Wound Healing, Senescence, and Senotherapeutics

Significance: Dermal repair is a tightly regulated process that becomes progressively impaired with aging, chronic diseases, and persistent tissue injury. Senescent cells (SnCs) accrue in the skin following damage and with advancing age, contributing to alterations in tissue homeostasis and repair. However, the role of SnCs in normal and impaired wound repair is pleiotropic and context-dependent, particularly in the context of age and chronic disease. Furthermore, the use of senotherapeutics that target SnCs can slow aging, mitigate chronic disease, and promote rejuvenation of aged tissues, implicating their potential efficacy in reverting dysregulated wound repair. Recent Advances: The implementation of multi-OMIC analysis examining SnCs has improved our understanding of SnC heterogeneity within the skin and identified distinct SnC subsets that differentially influence tissue repair and its dysfunction. These studies have facilitated the development of senotherapeutics that selectively eliminate SnCs or suppress their detrimental phenotype. Preclinical studies demonstrate that treatment with senotherapeutics can improve tissue integrity and restore regenerative capacity. Critical Issues: Despite significant progress, the types, functions, and temporal dynamics of SnC populations involved in wound healing remain poorly characterized. Further molecular and functional SnC phenotyping, especially under aged and diseased conditions, will be required to distinguish beneficial reparative senescence from persistent pathogenic senescence. In addition, optimal therapeutic timing, specificity, and delivery strategies remain unresolved. Paul D. Robbins Future Directions: Integrating multiomics approaches in preclinical and clinical studies will be required to distinguish beneficial transient senescence from persistent pathogenic senescence for the further development of SnC-targeting therapies.