Topical Rapamycin Evaluated as a Treatment for Skin Aging

Given the attention that descends upon any prospect of reversing skin aging, I should probably open by saying that much of the data here for extended low dose topical treatment with rapamycin over eight months, that regarding visible skin aging and collagen production, is no more exciting than that obtained by any number of other approaches, such as topical application of keratinocyte growth factor (KGF). Effect sizes are the only thing that matters, and also the one thing that all too many observers fail to consider. Looking at the paper, I would say that the primary point of interest is the 50% reduction in markers of cellular senescence in skin. Given what is known of rapamycin this seems unlikely to be a senolytic effect, so not destruction of existing senescent cells, but rather a reduction in the number of cells becoming senescent. This in turn suggests that there remains some meaningful level of ongoing natural clearance of lingering senescent cells at older ages.

This study demonstrates a clear impact of rapamycin treatment on both the molecular signature associated with senescence and the clinical signs of aging in the skin. These data support the idea that a reduction in the burden of senescent cells underlies these improvements. The results could reflect a modification of the senescent cells present in the skin or a reduction in the number of senescent cells. Although rapamycin has been shown to reduce pro-inflammatory secretions produced by senescent cells, the fact that p16INK4A is reduced suggests that the absolute number of senescent cells in the epidermis is reduced. This implies that rather than simply modifying senescent cells present in the tissue, rapamycin treatment is either reducing the number of cells entering senescence or increasing the clearance of senescent cells. Based on our studies demonstrating that rapamycin prevents the senescence transition and improves functionality in vitro, we favor the concept that rapamycin reduces entry into senescence, but we cannot rule out an additional role for clearance of senescent cells. Whether the reduction in senescent cells is due to reduced entry or increased clearance, a reduction in the burden of senescent cells would be expected to improve functionality.

Senescent cells produce pro-inflammatory cytokines, matrix metalloproteins, and reduced levels of anti-angiogenic factors, creating a secretory profile known as the Senescence-Associated Secretory Phenotype (SASP). Thus, we anticipate that rapamycin treatment reduces inflammatory cytokines in the skin, although the verification of this change represents a technical challenge due to the fact that such cytokines are present in picomolar amounts. One quantifiable aspect of skin biology that is improved by the rapamycin treatment is the incorporation of collagen VII into the basement membrane, which represents a functional measure of skin quality that is improved upon treatment with rapamycin. Collagen VII is essential for a functional skin barrier, and the levels of collagen VII decrease with age and specifically beneath wrinkles. Although the mechanism whereby rapamycin may increase collagen VII protein levels is not clear at this time, the known effects of rapamycin on autophagy and intracellular trafficking of vesicles may allow for intracellular processing of misfolded collagen and increase proper localization at the cell periphery and basement membrane.

A notable aspect of this study is the use of such a low dose of rapamycin (10 μM, or 0.001%) for topical application. Topical treatment with higher concentrations (0.1-1%) has been employed for the treatment of tuberous sclerosis complex (TSC) in adults and children and has shown efficacy. We chose to use rapamycin at a ten-fold lower dose because the concentrations used in TSC patients are intended to inhibit cell growth, while our aim was to improve cell function while maintaining proliferative potential and preventing senescence. The positive impact of our treatment regimen suggests that age-related therapy with rapamycin may be feasible at doses far below those associated with side effects; however, this possibility will require careful evaluation in each specific clinical setting.



Yes, choosing "any number of approaches " to combat skin aging topically is very frustrating. Which ones really move the needle? Do any of them? Right now I'm looking at choosing between methylene blue, mitoq lotion,Maple leaf extract, retin A, defensins, growth factors, peptides, dill extract, iris extract, rapamycin, calcium lotion, and on and on. All have promising studies - I've seen none "reverse skin aging". Has anyone found something truly effective, that offers more than "a glow" ?

Posted by: August at November 26th, 2019 11:01 AM

The epidermis consists of dead cells. Saying there were fewer senescent cells found is sort of an oxymoron. R is a huge molecule that would never reach the dermis, so I am mystified as to why this study was undertaken.

Posted by: JohnD at November 26th, 2019 11:53 AM

JohnD, when you go to the actual study you'll find that they used DMSO with the extremely low dose Rapa. It's likely the DMSO shuttered the rapa deeper into the skin. Of course this isn't practical for much more than a swipe on a hand....

"Participants enrolled in the study were provided with a container of rapamycin cream and a container of placebo (DMSO) in identical dispensers "

Posted by: August at November 26th, 2019 8:24 PM

Concerning the growth factor Reason well as dermal penetration... Below is quoted from a 2018 article in Allure magazine: ( Too bad the Marini product contains parabens)

"Growth factor molecules from any source are too large to penetrate intact skin, and there is no convincingly proven technology that can increase the penetration," says Mehta. And, yet, dozens of topical growth factor studies show measurable increases in collagen and elastin, and improvements in skin thickness, radiance, moisturization, pigmentation, and texture. How can growth factors be so accomplished if they're not even granted entry into the skin?"

"Leading researchers share a fascinating and widely accepted hypothesis, says Mehta: "When growth factors are applied to the skin in high concentrations, a very small fraction of them interact with the topmost layers of the skin, and initiates a communication chain that leads to stimulation of dermal fibroblasts," sparking collagen growth. The aforementioned 2009 Journal of Drugs in Dermatology study expands on the theory, but the science is superheavy, and the language explaining it, convoluted, so here's the gist: Growth factor serums essentially urge the living cells of your skin's surface layer to call down to collagen cells, Hey, pump out more growth factors! This order then incites swifter cell turnover and more robust growth-factor output, which then triggers more collagen creation down below the surface for glowier, plumper, prettier skin."

Posted by: August at November 27th, 2019 9:13 AM

Thanks for that insight August

Posted by: JohnD at November 27th, 2019 11:32 AM

'Participants were greater than 40 years of age with evidence of age-related photoaging and dermal volume loss and no major morbidities. Thirty-six participants were enrolled in the study, and nineteen[!] discontinued or were lost to follow-up.'

Hm... seems most participants didn't see improvements worth the hassle to continue their involvement in the study!?

Posted by: Jones at November 28th, 2019 5:38 AM

An even newer study sheds some light onto why this was effective.
First we know from a few months ago that decreasing autophogy in the skin is a cause of skin aging.

We know that rapamycin and low dose lithium upregulate autophagy. So that makes sense.
Now a study is out blaming loss of csb as a reason for skin aging:

As it turns out loss of csb with aging downregulates autophagy in the skin.
But Rapamycin and Luthium may be the saviors here by upregulating CSB and therefore skin autophogy.

" we propose that CSB acts as a sensor of mtDNA damage and regulates mitochondrial autophagy and that treatment with rapamycin or lithium chloride could potentially attenuate some symptoms related to CS."

I've also seen studies suggesting that Rapamycin/lithium combined is more effective than either alone at inducing autophogy.
Might then this " facial" be treated by the combo to see if there are even better effects?

Posted by: august 33 at December 19th, 2019 10:49 AM

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