Topical Navitoclax Treatment Reduces Skin Senescence and Improves Wound Healing in Mice
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.
I have for long time wondered why it's taken so long for medical scientists find a treatment to actually remove wrinkles. The first one to market would make alot of money. Additionally, maybe it would help the idea of rejuvenation become more mainstream and accepted.
So if we aren't going to live any longer, at least we're going to look good!
@Robert - I'd guess that senescent cell removal in the skin by itself might not remove wrinkles. I'd hazard guess that you might need to remove mutliple classes of SENS damage. Maybe combining a senolytic with glucosepane removal? Or with direct mitochondria transfer to the skin cells?
Even that might not be enough. But it would be interesting to see if combination therapies can visibly improve the look of aged mouse skin. Although this therapy alone might be doing that as the authors state:
"The consistent increase in collagen expression in aged skin following ABT-263 treatment is intriguing. Aged skin generally demonstrates decreased collagen content (up to 75%) and increased fragmentation and disorganization 28. ABT-263 appears to enhance collagen expression and production, potentially improving aged skin structure and function."
Disregarding cosmetic effects, the skin is one of the largest organs in the body, so this treatment would probably improve the health of middle aged and old individuals today if it was widely available. I wonder when and if this treatment will ever become available though?
@Mattp: The cosmetic business is huge. If just a portion of this money was diverted to rejuvenation, it would make a substantial impact in the industry, imo.
I certainly get a lot more general interest in life extension telling people they might look younger at 80 than they were at 40 than I do talking about methylation, mitochondrial DNA and C1QL1 overexpression.
Skin is a very important organ for a lot more than looks. What if we could make elderly skin less fragile to prevent excess bruising and bed sores for example.
skin protects our bodies from germs and regulates body temperature.
I'll be watching this development.
Oneskin by the way eliminated my dry flaky skin..but as I understand it, it's not a senolytic like this. It won't eliminate senescent cells, just slows down their development.
There are other skin challenges we could fix as well: iron overload in skin, glycation, dermal fat loss, hormone and growth factor loss, muscle weakness, etc…