Hair Cuts #1

Hair Cuts #1 (January 6, 2023 - February 24, 2023) ____________________________________________________________________________

Hairforce Academy - welcome to the inaugural HairDAO Monthly, where you can get your hairy alpha. These documents will stitch together the most important conversations and happenings within the DAO, providing a compressed recap of what you may have missed while you were off losing your hair.

Highlight: TGF-b vs PAI-1 The most promising target today in the hair loss community remains PAI-1. Inhibition of PAI-1 has showed strong benefits across a plethora of diseases, from brain injury to musculosketal atrophy to cellular senescence. While much of the work has been done mice thus far (to Dr. Ralf Paus’s chagrin), there exists strong evidence of PAI-1’s inhibition longevity effects in humans through a mutation in an American Amish community.

The gene was first covered by Follicle Thought in March 2021 through Eirion Therapeutics. However, today’s clinical trial system moves remarkably slowly. The question remains: is PAI-1 inhibition a viable hair loss treatment? We may get our first datasets sooner than later, and request that anyone researching a PAI-1 inhibitor uploads their response data to the HairDao Patient Portal, such that we can aggregate data to inform future researchers.

While those experimenting with PAI-1 are some of the best researchers in the world, one stand-out showed counterpoints that are to be considered. Synthetic Pug, a leader in cellular senescence research, ponders, “It seems like PAI-1 comes into play after TGF-B increases, so targeting TGF-B first (as hydrangea was hypothesized to do) would be a different mechanism but also lead to PAI-1 reduction. This seems more effective because of TGF-B's potential to activate NOX and downregulate SOD2, so by the time PAI-1 gets involved, it might already be too late.”

Pug’s point was rebutted by Pubehead (you read that correctly)--who states findings confirmed by those in the VitaDAO community, “Pai-1 reduction alone doesn't mean much unfortunately. For example, Vaughan tried a barrage of Pai-1 inhibitors in the transgenic mice, but TM5441 and its derivatives were the first to give phenotypic rescue. Seems there are intricacies on how it must be bound to Pai-1 in order to also effect vn-bound Pai-1.” We thus are left to question which of the two frequently discussed targets is more important to target. Only time and data will tell.

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Conversations This month’s additional conversations outlined much more than what is listed below, only highlighted due to their potential wide ranging effects. ● Across millions of Swedish men, Finasteride and Dutasteride are proven to cause depression. ● Retinoids–helping or hurting? It appears that the frequently prescribed drug does more harm than good, upregulating consequential genes such as PAI-1 and thus promoting inflammation and fibrosis, which lead to hair loss. ● If you like to party, we have bad news. Aspirin limits minoxidil response. ● Ultrasound may enhance topical drug delivery. We need more data. ● Jumpman’s DHT Theory of Hair Loss vs. Gusogu’s Prolactin Theory of Hair Loss vs. Synthetic Pug’s Cellular Senescence Theory of Hair Loss vs. Jaber’s Mechanical Theory of Hair Loss. While some have more supporting data than others, there remains much work to be done to find out who’s right. ● How can we learn from the many types of androgenic alopecia (receders vs diffuse thinners vs retrograde vs DUPA vs…).

Targets Other than PAI-1 and TGFb, there were numerous additional targets highlighted this month. ● HIF-1a inhibition. The high-level concept is similar to microneedling, that of hormesis (“what doesn’t kill you makes you stronger”). There are three levels of response to hypoxic stress, of which HIF-1a is the lowest. ● 3a-HSD–an oldie but a goodie. The enzyme degrades DHT and can be upregulated by sulforaphane, a natural compound found in broccoli sprouts. Why has research in 3a-HSD upregulators not continued, despite positive results (+6.7%) in a sulforaphane-based conditioner? ● LHX2–a crucial gene across a wide range of pathways. It is highly downregulated in bald scalps and has been shown to be upregulated in numerous promising treatments, such as PAI-1 inhibitors and Malliabiotech’s recombinant CD83 treatment. ● IL-10–Metabobbly believes that downregulating IL-10 is crucial to prevent cellular senescence more broadly. His IL-10 downregulation protocol has shown promise on his hair, with numerous hairs growing back pigmented. See his hi-definition photos for proof. ● GPC-1–upregulates WNT, one of the most important, proven pathways to regrow hair. Has any drug targeted this pathway yet?

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Treatments ● ASC-J9–an old androgen receptor inhibitor. Androscience refiled their trademark in 2023, sparking conversation that the company and treatment may still be alive. ● Tomorrow Labs’ hair restoration (Jumpman)--an HIF-1a downregulator. Shows promise across men and women in numerous hair measurement metrics. ● ISX9–activates WNT through axin degradation and (maybe) LRP6 upregulation.

Can this brain drug also help our hair? ● Lithium–another WNT promoter. We’ve talked about studying it with Ralf in the past, as it has proven hypertrichotic effects. Is there any record of how it regulates WNT? ● Moringa seeds–are they a natural finasteride? Benjels believes the phytosterols in them have a similar structure to DHT, thus creating a negative feedback loop (perhaps the upregulation of 3a-HSD, a DHT degrader). ● Hydrangea root–a natural PAI-1 and TGF-b inhibitor. Has anyone tested it yet? ● Quercitrin–activates the MAPK/CREB signaling pathway. ● Avenanthramides–an antioxidant. C3A remains our most promising antioxidant, although there may be other pathways, such as androgen receptor inhibition, at play.

Studies to Run We must vote on what to send to Ralf and Cutaneon as our 2-4 study ideas of the month. The natural compounds ● PRLR knockouts gene expression analysis. Can we see which genes are upregulated/downregulated by PRLR inhibition (Hope Medicine’s popular monoclonal antibody treatment), thus determining the true genes at play? ● A multi-ingredient nutraceutical, consisting of C3A (anti-oxidant and androgen receptor inhibitor), sulforaphane (3a-HSD upregulator and thus DHT downregulator), moringa seeds (DHT downregulator), and other natural compounds on scalp skin organ culture. Can we combine all ingredients together and test at once on scalp skin organ culture, assuming that the ingredients would not downregulate each other? ● RU58841–a decentralized data aggregation experiment. As the patient portal exits beta next week, can we test for whom RU58841 works without sides, such that patients do not need to speculate whether the drug will work for them? ● Topical dutasteride–a decentralized data aggregation experiment. Can topical dutasteride work without side effects? How high must the topical dosage be for an adequate amount to reach the base of hair follicles? ● Autophagy promoters–do other drugs pioneered by the longevity community, such as rapamycin and metformin, work to prevent hair loss? Have they been

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tested on scalp skin organ cultures, and is there a potential partnership with the longevity community if the results are promising? ● Topical RNA interference. Does the topical application of dumbbell-DNA vectors work on human tissue? It’s never been tested before.

Products ● The Patient Portal–a member-owned database. Right now, hair loss patient data is scattered across a plethora of databases, with little focus on hair specific questions and no rewards for data contributors. Our innovation is to: 1) create a single repository; 2) gather additional data that is highly relevant for hair specific analysis; and 3) reward data contributors proportionately. ● Gene knowledge graph–a model for the genes implicated in hair loss. Right now, hair loss genetic data is scattered across a plethora of papers. Can we aggregate their findings into a singular model, thus allowing us to predict which drugs will have the strongest downstream upregulation and downregulation effects? ● Mouse -> human skin conversion model–can we adequately estimate testing dosages in humans, based on mice literature of the past? This is foundational to translating numerous studies, and so either confirmation or critique of our model is highly valuable. ● Our podcast with Ralf–Ralf provides timelines for our T3/T4 results, history of thyroid hormones in hair loss, and much more. Notably, the HAIR token governs all assets in the HairDAO treasury, of which our JDA with Ralf’s company (CUTANEON) and provisional patent for the topical application of T3/T4 are two.

HAIR Earned This feature of HairDAO monthly’s is only possible due to the HairDAO community’s commitment to cutting-edge hair loss research. The following vested rewards are proposed as promised, which will soon have real value due to the launch of HAIR. ● Ralf Paus: 4,167.67 (see our contract with Ralf here). ● Jumpman: 2,800. Jumpman continues to lead the online hair loss community in establishing the most prominent gene targets. His work this month centered on PAI-1, HIF1a, LHX2, GPC1, and much more. ● Benjels: 2,200. Benjels continues to stand right behind Jumpman, analyzing a variety of targets and treatments. His work this month centered on both foundational work–perfecting the Patient Portal and analyzing study designs–as well as singular treatments and gene targets. ● Follicle Thought: 1,400. Like Benjels, Follicle Thought continues to provide a plethora of both foundational and analytical work. His highlights this month included the idea for HairDAO Monthly’s, numerous treatment recommendations, 4

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an introduction to MalliaBiotech, and continued press releases for the global hair loss community.

Synthetic Pug: 1,400. Synthetic Pug continues to lead the online hair loss community alongside Jumpman, providing analysis on both prominent theories of hair loss, individual genes, and treatments to target those genes. His most notable work research in cellular senescnece, TGF-b versus PAI-1, nuclear versus membrane androgen receptors, and much more.

Ryann: 800. A newcomer to the hair loss community, Ryann created a comprehensive, foundational overview of hair loss research for DAO members and hair loss research researchers globally. Ryann’s work has served as inspiration for our gene knowledge graph, which we hope he can help build.

Metabobbly: 800. A legend in English Parliament, Metabobbly entered HairDAO with a bang. He generated numerous early-stage treatment concepts, one of which is an anti-senescnece protocol designed by himself. He is actively monitoring the results of his protocol, with a patent likely to be completed by November.

Visangle: 600. If I had to bet, Visangle is f*cking jacked in person. He continued to provide foundational research to the DAO, specifically with respect to HIF-1a, ISX9, and ultrasound as a treatment method.

Dxdy: 400. Dxdy continues to lead HairDAO’s pursuit of natural compounds, with submitted work on quercitrin, moringa seeds, avenanthramides, and more.

God: 400. While we cannot find his new username now, God edited Ryann’s foundational document comprehensively. If you find God, please let us know.

Endana: 400. Endana continues to push numerous business development lines forward for the hair loss community, specifically with regards to Hope Medicine, Sirnagen, ASC-J9, verteporfin, and more.

HairwaytoHeaven: 400. Hairway provided significant analysis on the Patient Portal, the DAO’s operations as a whole, and numerous targets and treatments.

Jaber: 200. Jaber posed numerous questions on important high-level hair loss topics, such as the numerous types of androgenic alopecia and the mechanistic theory of hair loss.

Auksyakshal: 200. Auksyakshal posed numerous relevant questions on both high and low-level theories of androgenic alopecia, analyzing demographic trends, treatment trade-offs, and more.

Rat Milk: 100. Rat Milk provided business development work across two relevant treatments this month, ASC-J9 and sulforaphane (prostaphane is his recommendation for the pill form).

The 25 club. The rest of the members provided helpful one-off remarks on treatments, targets, foundational design of the DAO, and more: Pubehead, Ironbread, Rperez, Nomadd, BenjamTD, JP4444, Romeo, Vforvegeta, Gabe, 5

Gusogu, Prisma8, potential_Dingo, Kaluterosguy, BenjamTD, Lofihippo, yigitmakk, FatBoyDiggs, and Fgsfds. *All tokens issued in HairDAO Monthly’s are proposed to follow a vested issuance, to be determined at a near date as part of a broad tokenomics proposal (following the HAIR auction). All token allocations for all DAO contributors are contingent on 30mn HAIR issued. Should participants in the Initial Auction vote to change the total HAIR issued (in order to create a valuation that is attractive for future capital commitment), token allocations listed above may be affected proportionately. We are doing our best.

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