Senolytics Topically Administered to Skin for Antiaging Effects

There are so may senolytics, I would love to know which senolytic molecules would you try first? And your reason?

I still have some Dasatinib in my refrigerator, and I have used topical Retin A(tretinoin) for years, Retin A is believed the most powerful anti-aging topical drug so far, it would be interesting to compare the potency of Retin A with Dasatinib on myself, but I am worry if topical Dasatinib results in systemic absorption? I can’t find data about it.

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In the study using transcutol and rapamycin in formulation of a skin cream, they tested for systemic absorption of the rapamycin and saw none, so I think generally you are unlikely to get systemic entry of the drug based on transcutol-based skin cream formulations.

Dasatinib is an obvious first try for a senolytic skin cream.

Also: Navitoclax (ABT-263) rejuvenates human skin by eliminating senescent dermal fibroblasts in a mouse/human chimeric model - PubMed

and: Glutaminase inhibitors rejuvenate human skin via clearance of senescent cells: Mouse/human chimeric model study

Perhaps also fisetin, and quercetin?

and I have some more information coming soon from the conference I went to this past week.

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Thanks for sharing and waiting for more information coming from the conference.

Dasatinib can’t dissolve in transcutol, it looks like Dasatinib slightly soluble in ethanol, methanol, polyethyleneglycol 400 and propyleneglycol, and in one guide for child who can’t swallow Dasatinib, they put Dasatinib in the water for 5 minutes, then stirring it for 20 minutes.

I don’t know what’s the optimal concentration to prepare, are there any thing to reference?

Dasatinib is a crystalline white powder and exhibits pH dependent aqueous solubility (from 18.4
mg/ml at pH 2.6 to 0.008mg/ml at pH 6.0). It is very slightly soluble in acetone and acetonitrile and
slightly soluble in ethanol, methanol, polyethyleneglycol 400 and propyleneglycol. It is practically
insoluble in corn oil.

Dasatinib is characterized as a low solubility/high permeability (BCS II) compound according to the
Biopharmaceutics Classification System (BCS). In this context, dissolution of dasatinib can potentially
be rate-limiting for absorption.

For children who cannot swallow tablets:

  1. Choose a work space away from food, windows, and fans. Clean the area and place items needed on a paper towel.
  2. Wash hands and put on gloves
  3. Fill a drinking glass with 1 ounce or 30 ml of chilled orange juice or apple juice (without preservatives).
  4. Place the number of tablets required for the dose into the glass of juice.
  5. Let the tablets sit in the water for 5 minutes. Then begin stirring. Stir until all tablets are dissolved which may take up to 20 minutes.
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RapAdmin, Yes, Dasatinib! That’s exactly what I was thinking, but at what strength? If you’re going that route pass along your thoughts on ingredient mixing when you have time. Thanks.

Dr. Garcia has a rapa cream (via compounding pharmacy) which I also purchased like 6 months ago, my skin got worse. Now even with a retinal, my skin got much worse and then better, perhaps I didn’t give it enough time? So, I can honestly say, my skin is softer on OneSkin (no I don’t work for them or benefit), I can’t send a pic of that but I can assure you that’s a fact. I feel like a skin expert in trying different things. I’ve reordered OneSkin, gave it as a Christmas gift to my sister, but I’m always open to experiment a little. Recently, I started experimenting with Droplette, too early for any opinion.

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So - we may have a few more candidates for senolytic drugs that people can test for topical application for skin (since it seems much more safe to do this, than to be using them orally, until more testing).

Strong potential senolytics that I’m thinking of adding to my Senolytic skin cream include:

  • Sertraline
  • Fluvoxamine
  • Nortriptyline
  • Verapamil
  • Amiodarone

At the Longevity Summit at the Buck Center in December, Tim Peterson presented on his group’s work on senolytics. Tim is very focused on the longevity space, and did work in the Sabatini Lab working on mTOR.

It seems that there is a class of drugs that can be identified as “cationic amphiphilic drugs” that seem to be powerful senolytics. Many of these are generic psychiatric drugs (@DrM ) that are inexpensive and widely available (from US or Indian pharmacies, etc). I may try adding these to my planned senolytic skin cream that I’m going to create with Dasatinib in it, similar to how we’ve created the DIY rapamycin skin cream. Comments back from people who are knowledgeable about these drugs greatly appreciated.

Their project, described on Tim Peterson’s Lab website: https://timrpeterson.wustl.edu
Is as follows:

Senolytics are a powerful new class of longevity therapeutic.

They selectively kill disease-causing senescent cells that accumulate in our bodies as we age. In this project we will test a class of drugs we identified called cationic amphipathic drugs (CADs) that we’ve shown in preliminary studies to have powerful senolytic activity. Based on the drugs’ chemistry we propose this class acts like an intracellular soap to ‘clean out’ these ‘old’ senescent cells from the body. Because many of the drugs we’re testing are already in use in humans and are inexpensive, and we will make our results publicly available, our goal is to accelerate the longevity field by providing immediately useful therapies.

More details on the Open Senolytics program: Open Senolytics

Who is the team behind Open Senolytics?

Our team is led by Tim Peterson, Ph.D. and Sandeep Kumar, Ph.D. Dr. Peterson is an Assistant Professor at Washington University School of Medicine in St. Louis in the Departments of Medicine and Genetics. “WashU” is a perennially top five medical school in the U.S. in terms of publishing and funding. Dr. Peterson did his Ph.D. at MIT where he published multiple papers in Nature, Science, and Cell journal on one of the major aging pathways, mTOR, and the drug, rapamycin, that targets it. Dr. Peterson did his postdoctoral fellowship at Harvard University where he continued his work on longevity drug mechanisms focusing on the most commonly used drugs for osteoporosis, bisphosphonates and diabetes, metformin. Dr. Kumar similarly has a deep background in aging research most notably performing several seminal lifespan studies in worms.

Dr. Morten Scheibye-Knudsen at the University of Copenhagen will be assisting us with his AI-driven senescent cell detection algorithms (see below). These algorithms are helpful because they allow us much greater throughput in our experiments. Thus, we can test many more CADs.

A sample of some of the slides that Tim presented are below:

Substances with antihistamine and cationic amphiphilic characteristics, with potential (or confirmed) anti-SARS-CoV-2 activity

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830196/table/t0005/?report=objectonly
Paper Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830196/

Psychotropics with antihistamine and cationic amphiphilic properties and potential anti-SARS-CoV-2 activity (FIASMAs +/−) Preliminary data confirming anti-SARS-CoV-2 activity
Alimemazine/trimeprazine (−‡) [13]
Amitriptyline (+) [8]
Astemizole (+)
Benz(a)tropine (+) [18]
Cetirizine (−)
Chlorphenoxamine (−)
Chlorpromazine (+) [16], [18], [19]
Citalopram* (−)
Clomipramine (+) [19]
Clozapine (−)
Cyamemazine (−‡)
Escitalopram* (−) [8]
Flupent(h)ixol (+) [13]
Fluphenazine (+) [19]
Fluspirilene*(−#) [19]
Hydroxyzine (+) [17]
Levomepromazine/methotrimeprazine (−‡)
Mequitazine (−‡)
Metopimazine (−‡)
Penfluridol* (+)
Pimozide* (+) [21]
Pipamperone*(−)
Pipotiazine (−‡)
Promethazine (+) [19]
Perici(y)azine/propericiazine (−‡)
Quetiapine (−)
Tiethylperazine (−‡) [19]
Tiotixene (−‡)
Triflupromazine (+)
Zuclopenthixol (−‡)

Representative examples of cationic amphiphilic drugs that are identified in SARS-CoV-2 drug repurposing screens.

Source: https://www.researchgate.net/figure/Representative-examples-of-cationic-amphiphilic-drugs-that-are-identified-in-SARS-CoV-2_fig1_350363085

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https://www.biospace.com/article/antidepressant-fluvoxamine-potential-early-treatment-for-covid-19/
I had heard about fluvoxamine (Luvox) for OCD had benefits in early COVID. The MOA with so many medicines is speculated and probably often wrong or multifactorial. For example, the Selective Serotonin reuptake blocker theory of depression is slowly coming apart. So I am not surprised they can be repurposed for other tasks, including senolytic purposes.

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More reasons to think that topical senolytic skin cream may be a good thing:

Navitoclax (ABT-263) Rejuvenates Human Skin by Eliminating Senescent Dermal Fibroblasts in a Mouse/Human Chimeric Model

Chronic senescence, such as aging, contributes to age-related tissue dysfunction and disease development. The accumulation of senescent fibroblasts and the senescence-associated secretory phenotype is particularly implicated in this process. Removal of senescent cells has been reported to prevent tissue dysfunction and to extend the life span during aging. ABT-263 (navitoclax), which inhibits antiapoptotic proteins, is a leading antiaging drug; however, its role in human skin aging is unclear. This study aimed to determine the rejuvenating effects of ABT-263 on aging skin using a human skin graft mouse model. We assessed the viability of ABT-263-treated skin fibroblasts after inducing senescence. Aged human skin was transplanted under the back skin of nude mice and injected intraperitoneally with the drug or control. Analysis of the skin specimens revealed that ABT-263 induced selective elimination of senescent dermal fibroblasts. Senescent human skin treated with ABT-263 exhibited a decrease in the number of senescent cells and in the expression of aging-related secretory phenotype molecules, such as matrix metalloproteinases and interleukins and an increase in collagen density. Our results indicate that selective removal of senescent skin cells with ABT-263 can improve the aging phenotype of human skin without side effects. ABT-263 is, thus, a novel potential therapeutic agent for skin aging.

https://www.liebertpub.com/doi/10.1089/rej.2022.0048

Related:

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Downregulation of senescence-associated secretory phenotype by knockdown of secreted frizzled-related protein 4 contributes to the prevention of skin aging

There is growing evidence that the appearance and texture of the skin that is altered during the aging process are considerably enhanced by the accumulation of senescent dermal fibroblasts. These senescent cells magnify aging via an inflammatory, histolytic, and senescence-associated secretory phenotype (SASP). Secreted frizzled-related protein 4 (SFRP4) was previously determined to be expressed in dermal fibroblasts of aging skin, and its increased expression has been shown to promote cellular senescence. However, its role in the SASP remains unknown. We found that SFRP4 was significantly expressed in p16ink4a-positive human skin fibroblasts and that treatment with recombinant SFRP4 promoted SASP and senescence, whereas siRNA knockdown of SFRP4 suppressed SASP. Furthermore, we found that knockdown of SFRP4 in mouse skin ameliorates age-related reduction of subcutaneous adipose tissue, panniculus carnosus muscle layer, and thinning and dispersion of collagen fibers. These findings suggest a potential candidate for the development of new skin rejuvenation therapies that suppress SASP.

Companies are starting to target this market with commercial products:

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Fisetin and Quercetin are not colorless - both leave yellow pigment on skin and may have yellowing effect (like carotenoids) on skin if used frequently. It could be a problem in cream preparation. Is there any way to get rid of that color?

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gosh amazing results. What dose and duration you were only? Are you continuing the rapa regiment?

I used high doses of 20mg/week early on. Now I a currently doing 5mg week. I have been using rapa ~20 months.

Do we have any data about whether topical administration would be more beneficial for skin than administration via pills?

Do we have a comparison about topical vs systemic (oral) administration?

If a compound has senolytics properties and has low enough molecular weight, then it wouldn’t eliminate senescent cells even via pills? (also appearance is not only outer layer skin - there are also deeper layers of skin, bones, fat, etc. - where cream may not reach)

For example: Rapamycin decreased periodontitis and improved gum tissue in mice despite that it was given in microcapsules in food (little to no contact of Rapamycin with gum tissue)

No - we don’t have any comparisons on this yet. With regard to Rapamycin there has been only a single topical study on aging skin. And there have been no oral rapamycin studies for impact on skin.

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The Tim Peterson presentation from last December’s Longevity Conference. His presentation covered senolytics as outlined in this post above: Senolytics Topically Administered to Skin for Antiaging Effects - #30 by RapAdmin

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Just wondering if your daughter got any relief from her eczema with One Skin? My son has significant eczema and I might recommend it for him if it could be helpful.

have u even tried tacrolimus ? It got mostly rid of my dark reddish purplish pigmentations and also much of the swelling of which tretinoin and many other things did not. Also to the comment there have been no studies on rapamycin topical to skin is false. There has been at least one likely more on back of hand and an ongoing study using 8% rapa , i think much higher than needed. Though doubt that rapa… for the eczema would not work but tacrolimus likely would if anything would. Can be bought ready made for like .2% in a 10g ointment from Reliable in india for around $15 or so though with a $18 ship/handle fee for no matter how much u buy from them so u may as well order other things from them also… Not to say u couldn’t make a better one by formulating your own tacrolimus solution.l.

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Thanks for the idea, I will look into that.

Hi- wondering if you would be able to put in a link for Reliable in India. Couldn’t find it with a web search. Thanks…