We did a review of the data on topical rapamycin to target skin senescence. Here are the key takeaways:
The data suggests that the improvement observed may be due to the reduction of the overall burden of senescent cells. This could be due to rapamycin reducing the pro-inflammatory secretions produced by senescent cells, or it could be that rapamycin is reducing the number of senescent cells.
The fact that p16 is reduced suggests that the absolute number of senescent cells in the epidermis is reduced.
Rather than simply modifying senescent cells present in the tissue, rapamycin treatment either reduces the number of cells entering senescence or increases the clearance of senescent cells.
Whether the reduction in senescent cells is due to reduced entry into senescence or increased clearance, a reduction in the burden of senescent cells would be expected to improve functionality. Beyond skin health, the implication of these results suggests that rapamycin could be a powerful tool to reduce senescence throughout the body.
Senescent cells produce substances called pro-inflammatory cytokines, matrix metalloproteins, and reduced levels of anti-angiogenic factors, which together create an environment that can support tumor growth and negatively affect stem cells. This group of substances is known as the Senescence-Associated Secretory Phenotype (SASP). In normal cells and tissues, the SASP is closely linked to the expression of the p16INK4A protein. The results of the study suggest that rapamycin reduces inflammatory cytokines in the skin.
Rapamycin seems to improve the incorporation of collagen VII into the basement membrane of skin, which is a measure of skin quality. Collagen VII is important for maintaining a functional skin barrier, but its levels decrease with age and in areas where wrinkles form.
The mechanism by which rapamycin increases collagen VII protein levels is not fully understood, but it is thought that rapamycin’s effects on autophagy and vesicle trafficking may allow for the proper processing and localization of collagen at the cell periphery and basement membrane.
Collagen VII has also been linked to the clearance of misfolded proteins and extracellular pathogens, and may play a role in maintaining cell-cell junctional integrity.