Reversing Wrinkled Skin And Hair Loss In Mice By Restoring Mitochondrial Function. | HairLossTalk Forums
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Reversing Wrinkled Skin And Hair Loss In Mice By Restoring Mitochondrial Function.

Discussion in 'Hair Loss and Alopecia Published Studies' started by Squeegee 2.0, Jan 12, 2020.

  1. Squeegee 2.0

    Squeegee 2.0 Established Member My Regimen

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    Abstract
    Mitochondrial DNA (mtDNA) depletion is involved in mtDNA depletion syndromes, mitochondrial diseases, aging and aging-associated chronic diseases, and other human pathologies. To evaluate the consequences of depletion of mtDNA in the whole animal, we created an inducible mtDNA-depleter mouse expressing, in the polymerase domain of POLG1, a dominant-negative mutation to induce depletion of mtDNA in various tissues. These mice showed reduced mtDNA content, reduced mitochondrial gene expression, and instability of supercomplexes involved in oxidative phosphorylation (OXPHOS) resulting in reduced OXPHOS enzymatic activities. We demonstrate that ubiquitous depletion of mtDNA in mice leads to predominant and profound effects on the skin resulting in wrinkles and visual hair loss with an increased number of dysfunctional hair follicles and inflammatory responses. Development of skin wrinkle was associated with the significant epidermal hyperplasia, hyperkeratosis, increased expression of matrix metalloproteinases, and decreased expression of matrix metalloproteinase inhibitor TIMP1. We also discovered markedly increased skin inflammation that appears to be a contributing factor in skin pathology. Histopathologic analyses revealed dysfunctional hair follicles. mtDNA-depleter mice also show changes in expression of aging-associated markers including IGF1R, KLOTHO, VEGF, and MRPS5. mtDNA-repleter mice showed that, by turning off the mutant POLG1 transgene expression, mitochondrial function, as well as the skin and hair pathology, is reversed to wild-type level. To our knowledge that restoration of mitochondrial functions can reverse the skin and hair pathology is unprecedented.

    https://www.ncbi.nlm.nih.gov/pubmed/30026579

    41419_2018_765_Fig3_HTML.jpg
     
  2. Otis Mack

    Otis Mack Established Member My Regimen

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  3. EndlessPossibilities

    EndlessPossibilities Established Member My Regimen

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    i just posted about this here
    https://www.hairlosstalk.com/intera...r-function-through-sirt1.126746/#post-1865232



    No one notice how this mice lost hair in the male pattern baldness fashion the top and forward baldes and the back and sides still have hair
     
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  4. Squeegee 2.0

    Squeegee 2.0 Established Member My Regimen

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    Coenzyme Q10 deficiency associated with a mitochondrial DNA depletion syndrome: a case report.
    Montero R1, Sánchez-Alcázar JA, Briones P, Navarro-Sastre A, Gallardo E, Bornstein B, Herrero-Martín D, Rivera H, Martin MA, Marti R, García-Cazorla A, Montoya J, Navas P, Artuch R.
    Author information

    Abstract
    OBJECTIVES:
    To report on a case with a mitochondrial DNA (mtDNA) depletion syndrome.

    DESIGN AND METHODS:
    Laboratory studies were done in muscle biopsy and fibroblasts to evaluate coenzyme Q(10) (CoQ(10)) status and quantify mitochondrial DNA.

    RESULTS:
    Decreased CoQ(10) values and a 78% of mtDNA depletion were detected in muscle. Mutational studies failed to reveal any pathogenic mutation in nuclear genes related with mtDNA maintenance.

    CONCLUSIONS:
    mtDNA depletion syndrome was associated with CoQ(10) deficiency in our patient.


    https://www.ncbi.nlm.nih.gov/pubmed/19094978
     
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  5. Otis Mack

    Otis Mack Established Member My Regimen

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    Check out this video.

    I spotted something on the back of one of the untreated aging mouse(one one left) : BALDING SPOT @ about 2: 10



    Watch the whole video because this is about AGING VASCULAR HEALTH. Oooooh what a coincidence the mouse is developing hair loss on his back probably where his vascular health is the worst.
     
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  6. EndlessPossibilities

    EndlessPossibilities Established Member My Regimen

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    the thing is, this is just one issue with male pattern baldness. The problem has always been fibrosis.

    the fibrosis surround the hair follicle. Follicular fibrosis is the actual find.

    if you look at zoomed in scalp pictures of the condition you can see the development of circular looking lesions around the follicle.

    Inflammation causes fibrosis. What causes the inflammation is yet to be determined but i am starting to think toxic metal buildup in the follicle prompts the immune system to attack our hair resulting in fibrosis.
     
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  7. Otis Mack

    Otis Mack Established Member My Regimen

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    Fibrosis is just secondary to a non-growing hair follicle.

    There is a cytokine involved in causing anagen which just happens to dissolve fibrotic tissue. The follicle "knows about and how" to get rid of fibrosis simply when anagen begins.

    Many different non-scarring forms of hair loss have fibrotic streamers.
     
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  8. Otis Mack

    Otis Mack Established Member My Regimen

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    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398151/

    Psoriasis is also thought to be a skin disease caused by vascular problems. (table 1)

    Coincidentally...benoxaprofen is 75% effective in treating psoriasis.



    Probably...anything that can treat psoriasis effectively(benox, IL-17 antagonists, NO donors) will also treat
    Androgenetic Alopecia. There is a similar pattern of vasoconstriction in psoriasis also.

    https://www.physiology.org/doi/full/10.1152/ajpheart.00446.2017



    The impairments in endothelial function and reductions in NO bioavailability observed in the present study agree with findings in animal models used to investigate the vascular effects of inflammatory cytokines central to the pathology of psoriasis


    . Overexpression of IL-17 in mouse keratinocytes induces psoriasis-like skin inflammation, elevates serum cytokine concentrations, and

    reduces the vasodilatory response


    to acetylcholine due, at least in part, to a decrease in vascular NO bioavailability (
    38
     
    #8 Otis Mack, Jan 24, 2020
    Last edited: Jan 26, 2020
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  9. Squeegee 2.0

    Squeegee 2.0 Established Member My Regimen

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    Good find! Also Mitochondrial dysfunctions is associated with several vascular diseases.. just one example...

    The role of mitochondrial dysfunction in cardiovascular disease: a brief review.
    Chistiakov DA1, Shkurat TP2, Melnichenko AA3, Grechko AV4, Orekhov AN5,6.
    Author information

    Abstract
    Cardiovascular disease (CVD) is a leading cause of mortality worldwide. Proper mitochondrial function is necessary in tissues and organs that are of high energy demand, including the heart. Mitochondria are very sensitive to nutrient and oxygen supply and undergo metabolic adaptation to the changing environment. In CVD, such an adaptation is impaired, which, in turn, leads to a progressive decline of the mitochondrial function associated with abnormalities in the respiratory chain and ATP synthesis, increased oxidative stress, and loss of the structural integrity of mitochondria. Uncoupling of the electron transport chain in dysfunctional mitochondria results in enhanced production of reactive oxygen species, depletion of cell ATP pool, extensive cell damage, and apoptosis of cardiomyocytes. Mitophagy is a process, during which cells clear themselves from dysfunctional and damaged mitochondria using autophagic mechanism. Deregulation of this process in the failing heart, accumulation of dysfunctional mitochondria makes the situation even more adverse. In cardiac pathology, aberrations of the activity of the respiratory chain and ATP production may be considered as a core of mitochondrial dysfunction. Indeed, therapeutic restoration of these key functional properties can be considered as a primary goal for improvement of mitochondrial dysfunction in CVD. Key messages Mitochondrial dysfunction plays a crucial role in cardiovascular disease pathogenesis. Cardiovascular disease is associated with altered mithochondrial biogenesis and clearance. In cardiovascular disease, impaired mitochondrial function results in decreased ATP production and enhanced ROS formation.
     
  10. Squeegee 2.0

    Squeegee 2.0 Established Member My Regimen

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  11. EndlessPossibilities

    EndlessPossibilities Established Member My Regimen

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    Omg how did i miss this.

    why isnt anybody taking this drug?
     
  12. pegasus2

    pegasus2 Senior Member My Regimen

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    Because it was taken off the market 40 years ago.
     
  13. EndlessPossibilities

    EndlessPossibilities Established Member My Regimen

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    why hasnt anyone studied its mechanism behind the success
     
  14. Squeegee 2.0

    Squeegee 2.0 Established Member My Regimen

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    Repigmentation and new growth of hairs after anti–interleukin-17 therapy with secukinumab for psoriasis


    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031562/

    tileshop.jpg tileshop.jpg

     
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  15. Mandar kumthekar

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    Am I the only one who is not doctor on this forum?
     
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  16. Otis Mack

    Otis Mack Established Member My Regimen

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    While I think mito dysfunction is a complicating process in Androgenetic Alopecia, I wouldn't really call it the driver.

    Reason:

    in the human male to SCID mice study, just transplanting Androgenetic Alopecia follicles on that mouse wouldn't really solve any underlying mitochondrial problems by itself.

    The transplant tho could have supplied a much better blood flow than what was present in the human scalp and THEN helped mito function.

    So...I'm believing microcirculation problems are causing the subsequent problems we see in Androgenetic Alopecia.
     
  17. HairCook

    HairCook Experienced Member My Regimen

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    Apparently ursolic acid found in a lot of plants is also an inhibitor of il-17: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123037/

    It apparently also increases IGF-1: https://examine.com/supplements/ursolic-acid/

    And it is actually available as pure supplement: https://www.amazon.co.uk/ursolic-capsules-loose-increase-muscle/dp/B071NY5GFL

    Theoretically one could try it topically as it has a molecular weight of 456, and it is solubility:

    "Ursolic acid is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide (DMF), which should be purged with an inert gas. The solubility of ursolic acid in ethanol is approximately 0.5 mg/ml and approximately 10 mg/ml in DMSO and DMF. Ursolic acid is sparingly soluble in aqueous buffers".

    As it is acidid one would might also need to consider adjust its ph.

    Furthermore it seems to be a potent sirt1 agonist, some sources claim it being more potent than resveratrol:
    https://www.ncbi.nlm.nih.gov/pubmed/29758202
    https://www.ncbi.nlm.nih.gov/pubmed/27514536
    https://www.em-consulte.com/en/article/1034295
    http://www.eurekaselect.com/152808/article
     
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  18. ComeBackTemples

    ComeBackTemples Established Member My Regimen

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    Wow, interesting thread. So for dummies like me it is beneficial four our health to consume q10 and ursolic acid orally. Does anyone know what Kind of amount to take each day?

    My Plan was originally to get hold of trans-Resveratrol. However, after reading this threat it might make more sense to Stuck with ursolic acid!
     
  19. Squeegee 2.0

    Squeegee 2.0 Established Member My Regimen

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    Ursolic Acid seems to be a potent interleukin 17 inhibitor but the problem is.. try to find a pure form of it without paying big $$$$$ Most supplements are not at all in a pure form.

    https://ca.bodybuilding.com/store/ast/urso-x.html?skuId=AST980106
    Rosemary Extract (Rosmarinus officinalis) (leaf) containing 25% Ursolic Acid

    https://ca.bodybuilding.com/store/san/conquest-250.html?skuId=SAN950016
    Ursolic Acid (Derived From Paulownia Tomentosa [Thumb.] Steud.


    Quote for 98% ursolic acid from Alibaba
    Thanks for your inquiry.

    This is Tiffany Wang come from Arisun and we are the producer of Plant Extract. The products are exported to Europe, Southeast Asia, USA, and many other countries and got high reputation from the customers.

    About Rosemary Extract Powder,Please check my detailed quotation as follows:
    Product Name: Rosemary Extract

    Specification:Ursolic Acid 98%

    Price:FOB China US$1292.00


    Freight:US$45.00 from China to Canada by Fedex Express door to door service.

    Sum Amount:US$1337.00


    Packing: 1kg/Aluminum foil bag

    Shipment/Lead time: Prompt after the payment received.
    Payment: Alibaba Trade Assurance; Alipay, Western Union, T/T in advance.

    We suggest that you make shipment via Alibaba Trade Assurance,Alibaba will 100% ensure your money and account safety.

    Sincerely hope to establish a good cooperation with you



    Cyanin could be another option:

    The flavonoid cyanidin blocks binding of the cytokine interleukin-17A to the IL-17RA subunit to alleviate inflammation in vivo

    Cyanidin, a key flavonoid that is present in red berries and other fruits, attenuates the development of several diseases, including asthma, diabetes, atherosclerosis, and cancer, through its anti-inflammatory effects. We investigated the molecular basis of cyanidin action. Through a structure-based search for small molecules that inhibit signaling by the proinflammatory cytokine interleukin-17A (IL-17A), we found that cyanidin specifically recognizes an IL-17A binding site in the IL-17A receptor subunit (IL-17RA) and inhibits the IL-17A/IL-17RA interaction. Experiments with mice demonstrated that cyanidin inhibited IL-17A–induced skin hyperplasia, attenuated inflammation induced by IL-17–producing T helper 17 (TH17) cells (but not that induced by TH1 or TH2 cells), and alleviated airway hyperreactivity in models of steroid-resistant and severe asthma. Our findings uncover a previously uncharacterized molecular mechanism of action of cyanidin, which may inform its further development into an effective small-molecule drug for the treatment of IL-17A–dependent inflammatory diseases and cancer.


    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520994/
     
  20. Squeegee 2.0

    Squeegee 2.0 Established Member My Regimen

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    #20 Squeegee 2.0, Feb 18, 2020
    Last edited: Feb 18, 2020

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