Grancalcin (GCA) is a calcium-binding protein that functions as a secreted pro-senescent factor with significant pathological implications in aging-related diseases. GCA is secreted by macrophages and bone marrow-derived immune cells, where it promotes cellular senescence through binding to the plexin-B2 receptor and activating Arg2-mediated mitochondrial dysfunction 1. In skeletal tissue, macrophage-secreted GCA induces skeletal stem/progenitor cell senescence, impairing fracture healing in aged individuals 1. In Alzheimer's disease, bone marrow-derived GCA+ immune cells preferentially invade the hippocampus and cortex in a CCR10-dependent manner, where GCA competitively binds to LRP1 in microglia, inhibiting phagocytosis and clearance of amyloid-β plaques 2. Higher circulating GCA levels in Alzheimer's patients negatively correlate with cognitive function 2. The protein's pathological effects can be therapeutically targeted, as GCA-neutralizing antibodies enhance fracture healing in aged mice and improve cognitive function in Alzheimer's disease models 12. These findings establish GCA as a key mediator of age-related tissue dysfunction through its role in promoting cellular senescence and impairing regenerative processes.