Toxic advanced glycation end-products (TAGE) are major structures of cytotoxic AGEs derived from glyceraldehyde

Abstract

The habitual overconsumption of sugars has been implicated in the onset and/or development of lifestyle-related diseases (LSRD). Advanced glycation end-products (AGEs) have recently been proposed as one of the factors contributing to LSRD. Therefore, strategies that reduce AGEs may be used to effectively prevent and treat LSRD. AGE structures vary according to the types of reducing sugars/carbonyl compounds with which they react; therefore, the AGE structure primarily responsible for LSRD remains unknown. Among the various AGEs produced in the human body, glyceraldehyde (GA)-derived AGEs (GA-AGEs) exert strong cytotoxic effects that contribute to the onset/development of LSRD. The dysregulated metabolism of glucose/fructose associated with modern diets promotes the binding of excessive GA generated in cells to intracellular proteins, which results in the production and accumulation of GA-AGEs and, thus, many types of cellular damage. The toxic AGEs (TAGE) theory originated from our findings. The hypothesis proposed herein is that strongly cytotoxic TAGE structures are GA-derived 1,4-dihydropyrazine compounds, which differ from the known structures of GA-AGEs (i.e., GA-derived pyridinium compound, trihydroxy-triosidine, and pyrrolopyridinium lysine dimer derived from GA).