The multiple faces of RAGE--opportunities for therapeutic intervention in aging and chronic disease.

INTRODUCTION: This review focuses on the multi-ligand receptor of the immunoglobulin superfamily--receptor for advanced glycation endproducts (RAGE). The accumulation of the multiple ligands of RAGE in cellular stress milieux links RAGE to the pathobiology of chronic disease and natural aging. AREAS COVERED: In this review, we present a discussion on the ligands of RAGE and the implications of these ligand families in disease. We review the recent literature on the role of ligand-RAGE interaction in the consequences of natural aging; the macro- and microvascular complications of diabetes; obesity and insulin resistance; autoimmune disorders and chronic inflammation; and tumors and Alzheimer's disease. We discuss the mechanisms of RAGE signaling through its intracellular binding effector molecule--the formin DIAPH1. Physicochemical evidence of how the RAGE cytoplasmic domain binds to the FH1 (formin homology 1) domain of DIAPH1, and the consequences thereof, are also reviewed. EXPERT OPINION: We discuss the modalities of RAGE antagonism currently in preclinical and clinical studies. Finally, we present the rationale behind potentially targeting the RAGE cytoplasmic domain-DIAPH1 interaction as a logical strategy for therapeutic intervention in the pathological settings of chronic diseases and aging wherein RAGE ligands accumulate and signal.