Kidney, heart and brain: three organs targeted by ageing and glycation

Advanced glycation end-product (AGE) is the generic term for a heterogeneous group of derivatives arising from a non-enzymatic reaction between reducing sugars and proteins. In recent years, evidence has accumulated that incriminates AGEs in pathogenic processes associated with both chronic hyperglycaemia and age-related diseases. Regardless of their exogenous or endogenous origin, the accumulation of AGEs and their derivatives could promote accelerated ageing by leading to protein modifications and activating several inflammatory signalling pathways via AGE-specific receptors. However, it remains to be demonstrated whether preventing the accumulation of AGEs and their effects is an important therapeutic option for successful ageing. The present review gives an overview of the current knowledge on the pathogenic role of AGEs by focusing on three AGE target organs: kidney, heart and brain. For each of these organs we concentrate on an age-related disease, each of which is a major public health issue: chronic kidney disease, heart dysfunction and neurodegenerative diseases. Even though strong connections have been highlighted between glycation and age-related pathogenesis, causal links still need to be validated. In each case, we report evidence and uncertainties suggested by animal or epidemiological studies on the possible link between pathogenesis and glycation in a chronic hyperglycaemic state, in the absence of diabetes, and with exogenous AGEs alone. Finally, we present some promising anti-AGE strategies that are currently being studied. * AGE, : advanced glycation end-product; AGE-R, : AGE–receptor complex; BBB, : blood–brain barrier; CD, : cluster of differentiation; CKD, : chronic kidney disease; CML, : N e-carboxymethyl-lysine; ECM, : extracellular matrix; EGF, : epidermal growth factor; EMT, : epithelial-to-mesenchymal transition; FN3K, : fructosamine 3-kinase; FOXO4, : forkhead box protein O4; GEC, : glomerular endothelial cell; HbA1c, : glycated haemoglobin; IL, : interleukin; LDL, : low-density lipoprotein; MAPK, : mitogen-activated protein kinase; NF-κB, : nuclear factor-κB; RAGE, : receptor for AGE; RCEC, : rat microvascular endothelial cell; ROS, : reactive oxygen species; SIRT-1, : sirtuin 1 (silent mating type information regulation 2 homologue-1); SR, : sarcoplasmic reticulum; sRAGE, : soluble RAGE; TGF-β, : transforming growth factor β; TNF-α, : tumour necrosis factor α; VCAM-1, : vascular cell adhesion molecule-1; VEGF, : vascular endothelial growth factor