Senolytics Topically Administered to Skin for Antiaging Effects

[RapAdmin]

Some interesting points:

The test reagents dissolved in ethanol (20 lL of each) were topically applied to both sides of the ear 30 min before and 3 h after each challenge of oxazolone on days 7, 10 and 13.
…
co-treatment with dasatinib, LCB 03-0110 and tacrolimus at concentrations of 0.02%, 0.05% or 0.1% reduced the ear swelling significantly in a dose-dependent manner
…

Therefore, this result suggests that dasatinib and LCB 03-0110 do not provoke skin atrophy after prolonged treatment, even at higher-than-normal concentrations.
…
we think that dasatinib and LCB 03-0110 might offer advantages over steroidal drugs in treating inflammatory skin disease because they do not induce skin atrophy, the major adverse side-effect of steroidal drugs.
…
we expect that they would have potent anticancer activity.* 33

They also note in the paper:

dasatinib suppressed TNF-a production following stimulation of Toll-like receptor signalling with lipopolysaccharide (LPS). 31

"However, treatment with dasatinib and LCB 03-0110 significantly reduced the induction by an average of 63.4% and 66.1% respectively.

Another paper related to skin aging and inflammatory cytokines:

The role of cytokines in skin aging

Aged skin is characterized by a decrease in collagen content and skin thickness which result in dry, wrinkled skin that is easily bruised and takes a longer time to heal. Cytokines play a crucial role in the manifestation of these features of old skin. The pro-inflammatory cytokine tumor necrosis factor-alpha inhibits collagen synthesis and enhances collagen degradation by increasing the production of MMP-9. It also lowers the skin immunity and thus increases the risk of cutaneous infections in old age.

https://www.tandfonline.com/doi/full/10.3109/13697137.2013.802303

Full Paper: Sci-Hub | The role of cytokines in skin aging | 10.3109/13697137.2013.802303

Exercept:

TNF- α has a key role in inflammatory responses that occur in the skin. It is able to modulate the expression of the MMP gene and is responsible for inducing the production of MMP-9, an enzyme that causes skin aging by causing skin damage and does not allow its repair 52 . When the cells of the epidermis are exposed to persistent TNF- α , the production of MMP-9 is disturbed and the epidermis can be damaged irreversibly 52 .

Sounds like Dasatinib cream would be a good thing for our skin… significantly lowering inflammation and potentially removing senescent cells. I’m going to try a DIY project around this.

If others here are trying this - please do a pre and post photo (in identical lighting and conditions) to help demonstrate if its working. Perhaps do just one hand with the Dasatinib cream and one without (treatment as usual). And take photos every 3 months to compare.

[RapAdmin]

Dasatinib Ointment Promotes Healing of Murine Excisional Skin Wound

Dasatinib, a tyrosine kinase inhibitor, has been shown to produce anti-inflammatory activity and impair vascular integrity in vivo, including during skin wound healing, potentially promoting the repair process. Given that dasatinib is a lipophilic small molecule capable of penetrating skin, topical dasatinib might provide benefits in wound healing.

Following treatment with 0.2% dasatinib ointment, minor wound bleeding and scab reformation were observed during the late phase, which contributed to delayed healing. In conclusion, our data suggest that dasatinib ointment, mainly at 0.1%, promotes the repair process by reducing inflammation and producing a local and temporal vascular leakage, leading to an increase in fibrin(ogen) deposition, re-epithelialization, and angiogenesis. Therefore, topical dasatinib might be a potential novel candidate to facilitate skin wound healing.

Open Access Paper:

Dasatinib Ointment Promotes Healing of Murine Excisional Skin Wound - PubMed

The data demonstrated that 0.1% dasatinib ointment accelerated skin wound healing in association with reduced inflammation, impaired vascular integrity, increased fibrin(ogen) accumulation, improved keratinocyte proliferation, and enhanced angiogenesis at an early phase without affecting the late phase of repair in mice. However, 0.2% dasatinib ointment induced minor wound bleeding and scab reformation during the late phase, which contributed to delayed healing, although it appeared to promote the early phase of repair.

To prepare 0.1 and 0.2% ointments, 10 and 20 mg dasatinib powder (SML2589; Sigma) was weighed and added to 10 g ointment, respectively. Dasatinib ointments were freshly prepared for each experiment and kept at 2–8 °C until use.

[Bicep]

Nice! So I haven’t done any shopping for dasatinib yet. It comes as a powder from India? Cost?

[Bicep]

Also:

Quercetin topical application, from conventional dosage forms to nanodosage...

Why don’t they throw this in too?

[RapAdmin]

@Bicep

It comes as a powder from India? Cost?

You could buy it as Dasatanib API powder (active pharmaceutical ingredient)… but I wasn’t really thinking of that just because it could get complex. Any of the companies selling API powder are used to selling in many kilo quantities… not sure they’d want to deal with someone buying 5 grams or 10 grams of the stuff. No harm in trying, I guess.

I’m thinking of taking the 100mg tablets route, crush, and dissolve in transcutol or similar and then mix with CeraVe, Cetaphil or similar… It seems that a target dosing is 0.1% would be a reasonable starting point based on the study above that had good results with that dosing.

But if someone decides to buy the API powder, let us know how it goes.

[RapAdmin]

@Bicep

Why don’t they throw this in too?

@LaraPo has mentioned that you don’t want to use Quercetin because it will stain your skin yellowy orange.

[RapAdmin]

While I was researching the impact of TNF-alpha on skin aging and related cytokines, I came across this paper which looked interesting… out of UCSF (but done with a Korean skin cream company). I’m thinking that this might be a good “base” into which I could add my senolytic drug mixture.

As humans get older, we experience a low-level of inflammation—dubbed “inflamm-aging”—driven by an increase in molecules in the blood called cytokines. This age-related inflammation has been linked to serious chronic diseases, including Alzheimer’s disease, cardiovascular disease, and diabetes. Scientists initially thought that the inflammation stemmed from the immune system or the liver, but a group of dermatologists at UCSF have a different theory.

“The inflammation must come from an organ big enough that very minor inflammation can affect the whole body. Skin is a good candidate for this because of its size,” said study senior author Mao-Qiang Man, MD, a research scientist in the UCSF Department of Dermatology, who is based at the San Francisco VA Health Care System and is also a visiting professor at Southern Medical University in Guangzhou, China. “Once we get old, we have dermatological symptoms like itchiness, dryness, and changes in acidity. It could be that the skin has very minor inflammation, and because it’s such a large organ it elevates circulating cytokine levels.”

Our skin starts to deteriorate around age 50 with changes to epidermal pH, hydration, and the permeability barrier, which keeps water in and bacteria and other potential pathogens out. A loss of moisture and breaks in the permeability barrier cause the skin to release inflammatory cytokines. Ordinarily, these cytokines help to repair defects in the barrier, but in aging skin the barrier can’t be fixed as easily, so the inflammatory signals continue to be released, eventually reaching the blood.

“Until recently, the scientific community didn’t believe that skin could contribute to systemic inflammation and disease. But in the last five years, studies of psoriasis and dermatitis have shown that skin inflammation from these diseases likely increases the risk of heart disease," said study lead author Theodora Mauro, MD, a professor of dermatology at UCSF and the San Francisco VA Health Care System. “Aging skin is much more common than psoriasis or dermatitis, so the overall risk to the population from aging skin could far outweigh that seen from skin diseases. Decreasing inflammation simply by treating the skin dysfunction seen in aging could have profound health effects.”

In the study, published March 5, 2019 in the Journal of the European Academy of Dermatology and Venereology, Mauro, Man and colleagues attempted to reverse age-related skin damage using an over-the-counter skin cream formulated based on prior research by Man and colleagues, and which the researchers had previously shown to contribute to skin repair based on its beneficial ratio of three types of lipids (cholesterol, free fatty acids, and ceramides) that are vital for skin health.

Thirty-three older adults between the ages of 58 and 95 applied the cream all over their bodies twice a day for 30 days. After a month, the researchers measured blood levels of three cytokines—interleukin-1 beta, interleukin-6, and tumor necrosis factor (TNF) alpha—that have all been implicated in age-related inflammatory diseases. Using the cream reduced the amount of all three cytokines compared to both the participants’ levels before using the cream and the levels of similarly aged adults who did not use the cream. In fact, using the cream lowered participants’ cytokine levels to be nearly equivalent with people in their 30s, suggesting that rejuvenating the skin can reverse “inflamm-aging.” The cream also improved skin hydration, lowered pH, and repaired the permeability barrier.

Related research paper:

Topical applications of an emollient reduce circulating pro-inflammatory cytokine levels in chronically aged humans: a pilot clinical study

Because a previous study had shown that topical applications of Atopalm® (Supplemental Table 1), an over-the-counter, triple lipid formulation (Neopharm, South Korea), improves epidermal function in humans8, we chose this formulation. The entire skin surface of the treated, aged subjects was treated topically with ≈3ml of this formulation twice-daily for one month, while the parallel, aged cohort remained untreated. To ensure consistency in the volume of cream applied, as well as the timing of each application, all topical applications were performed by designated, trained staff. The untreated, young control group were recruited from the residents of Dalian City. This pilot study was carried out during the early Spring (i.e., from March 14 to April 14, 2017), to prove the concept that improvements in epidermal function can lower circulating levels of cytokines.

Paper: (pay walled): https://onlinelibrary.wiley.com/doi/10.1111/jdv.15540

Full Paper from Sci-Hub: Sci-Hub | Topical Applications of an Emollient Reduce Circulating Pro-Inflammatory Cytokine Levels in Chronically Aged Humans: A Pilot Clinical Study | 10.1111/jdv.15540

I think this is the product used in the study:

ATOPALM Face Cream

Amazon Atalopalm “store”: Amazon.com: ATOPALM

Ingredients of the product used in the study (not sure how it matches up with above cream):

[RapAdmin]

Related:

Consistent with these findings in chronologically aged mice, a pilot study in aged humans (58 to 95 years old without skin diseases) also demonstrated that correction of epidermal function by repeated topical applications of an emollient, previously shown to enhance epidermal function in normal humans, reduced circulating levels of IL-1β, IL-6 and TNFα.19 Together, this evidence suggests a pathogenic role for epidermal keratinocytes, and possibly dermal fibroblasts and/or subcutaneous tissues, in chronic aging-associated systemic inflammation. Moreover, the fact that improving epidermal function alone lowered circulating cytokine levels unlikely supports the primary role of other organs or tissues, including adipose tissue, in the pathogenesis of “inflammaging”. Finally, because these cytokines have been linked to the development of aging-associated disorders,1–6 we speculate further that exposure of skin to additional exogenous stressors, such as a reduced ambient humidity or to excessive psychological stress, both of which can provoke and exacerbate epidermal permeability abnormality and inflammation, could accelerate the development of inflammaging-associated disorders (Figure 1).

Taken together, this evidence suggests that strategies which enhance epidermal function in aged skin could reduce circulating levels of inflammatory cytokines, suggesting the potential utility of such corrective approaches as a strategy to prevent and/or mitigate chronic aging-associated disorders. Yet, further studies are needed to confirm that skin-derived “inflammaging” provoke the downstream development of these disorders.

Could Inflammaging and Its Sequelae Be Prevented or Mitigated? - PubMed

Full article (open access): Could Inflammaging and Its Sequelae Be Prevented or Mitigated? - PMC

Inflammaging and the Skin - PubMed

Can Skin Aging Contribute to Systemic Inflammaging? - PubMed

Open Access Article: https://www.jidonline.org/article/S0022-202X(21)02402-7/fulltext

Response to the above article (open access):

Our recent studies have shown that aged epidermis, in a futile attempt to restore normal barrier function, mounts a sustained cytokine response, and that these signaling molecules soon reach circulation (Ye et al., 2019). This link seems established, because restoration of barrier competence in aging skin by occlusive agents, such as petrolatum, normalizes both epidermal cytokine production and circulating levels of the age-related cytokines (IL-1β, IL-6, and TNF-α) (Man and Elias, 2019;Ye et al., 2019). In contrast,Pilkington et al., 2021 have ignored this literature, instead choosing to focus on senescent keratinocytes as the source of the inflammasome while ignoring the overarching role of barrier dysfunction in driving this sequence. We are concerned that this limited viewpoint could alter the choice of appropriate therapeutic options for treating aged skin.

https://www.jidonline.org/article/S0022-202X(21)01635-3/fulltext

[McAlister]

Here’s the published (and easier to read) version of that paper:
Acad Dermatol Venereol - 2019 - Ye.pdf (180.9 KB)

Also, here’s a supplemental figure that compares young, aged, and treated aged side by side:

[desertshores]

@RapAdmin

Dasatanib

“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”
As you can see dasatinib is not very soluble in most things. I couldn’t find any direct evidence that it is soluble in Transcutol, which is one of my favorite DIY skin lotion/spray ingredients.
I think that I will try a little lemon juice ( pH ~2-3) which will then mix quite well with Transcutol and water.
This should produce a spray that is pleasant.

I am currently using dasatinib in Transcutol and water, but I really have no way of telling how much dasatinib got dissolved and it will take some time to evaluate its effects.

sprycel-epar-scientific-discussion_en.pdf

[McAlister]

When you mixed the dasatinib into transcutol, did it form a homogenous solution? Generally speaking, when something isn’t soluble—you know. It will separate or form obvious clumps.

[desertshores]

It’s hard to tell because I am crushing tablets that have obvious fillers that are insoluble, so I always end up with a little grit at the bottom. After my mixture has soaked a while, I filter it and bottle it. I have no idea at this time how much dasatinib was dissolved. Since dasatinib should dissolve nicely in a little lemon juice, I should at least be getting a little more into my final solution.

[RapAdmin]

How do you mix the formulation - by hand, or do you have a good mixer. I used this for all my mixing: Amazon.com

I wonder if a good protocol for integrating dasatinib into a skin cream would be first to crush and dissolve the tablets in Salicylic acid (the BHA used in skincare products, is the most acidic at pH 3.0), then mix with transcutol for increased skin absorption, then mix with a standard skin cream - like CereVe or the Atopalm cream mentioned earlier in this thread.

Salicylic acid

[desertshores]

You could, but salicylic acid is something I usually put on warts.
Somehow the lemon juice seems more appealing.

I have a magnetic stirrer and heating plate, but I usually just crush up the tablets stir and let them set in the solvent for a few hours or overnight. Then I filter the mixture, before adding the Transcutol and water.

I don’t have a pH meter, but I do have some pH strips. The filtered “Real Lemon Juice” from the grocery store has a pH of ~ 2.5, so I should easily be able to dissolve 50 mg of dasatinib in 20m/L of lemon juice. Actually, I am in the process of doing that right now.

Obviously, from looking at the paper one would assume it’s the stomach acid that makes dasatinib bioavailable.

[vegasallen1]

Quercetin from Life Extension is white powder in capsules.

[RapAdmin]

Interesting… I’ll order some and try it. Generally Quercetin is described as a yellow powder, so I wonder what they’ve done to change the color. Seems likely to be soluble in transcutol.

Quercetin

The name quercetin (3,3’,4’,5,7-pentahydroxyflavone) [Figure 1] comes from the Latin word “Quercetum” which means Oak Forest, belongs to the class called flavonols that cannot be produced in the human body.[14] It is yellow color and is poorly soluble in hot water, quite soluble in alcohol and lipids and is insoluble in cold water. Quercetin is said to be one of the most widely used bioflavonoids for the treatment of metabolic and inflammatory disorders.

Source: Overviews of Biological Importance of Quercetin: A Bioactive Flavonoid - PMC.

[vegasallen1]

It’s called Bio-Quercetin.

[desertshores]

Are you sure it’s not just the capsule that is white? I cannot find any indication that Bio-Quercetin, which is also sold by Thorne, is not yellow.
Bio-Querticin is phosphatidylcholine-bound quercetin and is said to be 50 times more bioavailable than ordinary quercetin.
If you have some can you open a capsule and see what the color is?

[vegasallen1]

I did open one and verified that it’s a clear capsule with white powder.

[RapAdmin]

OK - I’m going to add it to my senolytic superskin cream!

Will report back and do pre and post photos of my hands.