Toxic AGEs (TAGE) theory: a new concept for preventing the development of diseases related to lifestyle
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Diabetology & Metabolic Syndrome Open Access
REVIEW
Toxic AGEs (TAGE) theory: a new concept for preventing the development of diseases related to lifestyle Masayoshi Takeuchi*
Abstract Background: The habitual excessive intake of sugar (i.e., sucrose and high-fructose corn syrup), which has been implicated in the onset of diabetes mellitus, induces excessive production of glyceraldehyde, a metabolite produced during glucose and fructose metabolism, in hepatocytes, neuronal cells, and cardiomyocytes. Main text: Toxic advanced glycation end-products (toxic AGEs, TAGE) are formed from reactions between glyceraldehyde and intracellular proteins, and their accumulation contributes to various cellular disorders. TAGE leakage from cells affects the surrounding cells and increases serum TAGE levels, promoting the onset and/or development of lifestyle-related diseases (LSRD). Therefore, serum TAGE levels have potential as a novel biomarker for predicting the onset and/or progression of LSRD, and minimizing the effects of TAGE might help to prevent the onset and/or progression of LSRD. Serum TAGE levels are closely related to LSRD associated with the excessive ingestion of sugar and/or dietary AGEs. Conclusions: The TAGE theory is also expected to open new perspectives for research into numerous other diseases. Keywords: Advanced glycation end-products (AGEs), Glyceraldehyde, Toxic AGEs (TAGE), Sucrose, High-fructose corn syrup (HFCS), Dietary AGEs, Lifestyle-related diseases (LSRD) Background Research on protein glycation (the Maillard reaction) began with the discovery of melanoidin by Maillard in 1912 [1]. The Maillard reaction was initially regarded as a browning reaction in the food chemistry field, and its effects on the taste of food have been studied. In 1968, hemoglobin A1c (HbA1c), an early glycation product, was first detected in the human body [2], while advanced glycation end-products (AGEs) were discovered by Cerami et al. in the 1980s [3]. The receptor for AGEs (RAGE) was cloned by Neeper and Schmidt et al. in 1992 [4], and RAGE transgenic mice were produced by Yamamoto et al. in 2001 [5]. AGE molecules, such *Correspondence: takeuchi@kanazawa‑med.ac.jp Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada‑machi, Ishikawa 920‑0293, Japan
as Nε-(carboxymethyl)lysine (CML) [6], pyrraline [7], and pentosidine [8], were subsequently identified, and the majority of anti-AGE antibodies used in 1996 were shown to recognize the CML structure [9]. Therefore, the concept that CML is the main structure of AGEs has spread worldwide. However, research into various anti-AGE antibodies by our group has demonstrated that AGE structures other than CML are more closely associated with clinical parameters [10]. We reported the concept of non-CML AGEs in 1999 [10], subsequently identified a non-CML AGE that exhibited strong cytotoxicity [11, 12], and proposed the hypothesis that “toxic AGEs (TAGE)” contribute to lifestyle-related diseases (LSRD) in 2004 [13]. The significance
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