Glycation and receptors: coming of AGE in the midst of danger.

The formation of advanced glycation end products (AGEs), first described in food science, is driven by hyperglycaemia (diabetes mellitus) and the modifications on long-lived proteins (natural ageing); AGE formation is enhanced by oxidative stress and inflammation, which are factors that accompany high-AGE settings of diabetes mellitus and ageing. Exogenous tobacco, ultra-processed foods, pollutants and alcohol contribute to AGE formation. Evidence demonstrates higher concentrations of AGEs in the blood and tissues of patients with diabetes mellitus than in samples from healthy control individuals. Despite AGE receptors mediating clearance and detoxification, the production and accumulation of AGEs persist in chronic diseases, facilitating their access to signal transduction receptors, such as receptor for AGE (RAGE). AGE-RAGE interaction accelerates atherosclerosis, diabetic kidney disease and bone, retinal and cardiac disease, as well as other complications. The discovery that the cytoplasmic tail of RAGE interacts with the formin diaphanous 1 sheds light on mechanisms of RAGE signal transduction. Although pharmacological targeting of AGEs has been tested in clinical trials, the lack of statistically significant benefits suggests that AGEs might not be the sole pathogenic species in chronic disease. Indeed, AGEs are members of a family of damage-associated molecular patterns. Hence, in the midst of cellular stress, effective therapeutic strategies seem to require broad approaches to targeting AGEs and their consequences, such as through blockade of AGE-receptor interactions.