Key Points
- Navitoclax reverses the age-related decline in a protein that maintains skin structure – collagen – to restore resilience.
- As a senolytic, Navitoclax eliminates senescent cells in human skin grafted to mice.
- Treatment with Navitoclax alleviates the abundance of harmful molecules secreted from senescent cells (part of the senescence associated secretory phenotype [SASP]) in the skin grafts.
As we grow older, our skin loses its vibrant appearance and begins to wrinkle. Age-associated wrinkles arise primarily from the loss of structural proteins called collagens. Recent research in rodents suggests senolytics – compounds that selectively eliminate senescent cells – reduce the abundance of the collagen-degrading inflammatory SASP and improve the function of cells that synthesize collagen (fibroblasts). Yet the applicability of these findings remains questionable due to differences between rodent and human skin. To get around the species differences and provide more meaningful data for humans, researchers have used human skin grafts on mice.
Published in Rejuvenation Research, Kishi and colleagues from Keio University in Japan find that treating human skin grafted to mice with Navitoclax alleviates the accumulation of age-associated senescent cells, most notably senescent fibroblasts. By eliminating these cells, Navitoclax also rids the skin of the SASP and restores the density of collagen. These findings provide evidence that Navitoclax can rejuvenate skin by eliminating senescent cells, reducing the SASP, and improving the skin’s collagen density.
Navitoclax Eliminates Senescent Cells to Restore Skin Resilience
Kishi and colleagues used skin grafts from men aged 78 to 91 years and transplanted them into the backs of young mice. Following Navitoclax treatment, the human skin grafts displayed a ~30% increase in collagen density. Since collagen gives the skin structural integrity and resilience, these findings suggest that Navitoclax improves aged skin health.
Kishi and colleagues monitored the levels of a protein stain for senescent cells – senescence associated ꞵ-galactosidase – in Navitoclax-treated mice with human skin grafts. The abundance of the senescent cell stain diminished by roughly 60% in Navitoclax-treated mice, suggesting that Navitoclax induces the death and removal of senescent cells.
To confirm that Navitoclax improves aged skin health by eliminating senescent cells, Kishi and colleagues measured the activity of genes for proteins associated with the SASP. The SASP are a collection of molecules secreted by senescent cells, including inflammatory and tissue-degrading molecules that become harmful when chronically activated. The Keio-based team found that Navitoclax reduces SASP genes activation levels by more than half, approximately the same levels seen in young skin. These results support that Navitoclax treatment reduces the activation of genes associated with the SASP, likely by eliminating senescent cells.
Identifying More Precise Ways to Deliver Navitoclax
The study provides evidence that the senolytic Navitoclax may lower levels of senescent cells, like senescent collagen-synthesizing fibroblasts, within skin to increase the proportion of non-senescent skin cells. Reducing senescent cells with Navitoclax treatment also diminishes the amount of inflammatory and collagen-degrading SASP components within skin. Improved viability of fibroblasts and reduced SASP levels may then contribute to higher collagen density and improved skin resilience. A limitation to the study was that Navitoclax was injected into mice intraperitoneally. This begs the question of whether other methods of applying Navitoclax could be more effective, such as a skin cream containing the compound. Additionally, Navitoclax has side effects, such as digestive problems, so using a more precise means of application to the skin may help with avoiding them.
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