-1-phosphate; P-NH2: free amino residues of proteins.

Figure 3

(A) Average total AGE contents in commonly consumed beverages in Japan (modified from [104]). Beverages were classified according to the Japanese Agricultural Standard (JAS). Average total AGE contents in commonly consumed beverages in Japan (modified from [104]). Beverages were classified according to the Japanese Agricultural Standard (JAS); (B) Average total AGE contents in commonly consumed foods in Japan (modified from [104]). Foods were classified according to the Standard Tables of Food Composition 2009.

Figure 4

Average total sugar contents in commonly consumed beverages in Japan (modified from [103]). Beverages were classified according to the JAS.