Metformin promotes wound healing in senescent fibroblasts by regulating SIRT1 and FAP-α

Skin aging is associated with fibroblast senescence, impaired wound healing, and dysregulation of markers such as Sirtuin 1 (SIRT1) and fibroblast activation protein-α (FAP-α). It is known that proliferation and migration decrease in aging fibroblasts, which delays the repair process. Metformin, a widely used anti-diabetic drug, can regulate cellular senescence pathways. This study evaluated the effects of metformin on wound healing and SIRT1 and FAP-α expression in senescent fibroblasts. Cellular senescence was induced in primary human dermal fibroblasts using 100 µM hydrogen peroxide (H₂O₂), as validated by a WST-8 assay and SA-β-gal staining. Wound healing assay and immunocytochemistry were performed on control, senescent, and metformin-treated groups (2.5, 5, and 10 mM). Wound closure was significantly impaired in senescent fibroblasts (38% at 72 h versus 89% in the control group). Metformin restored wound healing in a dose-dependent manner; the 10 mM group achieved 94% closure at 72 h, which was comparable to the control group. SIRT1 expression decreased in senescent fibroblasts (90.17 ± 4.67 vs. 124.83 ± 4.31 in controls, p < 0.001) and increased progressively with metformin treatment, reaching control levels at 10 mM. FAP-α expression increased in senescent fibroblasts (91.83 ± 4.36 vs. 78.17 ± 2.56 in controls, p < 0.05) and declined towards baseline with metformin treatment, being significantly reduced at 5 and 10 mM. Metformin improved wound healing capacity and normalized age-related alterations in SIRT1 and FAP-α expression in senescent fibroblasts. These results imply that metformin alleviates senescence-associated dysfunction, suggesting its potential as a therapeutic agent to enhance wound repair in aging skin.

Aging; FAP-α; Fibroblast; Metformin; SIRT1; Wound healing.