Cellular Senescence in Human Skin Aging: Leveraging Senotherapeutics (Rapamycin)

I suspect rapamycin skin cream should probably be in everyone’s bathroom cabinet… probably something we want to use all over our body (though lots of work to be done on figuring out the optimal dosing). And again, this paper suggests that we may want to try other skin senolytics like Dasatinib, or JAK inhibitors.

Senomodifiers or senomorphics are drugs that suppress the adverse effects of senescent cells without directly clearing them, such as JAK inhibitors [101] or rapamycin. Rapamycin, which targets the mTOR pathway regulating cell growth, metabolism, protein synthesis, and autophagy, has been found to reduce senescent cells in human skin, specifically dermal fibroblasts [56, 103], possibly because the SASP spreads senescence [92] and, hence, inhibiting the SASP could reduce senescent cell burden. Rapamycin inhibits the upregulation of IL-1α in senescent fibroblasts, which subsequently blocks IL-1α- induced secretion of other pro-SASP factors [104–106].

In accordance, rapamycin reduced signs of cellular skin aging in murine skin fibroblasts following UVB irradiation [105]. Indeed, 5 μM rapamycin significantly decreased SA-β-gal-positive cells, preserved elongated fibroblast morphology, and attenuated irradiation-induced reactive oxygen species release [105]. This was also described with the senomorphic and mTOR inhibitor, AZD8055, in foreskin fibroblasts [107]. Taken together, these observations suggest that targeting cellular senescence, in part, may contribute to skin rejuvenation and overall skin health. In addition, senotherapeutics could potentially block cancer pathways associated with cellular senescence, making them candidates to treat or prevent precancerous lesions, such as actinic keratoses.

Open Access Paper:

Full Paper: Cellular Senescence in Human Skin Aging: Leveraging Senotherapeutics | Gerontology | Karger Publishers

Related Reading:

Here: Senolytics Topically Administered to Skin for Antiaging Effects

Here: Rapamycin May Slow Skin Aging (Drexel U. Study)

Here: Where to buy Rapamycin Skin Cream

Here: DIY Professional Rapamycin Skin Cream Recipe


Some JAK inhibitors available from India at lower costs: (82 rupees or so to $1.00 US). You’d need to crush the tablets and dissolve in transcutol as people are doing in the DIY rapamycin cream: DIY Rapamycin skin cream

The Ruxolitinib cream seems to be in the $120 to $150 range… so more expensive.

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Other compounds mentioned in the initial paper that are also showing efficacy in treating senolytic cells in skin, are mentioned:

bioinformatics approaches were utilized to find compounds whose mechanisms of action targeted these senescent cell anti-apoptotic pathways. These agents included dasatinib (D), the Src tyrosine kinase inhibitor, and quercetin (Q), a naturally occurring flavonoid found in apple peels that targets other senescent cell anti-apoptotic pathways. First-generation senolytics also include fisetin, luteolin, curcumin, navitoclax (ABT263), and procyanidin C1 among others [84, 86, 93‒96] (PMID: 34873338). Second-generation senolytic agents are being identified through other drug discovery methods, including random high-throughput drug library screens, vaccines, toxin-loaded nanoparticles preferentially lysed by senescent cells, and immunomodulators [45, 97‒99]. In particular, the first-generation senolytic dasatinib and quercetin (D + Q) showed trends of reducing p16 and p21 expression in the human epidermis, suggesting their potential efficacy [100].

The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice



Intriguing. Quercetin and fisetin are easy to come by. Reading this paper leaves me tempted to add fisetin to my rapa serum. But I don’t know how they play together, or whether one would also mix the fisetin with transcultol to improve absorption (before diluting into cream, or water, as I do.) Anyone doing this or something similar?