Review examines AGE–RAGE signalling and limits of therapeutic targeting in chronic disease

A review in Nature Reviews Endocrinology examines the formation of advanced glycation end products (AGEs), their receptors and potential therapeutic targets in chronic disease. Hyperglycaemia and modifications to long-lived proteins contribute to AGE formation, while oxidative stress and inflammation enhance it. Tobacco, ultra-processed foods, pollutants and alcohol also contribute. The available preview does not provide study counts, sample sizes or quantitative treatment effects.

The review describes higher AGE concentrations in blood and tissues from patients with diabetes than in healthy controls. Although some AGE receptors support clearance and detoxification, persistent accumulation enables interactions with signalling receptors, including receptor for AGE (RAGE). The authors describe AGE–RAGE signalling as accelerating atherosclerosis, diabetic kidney disease and bone, retinal and cardiac disease. Interaction between the RAGE cytoplasmic tail and the formin diaphanous 1 helps explain downstream signalling mechanisms.

Pharmacological targeting of AGEs has been tested clinically, but the review reports a lack of statistically significant benefits. The authors suggest that broader strategies, including blockade of AGE–receptor interactions, may be needed because AGEs belong to a wider family of damage-associated molecular patterns. These approaches remain under preclinical and clinical investigation, rather than established treatments. Potential adaptive AGE functions, including antimicrobial and anti-tumour roles, further complicate therapeutic targeting.