IL-17 Protein Plays an Important Role in Skin Aging, FDA Approved Therapies Available

  • A team of researchers from IRB Barcelona and CNAG identifies the IL-17 protein as a determining factor in skin ageing. Local IL-17 orchestrates skin aging.
  • Blocking the function of IL-17 reduces the pro-inflammatory state and delays the appearance of age-related features in the skin, including hair follicle growth.
  • Published in the journal Nature Aging, the work opens up new perspectives in the development of therapies to improve skin ageing health.
  • There are numerous FDA-approved drugs already on the market that inhibit IL-17 (they are used for treatment of psoriasis).

Reversing the symptoms of ageing in skin

Previous studies had described that IL-17 is related to some autoimmune skin diseases, such as psoriasis, and there are existing treatments that block this protein. The team of researchers studied the response of various aspects to blocking IL-17 activity, including hair follicle growth, transepidermal water loss, wound healing, and genetic markers of ageing. These four parameters showed an improvement after treatment, as the acquisition of these ageing traits was significantly delayed.

“IL-17 protein is essential for vital body functions, such as defense against microbes and wound healing, so permanently blocking it would not be an option. What we have observed is that its temporary inhibition offers benefits that could be of interest at a therapeutic level,” says Dr. Guiomar Solanas, associate researcher at IRB Barcelona.

Future work by the researchers will focus on clarifying the ageing processes that are related to inflammatory states in the skin and how these are linked to IL-17. The team will also address whether IL-17 is involved in the ageing and deterioration of other tissues and organs.

Read the research Summary Press Release Here:

Full Research Paper (open access)

Targeting lymphoid-derived IL-17 signaling to delay skin aging

Skin aging is characterized by structural and functional changes that contribute to age-associated frailty. This probably depends on synergy between alterations in the local niche and stem cell-intrinsic changes, underscored by proinflammatory microenvironments that drive pleotropic changes. The nature of these age-associated inflammatory cues, or how they affect tissue aging, is unknown. Based on single-cell RNA sequencing of the dermal compartment of mouse skin, we show a skew towards an IL-17-expressing phenotype of T helper cells, γδ T cells and innate lymphoid cells in aged skin. Importantly, in vivo blockade of IL-17 signaling during aging reduces the proinflammatory state of the skin, delaying the appearance of age-related traits. Mechanistically, aberrant IL-17 signals through NF-κB in epidermal cells to impair homeostatic functions while promoting an inflammatory state. Our results indicate that aged skin shows signs of chronic inflammation and that increased IL-17 signaling could be targeted to prevent age-associated skin ailments.

https://www.nature.com/articles/s43587-023-00431-z

See Full Discussion on this News topic here: IL-17 Protein Plays an Important Role in Skin Aging, FDA Approved Therapies Available

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These look potentially interesting for pulsed or lower level dosing (?)

Types of IL-17 Inhibitors

IL-17 inhibitors are a type of drug called “injectables” that are self-administered by subcutaneous injection applied with a needle under the skin. All three IL-17 inhibitors follow a similar dosing schedule of once a week during the first month, followed by once-monthly dosing for maintenance after the first five weeks.11

Cosentyx (Secukinumab), Taltz (Ixekizumab), and Siliq (Brodalumab) are similar types of drugs, but they each have slightly different dosing. Be sure to ask your pharmacist or a healthcare provider about the specific dosing schedule for the type of IL-17 inhibitor you’re prescribed.

These IL-17 Inhibitors Are FDA Approved

Three IL-17 inhibitors—Cosentyx (secukinumab), Taltz (ixekizumab), and Siliq (brodalumab)—are FDA-approved for the treatment of plaque psoriasis and psoriatic arthritis.

Numerous studies have established that IL-17 inhibitors are generally well-tolerated, safe, and provide significant benefits for people with psoriasis, psoriatic arthritis, and ankylosing spondylitis.13

However, these biologic medications are not without risks. Most notably, IL-17 inhibitors are immunosuppressants. They tone down the immune system, which increases the risk of serious infections. Immunosuppressive therapies also weaken the immune system’s ability to detect and destroy cancer cells or fight the infections that cause cancer

https://www.verywellhealth.com/il-17-inhibitors-6503894#:~:text=Three%20IL-17%20inhibitors—Cosentyx,plaque%20psoriasis%20and%20psoriatic%20arthritis.

More information on these drugs:

Prices, at least for secukinumab, in India, seem to be commonly in the $50 to $150 range (per 150ml) … 82 rupees to the US$. But it does seem to have refrigeration requirements, which makes it difficult to ship from India to other parts of the world (not sure if this applies to the powder and the liquid formula, or just the liquid formula - do your research if buying).

USA pricing via GoodRX is a little higher ($5,000 to $7,000 per month it seems, see below):

https://www.goodrx.com/cosentyx

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Long-term safety of Secukinumab:

A systematic review and meta-analysis of the efficacy and safety of the interleukin (IL)-12/23 and IL-17 inhibitors ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab and tildrakizumab

Conclusion: Ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, and tildrakizumab were highly efficacious and generally well-tolerated when used as treatments for moderate to severe plaque psoriasis.

Open Access Paper:

Conclusions: This study provided a clear proof of beneficial effects of IL-17 inhibitors in improving joint disease activity in patients with PsA with an acceptable safety profile.

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This study indicates that both RAPA and DEX inhibit the production of IL-17 and IFN-γ by PBMCs. RAPA is much stronger in inhibiting the production of IL-17 than DEX.

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RAPA caused a significant reduction in IL-17 in both VKH patients and healthy controls. The production of IL-17 was almost totally blocked (>97%) by RAPA at a dosage of 10 ng/ml.

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This could be the main reason why joint pain relief is experienced by many Rapa users.

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Patent expires for Secukinumab in 2025 / 2026 it seems:

Cosentyx
Company: Novartis
2020 sales: $4 billion
Key patent expirations: 2025 to 2026

When Novartis’ Cosentyx arrived in 2015 as the first next-gen psoriasis treatment in the United States, the med’s blockbuster status was assured. In fact, the drug reached that milestone during its first full year on the market.

But another guarantee came with the launch—competition and plenty of it.

Despite challenges, the drug has managed to stay ahead of its rivals by adding indications and satisfying doctors and patients along the way.

Source: https://www.fiercepharma.com/special-report/top-15-blockbuster-patent-expirations-coming-decade

Though it may also be later… from different sources:

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@LaraPo I wonder if a mesotherapy approach might be useful with this drug for skin aging? (for easier self-administration and also to avoid any possible systemic issues that might arise with simultaneous use with rapamycin):

The Novartis patent suggests:

Preferred forms for administration include forms suitable for parenteral administration , e . g . by injection or infusion , for example by bolus injection or continuous infusion .
Where the product is for injection or infusion , it may take the form of a suspension , solution or emulsion in an oily or aqueous vehicle and it may contain formulatory agents , such as as suspending , preservative , stabilising and / or dispersing agent . Alternatively , the antibody molecule may be in dry form , for reconstitution before use with an appropriate sterile liquid .

Once formulated , the compositions of the invention can be administered directly to the subject. The subjects to be treated can be animals . However , it is preferred that the compositions are adapted for administration to human subiects .

The pharmaceutical compositions of this invention may be administered by any number of routes including , but not limited to , oral , intravenous , intramuscular , intra - arterial , intramedullary , intrathecal , intraventricular , transdermal , transcutaneous ( for example , see WO 98 / 20734 ) , subcutaneous , intraperitoneal , intranasal , enteral , topical , sublingual , intravaginal or rectal routes .

Hyposprays may also be used to administer the pharmaceutical compositions of the invention . Typically , the therapeutic compositions may be prepared as injectables , either as liquid solutions or suspensions . Solid forms suitable for solution in , or suspension in , liquid vehicles prior to injection may also be prepared .

Direct delivery of the compositions will generally be accomplished by injection , subcutaneously , intraperitoneally , intravenously or intramuscularly , or delivered to the interstitial space of a tissue . The compositions can also be administered into a lesion . Dosage treatment may be a single dose schedule or a multiple dose schedule.

Source: Novartis Patent https://worldwide.espacenet.com/publicationDetails/biblio?FT=D&locale=en_EP&CC=NL&NR=300749I2&KC=I2

and this is also interesting:

Secukinumab distributes into dermal interstitial fluid of psoriasis patients as demonstrated by open flow microperfusion

https://onlinelibrary.wiley.com/doi/10.1111/exd.12863

More information about intra-dermal injections (mesotherapy):

https://opentextbc.ca/clinicalskills/chapter/6-7-intradermal-subcutaneous-and-intramuscular-injections/

Looks like it can be administered in many different ways, including subcutaneously which is close to mesotherapy. Would be interesting to try. I’m currently using 3 pin nanosoft, 34 g, cartridges for intradermal injections. The depth is 1.2-1.5mm. Such needles are so thin (34g) that there’s no blood.

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That’s interesting. If the inhibition was over 97% at 10 ng/mL then it’s probably quite significant also at 1 ng/mL, which is well within concentrations that people reach for a few days after taking typical doses of rapamycin for longevity.

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They measured in blood. What I think we really want to know is how much IL-17 inhibition happens in the skin… wouldn’t we want a skin biopsy / tissue sample measure to better understand that. I don’t have much experience in this area - how representative is the blood measure, for skin measures?

Methods: Blood samples were drawn from 10 active VKH patients and 10 healthy individuals. PBMCs were cultured with or without anti-CD3 and anti-CD28 antibodies in the presence or absence of different concentrations of RAPA or DEX for 72 h

Full Research Paper here:

Inhibitory effect of rapamycin and dexamethasone on production of IL-17 and IFN-γ in Vogt–Koyanagi–Harada patients

https://sci-hub.ee/10.1136/bjo.2008.142489#

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This might help make an argument for higher dosing pulsed over longer periods of time… similar to the blood brain barrier issue / argument: Rapamycin and the Issue of Getting Through the Blood Brain Barrier

But it also suggests that with whatever dosing levels of rapamycin that people are using, they are likely getting some skin anti-aging benefits along with other organ, etc. anti-aging benefits.

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There are some companies offering blood tests for systemic IL-17 levels…

What I really wanted to find was a skin-level test that was commercially available. I found this paper on a skin biopsy method of evaluating IL-17 levels and it seemed to work when evaluating skin with psoriasis lesions, but not in regular skin … so it doesn’t sound like the IL-17 skin testing technology is quite where I’d like to see it.

Full Paper Available for Download (PDF): https://sci-hub.ee/10.1208/s12248-017-0094-4

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I’ve been researching RAPA as a potential substitute for Methotrexate, which I take for psoriatic arthritis. MTX doesn’t work that well and has frustrating side-effects, thinning skin being one of them. Thank you for this information.

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Th17 cells have recently emerged as a major player in inflammatory and autoimmune diseases via the production of pro-inflammatory cytokines IL-17, IL-17F, and IL-22. The differentiation of Th17 cells and the associated cytokine production is directly controlled by RORγt. Here we show that ursolic acid (UA), a small molecule present in herbal medicine, selectively and effectively inhibits the function of RORγt, resulting in greatly decreased IL-17 expression in both developing and differentiated Th17 cells. In addition, treatment with UA ameliorated experimental autoimmune encephalomyelitis. The results thus suggest UA as a valuable drug candidate or leading compound for developing treatments of Th17-mediated inflammatory diseases and cancer.

Ursolic Acid Suppresses Interleukin-17 (IL-17) Production by Selectively Antagonizing the Function of RORγt Protein*

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Yep, I think I will just stick to rapa to inhibit IL-17.
From the article you cite:

Both RAPA and DEX were able to significantly inhibit the production of IL-17 and IFN-γ by PBMCs from patients and healthy controls. RAPA was able to completely inhibit IL-17 production at a dosage of 10 ng/ml but only partially suppressed IFN-γ production even at a much higher concentration (1000 ng/ml). DEX inhibited the production of both IL-17 and IFN-γ by approximately 70%.

Conclusions: This study indicates that both RAPA and DEX inhibit the production of IL-17 and IFN-γ by PBMCs. RAPA is much stronger in inhibiting the production of IL-17 than DEX.

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That IL-17 inhibition might explain why rapamycin may help with hair growth and graying:

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Just realized that yes, we’ve discussed this compound in the past in the hair graying thread: Reverse Gray Hair, Hair Repigmentation - #38 by HawksFan

Seems like multiple lines of evidence are converging a bit here…

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Interesting comments by “Reason” of Fight Aging, seems to confirm the idea that trying to target just the skin may be a winning approach with this IL-17 protein and the existing drugs that can be used to inhibit it. At some point in the not too distant future I think I’d like to try the mesotherapy approach that @LaraPo has described in the past, using the existing IL-17 inhibitor drugs that were mentioned earlier in this thread. Perhaps this might also work with micro-needling approaches on the scalp for hair regrowth and repigmentation.

I also wonder if there is potential to use a mesotherapy version of a rapamycin injection formulation given the good inhibition of IL-17 that rapamycin has shown in studies. Sort of a “rapamycin injection Lite” version of what @Mac has done with his protocol: Intramuscular (IM) + Intranasal (IN) Rapamycin - A new paradigm for human longevity translation

The researchers show that blocking IL-17 slows the manifestations of skin aging. The challenge in this sort of approach is that inflammatory signal molecules are needed for the normal immune response to function correctly. The treatment of autoimmune conditions via blockade of various inflammatory signals has meaningful side-effects that include suppression of necessary immune responses. This is less of a concern if treatments target only the skin, but we should hope that researchers can identify more targeted, subtle ways to eliminate only excess inflammatory signaling in the rest of the aging body.

Source: https://www.fightaging.org/archives/2023/06/targeting-pro-inflammatory-cytokine-il-17-to-slow-skin-aging/

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What is considered a “typical dose” of Rapa for aging? I take 5mg per week and am curious if that’s considered typical.