Fight Aging!

Will senolytic drugs to destroy senescent cells and senomorphic drugs to reduce the harmful senescence-associated secretory phenotype (SASP) turn out to improve on present poor approaches to treat skin aging in humans? Few groups appear motivated to find out. Those developing senotherapeutics as drugs focus on more serious concerns than skin aging, and are arguably right to do so, while those developing senotherapeutics as cosmetics have little incentive to conduct expensive, robust clinical trials of their products. Success in selling cosmetic products has little connection with whether or not the products actually work. Nonetheless, we might hope that at some point someone will robustly quantify the effects of clearing senescent cells on the aging of human skin.

In recent years, researchers have attempted to counteract aging using senotherapeutics that selectively target senescent cells. Senotherapeutics are categorized into two groups. Senolytic drugs selectively eliminate senescent cells, and senomorphic drugs inhibit the negative effects of their SASP. Since the combination of dasatinib and quercetin was proposed as the first senolytic drug to suppress genes that are increased in senescent cells, many studies have shown that various substances such as ABT-737, ABT-263, A1155463, and fisetin have anti-aging properties.

In particular, ABT-263 and ABT-737, which are Bcl-2 inhibitors, have been found to selectively eliminate SA β-gal-positive senescent cells in skin both in vitro and ex vivo. Researchers demonstrated that either ABT-263 or ABT-737 treatment selectively eliminated dermal fibroblasts in an intrinsic skin aging mouse model. They also showed that the treatment increased the collagen density, epidermal thickness, and keratinocyte proliferation while reducing SASPs including MMP-1 and IL-6. Further, the team revealed that treatment with ABT-263 and ABT-737 also attenuated the induction of MMPs and decreased collagen density in the photoaging mouse model. In addition, ABT-263 showed potential in reducing pigmentation caused by photoaging in human skin inducing apoptosis of p16INK4A-positive fibroblasts with its senolytic activity, resulting in decreased levels of melanin and tyrosinase activity.

One of the most notable targets of senomorphic agents is the mechanistic target of rapamycin (mTOR) pathway, which regulates cellular metabolism and is linked to cellular growth, proliferation, and autophagy. The mTOR pathway is also involved in the synthesis of SASP. Rapamycin, an mTOR inhibitor, exhibited significant reduction in senescence markers and SASP as well as oxidative stress in UV-induced photoaged human dermal fibroblasts. Moreover, researchers revealed the potential anti-aging effect of topical application of rapamycin (an mTOR inhibitor). A total of 17 subjects over the age of 40 years with age-related photoaging of the skin applied a rapamycin-containing hand cream to the dorsum of one hand and a placebo hand cream to the other hand daily for 8 months and found that the rapamycin-treated hand had a decrease in p16 and an increase in collagen VII protein.

Taken together, these promising results suggest that senotherapeutics may be a novel therapeutic option for skin aging; however, the limitations of these drugs, such as their specificity, selectivity, and efficiency, still need to be addressed, and their mechanisms of action and side effects must be better understood.

Link: https://doi.org/10.3389/fphys.2023.1195272