The human erythrocyte can become both a metabolic “Achilles’ Heel” and a “Trojan Horse”: Likely consequences of persistent excessive glycolysis

There is convincing evidence that the glycolytic pathway whereby glucose is broken down to pyruvic acid and which occurs in most cells in the human body, is not necessarily a benign process. Much research has highlighted the deleterious effects of excessive glycolysis towards aging and lifespan [1-3], and the converse beneficial outcomes when glycolysis is partially suppressed [4-6]. The anti-aging effects of the mTOR inhibitor rapamycin can be explained, at least in part, by the fact that down-regulation of mTOR suppresses glycolysis and enhances mitogenesis and mitochondrial ATP synthesis, whilst upregulation of mTOR accelerates glycolysis [7-10]. This is because not only can glucose react non-enzymically with proteins to create advanced glycation endproducts (AGEs), but a number of the glycolytic intermediates are more reactive than glucose. The triose-phosphates, dihydroxyacetonephosphate (DHAP) and glyceraldehyde-3-phosphate (G3P), and their highly reactive decomposition product, methylglyoxal (MG), can all provoke synthesis of AGE (also called glycotoxins), following reaction with intracellular and extracellular proteins, nucleic acids and aminolipids [11-13]. Indeed, number of recent reviews and perspective pieces [14-16] have emphasized the role of dietary and endogenously generated glycotoxins inducing age-associated, deleterious effects throughout the body.