Age‐associated Senescent – T Cell Signaling Promotes Type 3 Immunity that Inhibits the Biomaterial Regenerative Response

Aging is associated with immunological changes that compromise response to infections and vaccines, exacerbate inflammatory diseases and can potentially mitigate tissue repair. Even so, age‐related changes to the immune response to tissue damage and regenerative medicine therapies remain unknown. Here, it is characterized how aging induces changes in immunological signatures that inhibit tissue repair and therapeutic response to a clinical regenerative biological scaffold derived from extracellular matrix. Signatures of inflammation and interleukin (IL)‐17 signaling increased with injury and treatment both locally and regionally in aged animals, and computational analysis uncovered age‐associated senescent‐T cell communication that promotes type 3 immunity in T cells. Local inhibition of type 3 immune activation using IL17‐neutralizing antibodies improves healing and restores therapeutic response to the regenerative biomaterial, promoting muscle repair in older animals. These results provide insights into tissue immune dysregulation that occurs with aging that can be targeted to rejuvenate repair. Aging alters immune responses, impairing tissue repair and response to regenerative treatments. In aged animals, injury increases inflammation and IL‐17 signaling, revealing age‐related communication between T cells and senescent cells that promotes type 3 immunity. Inhibiting this response with IL17‐neutralizing antibodies improves healing and biomaterial efficacy, suggesting potential strategies for countering age‐related immune dysregulation to promote tissue repair.