Endothelial senescence drives intrinsic skin aging via the neuroimmune CGRP-mast cell axis in mice

Aging is accompanied by progressive vascular dysfunction, but its effects on skin aging remain poorly understood. Although endothelial cell (EC) senescence is implicated in various age-related diseases, its specific role in dermal aging remains unclear. Here we show that EC senescence contributes to intrinsic skin aging through immune dysregulation. Using an EC-specific senescent mouse model, we observe mast cell activation driven by the neuropeptide calcitonin gene-related peptide (CGRP), independent of traditional IgE-mediated pathways. Senescent ECs secreted pro-inflammatory senescence-associated secretory phenotype (SASP) factors, activating dermal neurons to produce CGRP, leading to mast cell degranulation and subsequent skin aging phenotypes. Pharmacological stabilization of mast cells or inhibition of the EC-SASP-CGRP pathway significantly attenuate dermal thinning, collagen degradation, and delayed wound healing, which are hallmarks of intrinsic skin aging. These findings identify vascular senescence as an upstream regulator of skin aging through a neuroimmune mechanism and suggest potential therapeutic targets for age-related skin deterioration. (Figure presented.) © The Author(s) 2025.