The Role of Mast Cells in Skin Aging: Mechanisms and Therapeutic Advances

Mast cells (MCs) are innate immune cells primarily located in the papillary layer of the dermis that play a crucial role in the skin immune response by secreting mediators and recruiting effector cells. Increasing laboratory and clinical evidence indicates that MCs are not only passive participants but also key regulators of skin aging. MCs act as sensors and amplifiers of aging-related signals, integrating various stimuli, including the nature of the triggering factor, microenvironmental cues such as senescence-associated secretory phenotype (SASP) factors, and specific activation pathways. Upon activation, MCs release diverse mediators that engage signalling pathways including Fc epsilon RI (FcεRI), c-KIT, Toll-like receptors (TLRs) and Mas-related G-protein-coupled receptor X2 (MRGPRX2) thereby eliciting broad target cell responses. MCs engage in pathological crosstalk with fibroblasts, keratinocytes, melanocytes and immune cells, establishing self-perpetuating feedback loops that amplify aging-related processes. Collectively, these findings highlight the dual and context-dependent roles of MCs as not only protectors but also accelerators of skin aging, positioning them as promising therapeutic targets. The use of novel MC stabilisers such as ketotifen or luteolin, as well as phototherapy and other treatments, shows potential in mitigating skin aging and may offer valuable insights into novel therapeutic targets. Nonetheless, additional studies are required to dissect the underlying mechanisms and optimise targeted therapies to facilitate the development of precision medicine strategies.