Topical ABT-263 treatment reduces aged skin senescence and improves subsequent wound healing

Senescent cells accumulate in aging tissues, impairing their ability to undergo repair and regeneration following injury. Previous research has demonstrated that targeting tissue senescence with senolytics can enhance tissue regeneration and repair by selectively eliminating senescent cells in specific aged tissues. In this study, we focused on eliminating senescent skin cells in aged mice to assess the effects on subsequent wound healing. We applied ABT-263 (Navitoclax) and a DMSO control directly to the skin of 24-month-old mice over a 5-day period. Following ABT-263 treatment, aged skin showed decreased gene expression of senescent markers p16 and p21, accompanied by reductions in SA-ß-gal and p21-positive cells compared to the DMSO-treated skin. However, ABT-263 treatment also triggered a temporary inflammatory response and macrophage infiltration in the skin. Bulk RNA sequencing of ABT-263-treated skin revealed prompt upregulation of genes associated with wound healing pathways, including hemostasis, inflammation, cell proliferation, angiogenesis, collagen synthesis, and extracellular matrix organization. Aged mice treated with ABT-263 exhibited accelerated wound closure compared to the DMSO control group. In conclusion, topical ABT-263 effectively reduced several senescence markers in aged skin, thereby priming the skin for improved subsequent wound healing. This enhancement may be attributed to ABT-263-induced senolysis and the resulting inflammation, which in turn stimulated the expression of genes involved in extracellular matrix remodeling and wound repair pathways. Overall design: In this study, we focused on eliminating senescent skin cells in aged mice to assess the effects on subsequent wound healing. We applied ABT-263 (Navitoclax) and a DMSO control directly to the skin of 24-month-old mice over a 5-day period, excised and homogenized the skin, and profiled gene expression in the skin homogenate using RNA sequencing.