S
Snari
Iron
- Joined
- May 30, 2022
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I’ve just copied and pasted this from Reddit to get your guys thoughts.
“
(EDIT)This is a long-ass post, but I think that it's worth the read. More than broccoli at the very least.
As many of you know, there is a struggle to determine the specific genes associated with AGA. We know that DHT is involved through the Androgen Receptor (AR) gene, but we also know that Dutasteride, which inhibits upwards of 90% serum DHT, doesn't give life-long maintenance of hair (most long-term users of 5AR inhibitors tend to report minimal but noticeable hair loss, but this could be because of that small % of DHT I guess since scalp DHT is usually less inhibited than it is systemically) and provides limited cosmetically beneficial regrowth. There is also the issue of reversing the process of miniaturization. At some point, hair follicles will shrink in diameter and length to such a degree that not even AR blockers can save them. Furthermore, it is well-known by most people who have more than an hour's worth of research on hair loss forums that 5AR inhibitors sometimes just don't even work on people. This, coupled with the fact that non-balding men still have DHT in their scalp, leads us to believe that there is something more at play, possibly something which increases hair follicle sensitivity to DHT or maybe even proceeds DHT in overall importance in the ever-elusive downstream which leads to hair follicle miniaturization.
For a while, we were lacking in studies that analyze specific genes and their activities in balding vs non-balding scalps. Then, this gem dropped in 2016.
[https://www.sciencedirect.com/scien...ct.com/science/article/pii/S0022202X16310247)
There's a lot to unpack here, but I'm going to be sticking to the main point of this post-- TWIST-1.
*"At the 7p21.1 locus, we found TWIST1, a DP signature gene expressed in both BAB (balding) and BAN(not balding) (*[*Figure 1*](https://www.sciencedirect.com/science/article/pii/S0022202X16310247#fig1)*e and see* [*Supplementary Table S1*](https://www.sciencedirect.com/science/article/pii/S0022202X16310247#appsec1)*a), being up-regulated in BAB (*[*Table 1*](https://www.sciencedirect.com/science/article/pii/S0022202X16310247#tbl1)*)."*
***"Twist1, a basic helix-loop-helix protein, is crucial for anagen-to-catagen transition during the hair growth cycle with Twist1 protein ablation in adult mice DP resulting in prolonged anagen. Hence, TWIST1 up-regulation in DPCs of balding scalps compared to non-balding scalps may result in accelerated transition from anagen to catagen and thus a shortened period of anagen during the hair cycle, a phenomenon in balding scalps that leads to the formation of short vellus hairs instead of long terminal hairs."***
*"TWIST1 also interacts and binds to HDAC4 (*[*Danciu and Whitman, 2009*](https://www.sciencedirect.com/science/article/pii/S0022202X16310247#bib8)*) to regulate gene expression (*[*Gong and Li, 2002*](https://www.sciencedirect.com/science/article/pii/S0022202X16310247#bib17)*,* [*Lee et al., 2003*](https://www.sciencedirect.com/science/article/pii/S0022202X16310247#bib33)*). In addition, binding of TWIST1 at E-boxes in the AR promoter region results in up-regulated AR expression (*[*Shiota et al., 2010*](https://www.sciencedirect.com/science/article/pii/S0022202X16310247#bib49)*). Our observation of both TWIST1 and AR up-regulation in BAB compared to BAN could be attributed to increased regulation of AR expression by the increased TWIST1 levels in BAB compared to BAN. This potential relationship between AR and TWIST1 in balding DPC, which to our knowledge has not been considered previously, provides support for these two candidate genes to be the causative AGA genes at the 7p21.1 and Xq12 susceptibility loci."*
Now, if you're paying attention you might think that inhibiting a regulator of the hair cycle might be bad for hair. You might also think that inhibiting the proteins produced by this shit could be dangerous. While it's true that TWIST-1 is known to have an important role in cranial development (there is a genetic disease called Saethre-Chotzen which is caused by a mutation or deletion of the TWIST-1 gene and results in craniomalformation **BUT A KNOWN "SYMPTOM" OF THE DISEASE IS A LOW, FLAT, NORWOOD 0**), experiments have been conducted where TWIST-1 was knocked out following the formation of the skull in mice and there were found to be no ill-effects. In fact, it's currently being studied as a preferential cancer target gene following the development of the skull.
[https://www.ncbi.nlm.nih.gov/pmc/ar...ww.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/)
*"We found that Twist1 is expressed in several tissues, including fibroblasts of the mammary glands and dermal papilla cells of the hair follicles. We developed a tamoxifen-inducible Twist1 knockout mouse model; Twist1 knockout in 6-week-old female mice did not affect mammary gland morphogenesis and function during pregnancy and lactation. In both males and females, the knockout did not influence body weight gain, heart rate, or total lean and fat components. The knockout also did not alter blood pressure in males, although it slightly reduced blood pressure in females. Although Twist1 is not cyclically expressed in dermal papilla cells, knockout of Twist1 at postnatal day 13 (when hair follicles have developed) drastically extended the anagen phase and accelerated hair growth. These results indicate that Twist1 is not essential for maintaining an overall healthy condition in young and adult mice and that loss of function facilitates hair growth in adulthood, supporting Twist1 as a preferential target for cancer therapy."*
*"Importantly, expression of Twist1 expression is induced in and associated with many types of aggressive cancers, including breast,*[*23*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib23) *prostate,*[*24,25*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib24) *gastric,*[*26,27*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib26) *liver,*[*28,29*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib28) *bladder,*[*30,31*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib30) *esophageal,*[*32,33*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib32) *and pancreatic cancers.*[*34*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib34) *Twist1 plays multiple roles in cancer initiation, progression, and metastasis. Specifically, Twist1 can override the failsafe cell senescence and apoptotic responses triggered by oncogenes,*[*35–37*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib35) *increase cancer cell resistance to endocrine therapy and chemotherapy,*[*38,39*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib38) *enhance cancer stem cell populations,*[*40–42*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib40) *and facilitate cancer cells to invade and metastasize.*[*23,43–48*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib23)*"*
*"Because our data indicated a specific expression of Twist1 protein in DP cells, we hypothesized that Twist1 may play an important role in DP cells to regulate hair follicles. To define the role of Twist1 in hair follicle cycling, we treated 13-day-old Twist1f/f and CreERT2;Twist1f/f (referred to as Twist1Δ/Δ after tamoxifen treatment) mice with tamoxifen for 3 days, shaved the hair on the back twice (on P13 and P49), and examined hair growth from P15 to P67. After the first shave on P13, the hair grew significantly faster in Twist1Δ/Δ mice versus Twist1f/f mice (photographed on P27). On P35, the hair in Twist1f/f mice had grown back, and showed similar thickness as the hair of Twist1Δ/Δ mice (*[*Figure 4*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/figure/fig4/)*A). After the second shave on P49, when the hair follicles of normal mice are in the telogen phase of the hair growth cycle, the hair in Twist1f/f control mice showed very little growth until P67, whereas the hair in Twist1Δ/Δ mice still maintained rapid growth as examined on P67 (*[*Figure 4*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/figure/fig4/)*A). Importantly, Twist1 protein was detected in DP cells in Twist1f/f mice but not in Twist1Δ/Δ mice, as examined by IHC on P15, P18, P23, P29, P45, and P61 (*[*Figure 4*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/figure/fig4/)*B), validating the constant status of Twist1 knockout in the hair follicles of Twist1Δ/Δ mice (data not shown). These results indicate that Twist1 plays an essential role in regulating the hair growth cycle, and that inducible knockout of Twist1 significantly extends the hair-growth phase in adult mice."*
**"These results further support the notion that inducible knockout of** ***Twist1*** **in young mice leads to arrest of the hair follicle cycle at the anagen phase in adulthood."**
​
[The triangles indicate a silencing of TWIST, ff is control](https://preview.redd.it/a8sld4gcetc91.jpg?width=762&format=pjpg&auto=webp&s=a09f0df51f2cad5da6a0ae534266ae26781264a6)
Okay, so these are mice and I know that a lot of you might be rolling your eyes, but I would note that the first study I mentioned also associated TWIST-1 with miniaturization of the hair follicle in humans due to its shortening of the anagen phase caused by upregulation in balding vs non-balding scalps (a phase which was prolonged indefinitely in the TWIST-less mice).
So, why does inhibition of TWIST prolong anagen? The answer lies in R-spondin, which is essentially what is responsible for growing hair during the anagen phase. If you're interested in learning more about that, below is a good article that discusses its role in the WNT pathway.
[https://www.ncbi.nlm.nih.gov/pmc/ar...ww.ncbi.nlm.nih.gov/pmc/articles/PMC3937510/)
Catagen is initiated by a reduction of R-spondins mediated by FGFR, and Twist1 has been shown to regulate FGFR. If Twist1 is inhibited then r-spondins should be upregulated in the HF. R-spondins stabilize Wnt receptors which strongly upregulates Wnt signaling and maintains beta-catenin nuclear translocation, and induces hair growth.
[https://www.nature.com/articles/s41...//www.nature.com/articles/s41467-020-18643-x)
Another interesting point is the role of TWIST-1 in CRPC (Castration-Resistance Prostate Cancer). As many of you may or may not be aware, prostate issues are often related to or share the same cause as hair issues caused by AGA(Proscar was a prostate drug, after all).As the name suggests, this is a type of prostate cancer that is resistant even to total AR depletion through hardcore drugs like Enzalutamide. A 2009 study titled "Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression" highlighted an interesting process observed after injection of hydrogen-peroxide to induce castration.
[https://pubmed.ncbi.nlm.nih.gov/19802001/](https://pubmed.ncbi.nlm.nih.gov/19802001/)
*"Moreover, Twist1 was shown to regulate AR expression through binding to E-boxes in AR promoter region. Silencing of Twist1 suppressed cell growth of AR-expressing LNCaP cells as well as castration-resistant LNCaP derivatives by inducing cell-cycle arrest at G1 phase and cellular apoptosis. These findings indicated that castration-induced oxidative stress may promote AR overexpression through Twist1 overexpression, which could result in a gain of castration resistance."*
Essentially, in the prostate TWIST-1 overexpression (which is found in balding scalps but absent in non-balding scalps) increases AR activity, a phenomenon which, if it works the same way on the scalp, likely explains the higher DHT levels found in balding scalps. The first study indicates that this is the case.
So let’s put the pieces together the best we can. TWIST-1 is shown to be over expressed in balding vs non-balding scalps. A tell-tale symptom (literally, it is listed as a genuine symptom on all medical websites) of a genetic disease caused by TWIST-1 mutation or deletion is a low, flat, frontal hairline. I’ve been scouring the internet looking for pictures of people with the disease and have yet to find a single male who goes beyond NW 1, notably even into older ages. TWIST-1 has been proven to further promote the androgen receptor, which I think is the actual answer to the “why do bald scalps have more DHT” question. The process of miniaturization is the progressive shortening of the Anagen phase. Anagen is ended when Catagen starts. TWIST-1 plays a “crucial role” in transitioning the hair follicle from Anagen to Categen. Experiments with TWIST-less mice have proven that this is a genuine concept and not some early-stage hypothesis. More TWIST-1 expression+ the AR receptor (not sure exactly what it does) probably= faster Catagen= shorter Anagen= our bald ass heads. There’s also a lot of other shit like Prolactin that we’re pretty sure plays a role somehow but I won’t get into that right now. TWIST-1 is positively correlated with and has a scientifically proven effect on the Androgen Receptor, the only thing that we know for sure has something to do with this shit. It also is likely one of the causes of literally a dozen or so cancers (high TWIST-1 expression is considered a sign of poor prognosis in prostate cancer, which the overwhelming majority of men will get if they live long enough). I mean, what the hell do we need this shit for after it gives me my skull? We talk a lot about the trash hormone, but what about this shitty gene?
There's a lot more I could say about this, but I'll keep it short as I am not an expert on the subject and can not guarantee that inhibition of TWIST-1 signaling will be a "cure". However, the science is strong with this one. I think that research has established TWIST-1's role in AGA and that inhibition will likely have a very strong effect that could be "cure-level". At the end of the day, though, it could just all be broscience (but there is at least a good amount of data to suggest that there might be some hope at this point).
My optimism should not indicate that you should stop taking your fin because "the cure is here!". I am just an amateur with zero professional experience in this field who wants to keep his hair and is extrapolating from shit I saw on hair loss forums.
I am also noting that there is a group buy occurring where people are buying molecules that inhibit the effects of TWIST-1. I am not going to advertise this group because I know there are some people on here who are definitely going to try and buy some and try it out without us knowing the full effects of TWIST-1 inhibition. If the dosage and molecules are correct, however, we should see what inhibition of TWIST-1 does for hair in less than a year. This is not a "sketchy new startup" with a random growth-promoter that has only been proven on mice, this is attacking a genetic signal which has been strongly hypothesized as a top factor in AGA. If you're ever going to pay attention to the endless flood of research articles and hypotheses related to AGA, this would be it. I'm pretty much just going to pop my fin and pray to God if this doesn't work.
I'm going to end this post by showing you pictures of men with Saethre-Chotzen Syndrome (deletion or mutation of TWIST-1 gene). Keep in mind that the skull shape present in these people is caused by lack of TWIST-1 during early development only and that studies have shown knockout of TWIST-1 following cranial development to be completely safe in mice. Just look at the hairlines on these old white men. Not even a little maturation.
“
(EDIT)This is a long-ass post, but I think that it's worth the read. More than broccoli at the very least.
As many of you know, there is a struggle to determine the specific genes associated with AGA. We know that DHT is involved through the Androgen Receptor (AR) gene, but we also know that Dutasteride, which inhibits upwards of 90% serum DHT, doesn't give life-long maintenance of hair (most long-term users of 5AR inhibitors tend to report minimal but noticeable hair loss, but this could be because of that small % of DHT I guess since scalp DHT is usually less inhibited than it is systemically) and provides limited cosmetically beneficial regrowth. There is also the issue of reversing the process of miniaturization. At some point, hair follicles will shrink in diameter and length to such a degree that not even AR blockers can save them. Furthermore, it is well-known by most people who have more than an hour's worth of research on hair loss forums that 5AR inhibitors sometimes just don't even work on people. This, coupled with the fact that non-balding men still have DHT in their scalp, leads us to believe that there is something more at play, possibly something which increases hair follicle sensitivity to DHT or maybe even proceeds DHT in overall importance in the ever-elusive downstream which leads to hair follicle miniaturization.
For a while, we were lacking in studies that analyze specific genes and their activities in balding vs non-balding scalps. Then, this gem dropped in 2016.
[https://www.sciencedirect.com/scien...ct.com/science/article/pii/S0022202X16310247)
There's a lot to unpack here, but I'm going to be sticking to the main point of this post-- TWIST-1.
*"At the 7p21.1 locus, we found TWIST1, a DP signature gene expressed in both BAB (balding) and BAN(not balding) (*[*Figure 1*](https://www.sciencedirect.com/science/article/pii/S0022202X16310247#fig1)*e and see* [*Supplementary Table S1*](https://www.sciencedirect.com/science/article/pii/S0022202X16310247#appsec1)*a), being up-regulated in BAB (*[*Table 1*](https://www.sciencedirect.com/science/article/pii/S0022202X16310247#tbl1)*)."*
***"Twist1, a basic helix-loop-helix protein, is crucial for anagen-to-catagen transition during the hair growth cycle with Twist1 protein ablation in adult mice DP resulting in prolonged anagen. Hence, TWIST1 up-regulation in DPCs of balding scalps compared to non-balding scalps may result in accelerated transition from anagen to catagen and thus a shortened period of anagen during the hair cycle, a phenomenon in balding scalps that leads to the formation of short vellus hairs instead of long terminal hairs."***
*"TWIST1 also interacts and binds to HDAC4 (*[*Danciu and Whitman, 2009*](https://www.sciencedirect.com/science/article/pii/S0022202X16310247#bib8)*) to regulate gene expression (*[*Gong and Li, 2002*](https://www.sciencedirect.com/science/article/pii/S0022202X16310247#bib17)*,* [*Lee et al., 2003*](https://www.sciencedirect.com/science/article/pii/S0022202X16310247#bib33)*). In addition, binding of TWIST1 at E-boxes in the AR promoter region results in up-regulated AR expression (*[*Shiota et al., 2010*](https://www.sciencedirect.com/science/article/pii/S0022202X16310247#bib49)*). Our observation of both TWIST1 and AR up-regulation in BAB compared to BAN could be attributed to increased regulation of AR expression by the increased TWIST1 levels in BAB compared to BAN. This potential relationship between AR and TWIST1 in balding DPC, which to our knowledge has not been considered previously, provides support for these two candidate genes to be the causative AGA genes at the 7p21.1 and Xq12 susceptibility loci."*
Now, if you're paying attention you might think that inhibiting a regulator of the hair cycle might be bad for hair. You might also think that inhibiting the proteins produced by this shit could be dangerous. While it's true that TWIST-1 is known to have an important role in cranial development (there is a genetic disease called Saethre-Chotzen which is caused by a mutation or deletion of the TWIST-1 gene and results in craniomalformation **BUT A KNOWN "SYMPTOM" OF THE DISEASE IS A LOW, FLAT, NORWOOD 0**), experiments have been conducted where TWIST-1 was knocked out following the formation of the skull in mice and there were found to be no ill-effects. In fact, it's currently being studied as a preferential cancer target gene following the development of the skull.
[https://www.ncbi.nlm.nih.gov/pmc/ar...ww.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/)
*"We found that Twist1 is expressed in several tissues, including fibroblasts of the mammary glands and dermal papilla cells of the hair follicles. We developed a tamoxifen-inducible Twist1 knockout mouse model; Twist1 knockout in 6-week-old female mice did not affect mammary gland morphogenesis and function during pregnancy and lactation. In both males and females, the knockout did not influence body weight gain, heart rate, or total lean and fat components. The knockout also did not alter blood pressure in males, although it slightly reduced blood pressure in females. Although Twist1 is not cyclically expressed in dermal papilla cells, knockout of Twist1 at postnatal day 13 (when hair follicles have developed) drastically extended the anagen phase and accelerated hair growth. These results indicate that Twist1 is not essential for maintaining an overall healthy condition in young and adult mice and that loss of function facilitates hair growth in adulthood, supporting Twist1 as a preferential target for cancer therapy."*
*"Importantly, expression of Twist1 expression is induced in and associated with many types of aggressive cancers, including breast,*[*23*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib23) *prostate,*[*24,25*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib24) *gastric,*[*26,27*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib26) *liver,*[*28,29*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib28) *bladder,*[*30,31*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib30) *esophageal,*[*32,33*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib32) *and pancreatic cancers.*[*34*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib34) *Twist1 plays multiple roles in cancer initiation, progression, and metastasis. Specifically, Twist1 can override the failsafe cell senescence and apoptotic responses triggered by oncogenes,*[*35–37*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib35) *increase cancer cell resistance to endocrine therapy and chemotherapy,*[*38,39*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib38) *enhance cancer stem cell populations,*[*40–42*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib40) *and facilitate cancer cells to invade and metastasize.*[*23,43–48*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/#bib23)*"*
*"Because our data indicated a specific expression of Twist1 protein in DP cells, we hypothesized that Twist1 may play an important role in DP cells to regulate hair follicles. To define the role of Twist1 in hair follicle cycling, we treated 13-day-old Twist1f/f and CreERT2;Twist1f/f (referred to as Twist1Δ/Δ after tamoxifen treatment) mice with tamoxifen for 3 days, shaved the hair on the back twice (on P13 and P49), and examined hair growth from P15 to P67. After the first shave on P13, the hair grew significantly faster in Twist1Δ/Δ mice versus Twist1f/f mice (photographed on P27). On P35, the hair in Twist1f/f mice had grown back, and showed similar thickness as the hair of Twist1Δ/Δ mice (*[*Figure 4*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/figure/fig4/)*A). After the second shave on P49, when the hair follicles of normal mice are in the telogen phase of the hair growth cycle, the hair in Twist1f/f control mice showed very little growth until P67, whereas the hair in Twist1Δ/Δ mice still maintained rapid growth as examined on P67 (*[*Figure 4*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/figure/fig4/)*A). Importantly, Twist1 protein was detected in DP cells in Twist1f/f mice but not in Twist1Δ/Δ mice, as examined by IHC on P15, P18, P23, P29, P45, and P61 (*[*Figure 4*](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791869/figure/fig4/)*B), validating the constant status of Twist1 knockout in the hair follicles of Twist1Δ/Δ mice (data not shown). These results indicate that Twist1 plays an essential role in regulating the hair growth cycle, and that inducible knockout of Twist1 significantly extends the hair-growth phase in adult mice."*
**"These results further support the notion that inducible knockout of** ***Twist1*** **in young mice leads to arrest of the hair follicle cycle at the anagen phase in adulthood."**
​
[The triangles indicate a silencing of TWIST, ff is control](https://preview.redd.it/a8sld4gcetc91.jpg?width=762&format=pjpg&auto=webp&s=a09f0df51f2cad5da6a0ae534266ae26781264a6)
Okay, so these are mice and I know that a lot of you might be rolling your eyes, but I would note that the first study I mentioned also associated TWIST-1 with miniaturization of the hair follicle in humans due to its shortening of the anagen phase caused by upregulation in balding vs non-balding scalps (a phase which was prolonged indefinitely in the TWIST-less mice).
So, why does inhibition of TWIST prolong anagen? The answer lies in R-spondin, which is essentially what is responsible for growing hair during the anagen phase. If you're interested in learning more about that, below is a good article that discusses its role in the WNT pathway.
[https://www.ncbi.nlm.nih.gov/pmc/ar...ww.ncbi.nlm.nih.gov/pmc/articles/PMC3937510/)
Catagen is initiated by a reduction of R-spondins mediated by FGFR, and Twist1 has been shown to regulate FGFR. If Twist1 is inhibited then r-spondins should be upregulated in the HF. R-spondins stabilize Wnt receptors which strongly upregulates Wnt signaling and maintains beta-catenin nuclear translocation, and induces hair growth.
[https://www.nature.com/articles/s41...//www.nature.com/articles/s41467-020-18643-x)
Another interesting point is the role of TWIST-1 in CRPC (Castration-Resistance Prostate Cancer). As many of you may or may not be aware, prostate issues are often related to or share the same cause as hair issues caused by AGA(Proscar was a prostate drug, after all).As the name suggests, this is a type of prostate cancer that is resistant even to total AR depletion through hardcore drugs like Enzalutamide. A 2009 study titled "Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression" highlighted an interesting process observed after injection of hydrogen-peroxide to induce castration.
[https://pubmed.ncbi.nlm.nih.gov/19802001/](https://pubmed.ncbi.nlm.nih.gov/19802001/)
*"Moreover, Twist1 was shown to regulate AR expression through binding to E-boxes in AR promoter region. Silencing of Twist1 suppressed cell growth of AR-expressing LNCaP cells as well as castration-resistant LNCaP derivatives by inducing cell-cycle arrest at G1 phase and cellular apoptosis. These findings indicated that castration-induced oxidative stress may promote AR overexpression through Twist1 overexpression, which could result in a gain of castration resistance."*
Essentially, in the prostate TWIST-1 overexpression (which is found in balding scalps but absent in non-balding scalps) increases AR activity, a phenomenon which, if it works the same way on the scalp, likely explains the higher DHT levels found in balding scalps. The first study indicates that this is the case.
So let’s put the pieces together the best we can. TWIST-1 is shown to be over expressed in balding vs non-balding scalps. A tell-tale symptom (literally, it is listed as a genuine symptom on all medical websites) of a genetic disease caused by TWIST-1 mutation or deletion is a low, flat, frontal hairline. I’ve been scouring the internet looking for pictures of people with the disease and have yet to find a single male who goes beyond NW 1, notably even into older ages. TWIST-1 has been proven to further promote the androgen receptor, which I think is the actual answer to the “why do bald scalps have more DHT” question. The process of miniaturization is the progressive shortening of the Anagen phase. Anagen is ended when Catagen starts. TWIST-1 plays a “crucial role” in transitioning the hair follicle from Anagen to Categen. Experiments with TWIST-less mice have proven that this is a genuine concept and not some early-stage hypothesis. More TWIST-1 expression+ the AR receptor (not sure exactly what it does) probably= faster Catagen= shorter Anagen= our bald ass heads. There’s also a lot of other shit like Prolactin that we’re pretty sure plays a role somehow but I won’t get into that right now. TWIST-1 is positively correlated with and has a scientifically proven effect on the Androgen Receptor, the only thing that we know for sure has something to do with this shit. It also is likely one of the causes of literally a dozen or so cancers (high TWIST-1 expression is considered a sign of poor prognosis in prostate cancer, which the overwhelming majority of men will get if they live long enough). I mean, what the hell do we need this shit for after it gives me my skull? We talk a lot about the trash hormone, but what about this shitty gene?
There's a lot more I could say about this, but I'll keep it short as I am not an expert on the subject and can not guarantee that inhibition of TWIST-1 signaling will be a "cure". However, the science is strong with this one. I think that research has established TWIST-1's role in AGA and that inhibition will likely have a very strong effect that could be "cure-level". At the end of the day, though, it could just all be broscience (but there is at least a good amount of data to suggest that there might be some hope at this point).
My optimism should not indicate that you should stop taking your fin because "the cure is here!". I am just an amateur with zero professional experience in this field who wants to keep his hair and is extrapolating from shit I saw on hair loss forums.
I am also noting that there is a group buy occurring where people are buying molecules that inhibit the effects of TWIST-1. I am not going to advertise this group because I know there are some people on here who are definitely going to try and buy some and try it out without us knowing the full effects of TWIST-1 inhibition. If the dosage and molecules are correct, however, we should see what inhibition of TWIST-1 does for hair in less than a year. This is not a "sketchy new startup" with a random growth-promoter that has only been proven on mice, this is attacking a genetic signal which has been strongly hypothesized as a top factor in AGA. If you're ever going to pay attention to the endless flood of research articles and hypotheses related to AGA, this would be it. I'm pretty much just going to pop my fin and pray to God if this doesn't work.
I'm going to end this post by showing you pictures of men with Saethre-Chotzen Syndrome (deletion or mutation of TWIST-1 gene). Keep in mind that the skull shape present in these people is caused by lack of TWIST-1 during early development only and that studies have shown knockout of TWIST-1 following cranial development to be completely safe in mice. Just look at the hairlines on these old white men. Not even a little maturation.
