Agrin at the crossroads of aging: A pleiotropic regulator in age-related diseases

Aging is a significant risk factor for numerous age-related diseases, and elucidating its key molecular mechanisms is crucial for disease prevention and treatment. Agrin, initially identified for its role in neuromuscular junction development, is an extracellular matrix protein. Recent studies have revealed its broad functions in maintaining tissue homeostasis and facilitating cellular signal transduction. During aging, alterations in the expression and function of Agrin may participate in the regulation of tissue repair, inflammatory responses, and intercellular communication, thereby influencing the onset and progression of various age-related diseases. This review systematically examines the central role of Agrin in age-related diseases such as Alzheimer's disease, ischemic stroke, myocardial infarction, osteoarthritis, and type 2 diabetes. Accumulating evidence indicates that Agrin exhibits a distinct ''double-edged sword'' characteristic across different disease stages or tissue contexts-exerting protective effects in some scenarios while promoting pathological progression in others. We summarize current findings on the involvement of Agrin in disease mechanisms, including the regulation of amyloid deposition, blood-brain barrier integrity, synaptic function, inflammatory responses, and tissue repair. Furthermore, we discuss potential Agrin-targeted therapeutic strategies. We propose that Agrin represents a critical molecular node linking aging mechanisms with multiple age-related diseases. A deeper understanding of its context-dependent functional switching and the development of precise targeting approaches hold substantial promise for the prevention and treatment of age-related pathologies.