Senolytic drugs clear lingering senescent cells from aged tissues. The mechanisms are quite diverse, but most senolytic therapies either sabotage the ability of senescent cells to resist their primed apoptosis machinery, thus promoting programmed cell death, or encourage the immune system to more rapidly and aggressively destroy senescent cells. Interestingly, comparatively little research and development has taken place on topical senolytics; one might look at OneSkin as an example, but these efforts are far outnumbered by programs aiming to produce senolytic drugs that affect the whole of the body, or at least major internal organs.
In today’s open access paper, researchers report on the topic use of the senolytic drug navitoclax (or ABT-263). Navitoclax is a larger molecule than one would expect to be able to pass the skin barrier, but here the researchers use DMSO as a permeability enhancer and it appears to work. Using aged mice, the researchers demonstrate reduced markers of cellular senescence in skin and enhanced wound healing following a topical senolytic treatment.
Topical ABT-263 treatment reduces aged skin senescence and improves subsequent wound healing
Senescent cells (SnC) 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 SnCs in specific aged tissues. In this study, we focused on eliminating SnC skin cells in aged mice to assess the effects on subsequent wound healing. We applied ABT-263 directly to the skin of 24-month-old mice over a 5-day period.
Following topical ABT-263, aged skin demonstrated decreased gene expression of senescent markers p16 and p21, accompanied by reductions in SA-β-gal and p21-positive cells compared to DMSO controls. However, ABT-263 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 skin pre-treated with topical ABT-263 exhibited accelerated wound closure.
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 which in turn stimulates the expression of genes involved in extracellular matrix remodeling and wound repair pathways.
