The Science on Rapamycin for Skin - 2 papers - Your Thoughts?

There have been two papers I've seen that have focused on rapamycin's topical for aging skin  See links below.

The second study was comparing it to a proprietary peptide, in a test done by OneSkin in San Francisco.  While the focus of the Oneskin peptide study was their own product, their comparison with topical Rapamycin is extremely interesting with details not seen in other studies.  Can someone who understands the science in this Oneskin study comment on the results in this research - it doesn't sound good for either Rapamycin or retinol despite what appear to be visually positive impacts on skin quality:

"Rapamycin is a long studied molecule affecting mTOR/nutrient signaling and has recently been shown to decrease P16 levels of aging skin 21, therefore it was chosen as a positive control of senotherapeutic effect in aging skin models. When added to culture media, peptide 14 promoted the maintenance of the overall structure of the 3D skin equivalents created with cells from 48yr old donors, as analyzed by H&E staining, whereas Rapamycin caused a detrimental effect in overall skin structure, including a a thinner and more disorganized epidermis. The effect of both molecules was quantified according to morphological changes analyzed through an unbiased skin score and showed that, while peptide 14 treatment significantly increased the score, Rapamycin treatment led to a decrease (Fig. 3A). The mRNA expression of the peptide 14-treated epidermis from 3D skin equivalents built from donors aged 32, 48, and 60 years exhibited a significant decrease in P16 and a trend towards decreased IL6, in addition to a significant increase in Keratin 1 (a marker of keratinocyte terminal differentiation) and 14 (a marker of non-differentiated, proliferative keratinocytes) (Fig. 3B). Rapamycin induced a significant increase in P16 expression, a trend towards increased expression of inflammatory markers (IL6 and IL8), and a significant decrease in Keratin 1 gene expression levels (Fig. 3B). In the dermis, peptide 14 treatment promoted a significant reduction in B2M gene expression, a pro-aging factor, as well as in the expression ofIL8. Rapamycin treatment induced no significant changes in these markers and increased Matrix Metalloproteinase-1 (MMP1) gene expression, indicative of breakdown of the extracellular matrix (Fig. 3C). Rapamycin and peptide 14 significantly reduced gene expression of Hyaluronidase-1 (HYAL1), which plays a role in the degradation of hyaluronic acid (Fig 3C). Unlike Rapamycin, peptide 14 treatment stimulated increased gene expression of Collagen 1 and

The genotoxic agent Etoposide was also utilized to induce cellular senescence and further confirm the efficacy of peptide 14. The obtained results confirmed that Etoposide effectively induced cellular senescence and cell death (Fig. 2G), and treatment with peptide 14 significantly reduced cellular senescence levels, as measured by SA-BGal (Fig. 2H).

Hyaluronan Synthase-2 (HAS2) (Fig. 3C). Therefore, compared to Rapamycin, peptide 14 treatment of 3D human skin equivalents significantly improved numerous markers of skin health and longevity.

Histological imaging depicted a significant increase in epidermal area with increasing concentration of peptide 14 and no significant changes were observed with Rapamycin treatment compared to control (Fig. 3D, E). In the epidermis of treated skins, both peptide 14 and Rapamycin decreased P16 mRNA expression yet only peptide 14 treatments decreased B2M expression (Fig. 3F). IL8 and tyrosinase (TYR) gene expression were significantly reduced in all treatments though an increase in Keratin 1 and 14 was only observed with peptide 14 treatment (Fig. 3F). In the dermis, peptide 14 treatment more drastically decreased P16 mRNA expression compared to Rapamycin treatment and only the higher concentration of peptide 14 was able to reduce B2M gene expression (Fig. 3G). Rapamycin treatment did reduce both IL8 and HYAL1 gene expression and, similarly to peptide 14, was able to increase HAS2 expression (Fig. 3G). Peptide 14 treatment also increased dermal Collagen 1 and the proliferation marker Ki67 in dermis though did increase HYAL1 and MMP1 gene expression in the higher concentration (Fig. 3G).

In order to have a more in depth understanding of how both peptide 14 and Rapamycin treatments might alter skin's biological age, the 79 year old ex vivo skin biopsies were processed for DNA isolation and methylome analysis. Using the Skin-Specific DNA methylation algorithm developed by our group 32, we observed that while Rapamycin treatment did not generate any significant alterations (p=0.21), peptide 14 treatment significantly reduced the DNA methylation age (p<0.01) (Fig. 3H).

Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial

https://link.springer.com/article/10.1007/s11357-019-00113-y

 

The second and more recent one was this:

Senotherapeutic peptide reduces skin biological age and improves skin health markers

https://www.biorxiv.org/content/10.1101/2020.10.30.362822v2

Full PDF:
https://www.biorxiv.org/content/10.1101/2020.10.30.362822v2.full.pdf

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  • Interesting, thanks for posting. I read some of this before where they said rapamycin didnt work very well but not this level of detail on it. I actually was going to purchase some of the oneskin when it launched, but I figured I would wait and see if people liked it or not. Well it sold out immediately and hasnt been in stock since.

    This is interesting that their peptide was able to reduce the methylation age of the skin, I dont think I read that before.

    I do wonder what the heck this stuff is. I dont like that it is a mystery ingredient. I wonder how it compares to Katchers topical formula or perhaps....... it is the same thing!?

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  • As Fred said, thank you for posting. I'm curious about the statement "despite what appear to be visually positive impacts on skin quality".  I say this as I have yet to see one before and after photo of anyone using either a topical version or simply via pill, demonstrating any positive facial skin difference through the use of rapamycin. All I see are people making such claims. Can you direct me to some?

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    • Michael Here is some coverage on that from the first research paper:

      https://link.springer.com/article/10.1007/s11357-019-00113-y/figures/3

      I've used Rapamycin cream I used myself - at .1% level - nightly on hands and face for 6 months and it definitely made a positive difference visually (eliminating many smaller/finer wrinkles), but still... I tend to believe the research on the underlying biological changes more than my own short term visual changes... so I have yet to decide whether I will make any more rapamycin cream (I also take 6mg to 10mg per week, but that's orally).  

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      • Michael
      • Michael.1
      • 1 yr ago
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      Brin Chikovski Appreciate it.

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  • Has anyone compared Rapamycin on skin to the available Tacrilimus skin ointment?

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