A possible way to cure baldness... Sonic hedgehog REVIEW

[Swoop]

Anyway so how does SHH come into this? Well if you look at that mice study posted in this thread (yeah I know mice sucks it's useless);

Cell cycle re-entry by cochlear supporting cells and/or hair cells is considered one of the best approaches for restoring hearing loss as a result of hair cell damage. To identify mechanisms that can be modulated to initiate cell cycle re-entry and hair cell regeneration, we studied the effect of activating the sonic hedgehog (Shh) pathway. We show that Shh signaling in postnatal rat cochleae damaged by neomycin leads to renewed proliferation of supporting cells and hair cells. Further, proliferating supporting cells are likely to transdifferentiate into hair cells. Shh treatment leads to inhibition of retinoblastoma protein (pRb) by increasing phosphorylated pRb and reducing retinoblastoma gene transcription. This results in upregulation of cyclins B1, D2, and D3, and CDK1.

Hair cells and supporting cells of the inner ear are derived from sensory progenitor cells [4]. Their development involves permanent exit from the cell cycle, cell fate determination, and differentiation. Differentiated mammalian hair cells remain in a permanent quiescent state throughout life. Although cochlear supporting cells in newborn mice can be induced to divide and regenerate new hair cells in vitro [5], spontaneous auditory hair cell regeneration in vivo has not been observed after hair cell loss. Cell cycle exit by progenitor cells and maintenance of the quiescent status of differentiated hair cells and supporting cells are controlled by negative cell growth proteins, including p27kip1, p19ink4d, pRb, and p21cip1.

We found that Shh could trigger postnatal rat cochlear epithelial cell proliferation and production of hair cells after ototoxic damage. Some of the Shh-induced hair cells expressed early hair cell markers Sox2 and Pax2, indicating that they likely resulted from transdifferentiation that followed developmental sequences. However, we can not rule out the possibility that upon Shh treatment existing hair cells divide along with induction of progenitor genes.

Also the observations of people taking SHH antagonists are important. At the very least it seems to modulate hair cycle function, seeing how severe alopecia is in up to of 60% or more of cases which can even be long lasting after cessation of treatment. Secondly they also do an excellent job in switching the hair follicle cycle in mice. As also displayed in that latest study of A.M Christiano. Although that is a terrible weak argument, because mice are a horrible Androgenetic Alopecia model. At best they can be studies for hair follicle cycle modulation, but even that is up to debate.

The thing is we have zero observational evidence to go by of any SHH agonist, simply because there is none. And it's obvious why. These bad factors protect you from things like cancer too. So there are only SHH antagonists on the market (anti-cancer). Given this that Androgenetic Alopecia is not a life threathening disease the decision of Proctor & Gamble to have stopped the compound is a logical one. It also displayed toxicity in pre-clinical models.

Similarly 17b-estradiol is classified as a carcinogenic compound. I have seen some studies of 17b-estradiol and on breast tissue/breast cancer and indeed it seems to stimulate proliferation too, and oppose the bad guys in that sense. I call them bad guys but they are not really bad guys too because they protect you. However in Androgenetic Alopecia they might be bad guys as they might stop cell function. You know when we would take 17b-estradiol with suppressing androgen/AR axis we grow these lovely titties gyno, it's great for our hair too. Perhaps it just likes to stimulate cells both on the scalp and in the titty region .

Growing evidence indicates that HH regulates diverse quiescent stem cell populations, but the exact roles that HH signaling plays in adult organ homeostasis and regeneration remain poorly understood. Here, we review recently identified functions of HH in modulating the behavior of tissue-specific adult stem and progenitor cells during homeostasis, regeneration and disease. We conclude that HH signaling is a key factor in the regulation of adult tissue homeostasis and repair, acting via multiple different routes to regulate distinct cellular outcomes, including maintenance of plasticity, in a context-dependent manner.

@InBeforeTheCure, I also saw quite many pathways implicated in your analysis that correspond to all the above? I think you mentioned you thought SHH wouldn't do much. SHH interacts with Cyc d1, myc, blc-2 , sox2, pax genes, fox genes etc. Curious to why you are so confident that this will not do anything. In the context of my story SHH would try to push the cells to function again perhaps?

I'm not saying it would be the cure, but still it should modulate at least the hair follicle cycle in some way IMO... Anyway it's a mystery we will probably never get to know.

 

[menti]

Anyway so how does SHH come into this? Well if you look at that mice study posted in this thread (yeah I know mice sucks it's useless);







Also the observations of people taking SHH antagonists are important. At the very least it seems to modulate hair cycle function, seeing how severe alopecia is in up to of 60% or more of cases which can even be long lasting after cessation of treatment. Secondly they also do an excellent job in switching the hair follicle cycle in mice. As also displayed in that latest study of A.M Christiano. Although that is a terrible weak argument, because mice are a horrible Androgenetic Alopecia model. At best they can be studies for hair follicle cycle modulation, but even that is up to debate.

The thing is we have zero observational evidence to go by of any SHH agonist, simply because there is none. And it's obvious why. These bad factors protect you from things like cancer too. So there are only SHH antagonists on the market (anti-cancer). Given this that Androgenetic Alopecia is not a life threathening disease the decision of Proctor & Gamble to have stopped the compound is a logical one. It also displayed toxicity in pre-clinical models.

Similarly 17b-estradiol is classified as a carcinogenic compound. I have seen some studies of 17b-estradiol and on breast tissue/breast cancer and indeed it seems to stimulate proliferation too, and oppose the bad guys in that sense. I call them bad guys but they are not really bad guys too because they protect you. However in Androgenetic Alopecia they might be bad guys as they might stop cell function. You know when we would take 17b-estradiol with suppressing androgen/AR axis we grow these lovely titties gyno, it's great for our hair too. Perhaps it just likes to stimulate cells both on the scalp and in the titty region .

@InBeforeTheCure, I also saw quite many pathways implicated in your analysis that correspond to all the above? I think you mentioned you thought SHH wouldn't do much. SHH interacts with Cyc d1, myc, blc-2 , sox2, pax genes, fox genes etc. Curious to why you are so confident that this will not do anything. In the context of my story SHH would try to push the cells to function again perhaps?

I'm not saying it would be the cure, but still it should modulate at least the hair follicle cycle in some way IMO... Anyway it's a mystery we will probably never get to know.

hello swoop ..i would like you to have a look at your thread understand androgenetic alopecia..thanks

 

[Giiizmo]

It would be nice if you didn't have to bump old threads to get his attention, this section is depressing enough.

 

[Pray The Bald Away]

It would be nice if you didn't have to bump old threads to get his attention, this section is depressing enough.

Swoop bumped this thread with a post.

 

[abcdefg]

I dont think forum users experimenting on themselves using most likely the most basic easily obtainable topical vehicles is really representative of effectiveness of a certain pathway.
There is no reproducible or documentation on anything they do. Every single person could be doing it completely wrong, and no one ever knows what to even do differently because no one knows what or how they did it. All those tiny details that most people dont like to think about or gloss over for the ghetto way all matter and amount to differences. Tiny differences all add up.

 

[InBeforeTheCure]

@InBeforeTheCure, calling your here primarily but if others want to chime in/discuss please do. I'll try to explain it in a simple way, so everyone can understand it. It has to do with SHH and I'm really wondering if it wasn't a black day for us all when development of the small molecule was ceased to due safety concerns;

http://phx.corporate-ir.net/phoenix.zhtml?c=123198&p=irol-newsArticle&ID=997941&highlight=

In Androgenetic Alopecia as a hair follicle miniaturizes based on observation we see that the DP size decreases. Apparently DP size governs hair follicle size as shown in studies. Furthermore Cotsarelis has shown that in bald scalp in men retains hair follicle stem cells but there is a lack of progenitor cells. Now we can perhaps conclude that there is a lack of progenitor cells and DP cells. The DP seems to control progenitors though as shown in some papers (1)..



Here is another study;



Therefore based on this we could perhaps say that the earlier event of the chain is happening in the DP rather than the progenitors. After all it would be illogical to think otherwise. As the hair progenitor cells seem to be dependent on the activity of the dermal papilla niche. The observations in a miniaturized hair follicle confirm this. Indeed a decline of DP niche function would probably automatically mean a decline of progenitor cells.

So perhaps it's logical to assume that the decline of DP is one of the first events that happens in the hair follicle as Androgenetic Alopecia rages through. However as you can see from the latest quote the dermal papilla number is actively regulated in the context of the regenerative phase of the hair cycle. Meaning that between cycling through anagen - catagen - telogen the numbers and size of DP is not static. So perhaps the primary event is indeed not a decline of DP but rather a problem with the event that governs this phenomenon. We don't know exactly from where the DP get's actively regulated in a hair follicle cycle... However on the other hand one should know that the DP is the main and primary androgen site of the hair follicle.

Yeah, that's interesting about the DP cell number being dynamic. It seems like early anagen (P24) is when the dermal sheath cells are proliferating and by mid anagen (P27) this has dropped off significantly:

Comparison of cell proliferation within DS and DP compartments showed that mitotic activity was almost exclusively localized to cells within the DS (Figures S1B–S1D). That is, 38% of DS cells were dividing during early anagen and declined to 8.6% at mid-anagen and finally 2.1% at catagen. In contrast, 0.76% of DP cells per follicle were found to be dividing and this was only observed during early anagen stage (Figure S1D).

Source: http://www.cell.com/developmental-cell/fulltext/S1534-5807(14)00688-1

And Shh expression is strongest during early anagen, right? So maybe Shh from transit amplifying cells in early anagen could cause dermal sheath proliferation? If that's the case, dermal papilla cell number and progenitor cell number would both control each other -- larger DP -> more progenitor cells -> more transit amplifying cells -> stronger Shh signal -> larger DP -> etc. Then HF miniaturization could conceivably start with either malfunction in DPCs (as is likely the case in Androgenetic Alopecia) or with depletion of progenitor cells. Maybe the latter is the case in hypotrichosis simplex -- there of course they have a dysfunctional version of APCDD1, a Wnt inhibitor (therefore Wnt would be hyperactive), and also suffer HF miniaturization. Aberrant Wnt signaling in CD34+ stem cells causes cellular senescence and depletion (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939833/):

Epidermal integrity is a complex process established during embryogenesis and maintained throughout the organism lifespan by epithelial stem cells. While Wnt regulates normal epithelial stem cell renewal, aberrant Wnt signaling can contribute to cancerous growth. Here, we explored the consequences of persistent expressing Wnt1 in an epidermal compartment that includes the epithelial stem cells. Surprisingly, Wnt caused the rapid growth of the hair follicles, but this was followed by epithelial cell senescence, disappearance of the epidermal stem cell compartment, and progressive hair loss. While Wnt1 induced the activation of β-catenin and the mTOR pathway, both hair follicle hyperproliferation and stem cell exhaustion were strictly dependent on mTOR function. These findings suggest that whereas activation of β-catenin contributes to tumor growth, epithelial stem cells may be endowed with a protective mechanism that results in cell senescence upon the persistent stimulation of proliferative pathways that activate mTOR, ultimately suppressing tumor formation.

The progressive changes in the HF structures and subsequent hair loss led us to explore whether prolonged exposure to Wnt1 induces cell apoptosis or senescence. While we could not detect the accumulation of apoptotic cells in response to Wnt1 expression (not shown), we observed that Wnt1 can promote cell senescence as judged by the detection of DNA-double strand breaks revealed by the presence of γ-H2AX foci in cell nuclei (Motoyama and Naka, 2004) and the expression of endogenous β-Gal activity at pH 6, a known characteristic of senescent cells (SAβ-Gal) (Dimri et al., 1995) (Figures 5A–B). Surprisingly, this correlated with the complete absence of CD34+ HF stem cells when compared to littermates (Figure 5C).

Rapamycin was able to prevent a lot of the DNA damage response, but not all of it. The mTOR activation they attribute to inhibition of GSK3. GSK3 positively phosphorylates TSC2, which inhibits mTORC1 activity. I guess people should be cautious about overusing GSK3beta inhibitors like LiCl and VPA for this reason -- it might backfire.

But let's just all put this together and look at it from a more simple view. Let's just assume that because of Androgenetic Alopecia some cell function stops somewhere. I mean can't we actually look at it from such a simple view? After all something has to stop functioning the way it supposed to do that leads to the miniaturization process. Look at it from an abstract point of view.

Now I have already linked to many studies that seem to point out senescence/cell cycle arrest in DP, here are a few;

<snip>

Hell, so let's just pick last study of the differential expression analysis between balding and non-balding DP and the micro RNA's involved in there and what they say about that;









Now I wanted to divide factors. There would be factors that would stop the cells from functioning and there are factors that would try to do their best to push the cells to start functioning the way they did in the beginning. So if we take some factors from the above studies and divide them

- Factors that stop cells from functioning

CDKN1/P21, BAK1, P27, P57, P51, pRB etc.

- Factors that would oppose some of the above factors (depends on the context though, it's more difficult in reality)

WNT, SHH, MYC, JUN, FOS, MAPK/ERK pathway, BCL-2 etc, Cyclin D1, growth factors...

Now the thing is let's look at observations what treatments actually grow hair. I'm going to pick two that is minoxidil and 17b-estradiol

Minoxidil might have impact on

- P21 decrease
- BCL-2/BAX
- B-catenin (WNT pathway)
-P53 decrease
- ERK/AKT
- Adenosine upregulation,
- VEGF (among other growth factors)
- PGE2

Now you can see that minoxidil not only does it seem to stimulate some factors that would oppose some of the bad guys, it might even have impact on some of these bad guys by decreasing them. I can link to any study showing these factors and implications with minoxidil btw.

Now let's look at some factors 17b-estradiol influences, it's much and complicated anyway;



But yeah if you look at this study; http://press.endocrine.org/doi/full/10.1210/er.2006-0020. You can see more interactions with estrogen with the MAPK pathway, WNT and many more.

Can we say based on this that perhaps why minoxidil and estrogen work is partly through this mechanism? Inhibit androgen/AR. Add minoxidil and estrogen. Then you get rid of the pathway chain in the first place (androgen/AR), but secondly you are now adding 2 molecules that will try their best to push these cells to performing their normal function again?

Possibly. Minoxidil and estrogen are different though in that while minoxidil causes hair growth everywhere, estrogen has different effects on different hair types -- it promotes head hair growth but doesn't do the same for facial hair growth. Do you know why exactly?

 

[InBeforeTheCure]

Anyway so how does SHH come into this? Well if you look at that mice study posted in this thread (yeah I know mice sucks it's useless);

Also the observations of people taking SHH antagonists are important. At the very least it seems to modulate hair cycle function, seeing how severe alopecia is in up to of 60% or more of cases which can even be long lasting after cessation of treatment. Secondly they also do an excellent job in switching the hair follicle cycle in mice. As also displayed in that latest study of A.M Christiano. Although that is a terrible weak argument, because mice are a horrible Androgenetic Alopecia model. At best they can be studies for hair follicle cycle modulation, but even that is up to debate.

The thing is we have zero observational evidence to go by of any SHH agonist, simply because there is none. And it's obvious why. These bad factors protect you from things like cancer too. So there are only SHH antagonists on the market (anti-cancer). Given this that Androgenetic Alopecia is not a life threathening disease the decision of Proctor & Gamble to have stopped the compound is a logical one. It also displayed toxicity in pre-clinical models.

Similarly 17b-estradiol is classified as a carcinogenic compound. I have seen some studies of 17b-estradiol and on breast tissue/breast cancer and indeed it seems to stimulate proliferation too, and oppose the bad guys in that sense. I call them bad guys but they are not really bad guys too because they protect you. However in Androgenetic Alopecia they might be bad guys as they might stop cell function. You know when we would take 17b-estradiol with suppressing androgen/AR axis we grow these lovely titties gyno, it's great for our hair too. Perhaps it just likes to stimulate cells both on the scalp and in the titty region .

Haha yeah, but the same is true for androgens for certain cell types -- they stimulate facial hair growth, body hair growth, prostate cell proliferation and carcinogenesis. In fact, I wouldn't be surprised if androgens may also be trying to promote proliferation of DPCs in Androgenetic Alopecia (possibly through mTOR), but this puts them under stress.

@InBeforeTheCure, I also saw quite many pathways implicated in your analysis that correspond to all the above? I think you mentioned you thought SHH wouldn't do much. SHH interacts with Cyc d1, myc, blc-2 , sox2, pax genes, fox genes etc. Curious to why you are so confident that this will not do anything. In the context of my story SHH would try to push the cells to function again perhaps?

I'm not saying it would be the cure, but still it should modulate at least the hair follicle cycle in some way IMO... Anyway it's a mystery we will probably never get to know.

What I said was something like "I don't think Shh agonists would work miracles for Androgenetic Alopecia", but I could be wrong of course. I thought it might initiate anagen but not reverse miniaturization at best, but if Shh is what causes dermal sheath proliferation, it's a lot more interesting. However, I thought people had tried Shh agonists with good, but not spectacular results?

 

[Swoop]

Indeed I was thinking of a similar feedback loop... Although I also look at it from just SHH being a very strong and stimulative signal for (stem)cells.

Rapamycin was able to prevent a lot of the DNA damage response, but not all of it. The mTOR activation they attribute to inhibition of GSK3. GSK3 positively phosphorylates TSC2, which inhibits mTORC1 activity. I guess people should be cautious about overusing GSK3beta inhibitors like LiCl and VPA for this reason -- it might backfire.

Funny, yeah I was having the same thoughts in the past (hyperproliferation) and it came back to me after your analysis. I read another study similarly to the one you show that aberrant signalling of X factor causes miniaturization. I can't find it though currently so perhaps it's the one you showed. Then again if it was due to WNT, wouldn't it be illogical to think this? I mean valproic acid... And take SM04450, I mean they don't really seem to damage hair but they do have weak hair growth activity. Shouldn't that then speed up hair growth?

mTOR is interesting though. Insulin resistance and the likes of metabolic syndrome are associated with increased mTOR activity, right? This leads to all sort of stuff like a decrease of autophagy, general anti-longevity factors etc.

Truth is, I have no doubt that insulin resistance, metabolic syndrome for instance might speed up Androgenetic Alopecia, or in general "living" extremely unhealthy. This might be indeed due to extra stress of mTOR for instance and downstream bad effectors that come with it. This will put extra stress on the cells.

On the other hands things like insulin resistance and metabolic syndrome decrease SHBG, which leads to a higher FAI, which leads to more DHT and less estrogen. Correlations have been made many times between low SHBG levels and (aggresive) Androgenetic Alopecia.. Some of them (but there are few more);

1.
Abstract Sex hormone-binding globulin and risk of hyperglycemia in patients with androgenetic alopecia.
BACKGROUND: Low circulating levels of sex hormone-binding globulin (SHBG) are a strong predictor of the risk of type 2 diabetes. Androgenetic alopecia (Androgenetic Alopecia) has been related to an increase in cardiovascular risk, but the mechanism of this association has not been elucidated. Androgenetic Alopecia can be associated with low levels of SHBG and insulin resistance, which could be related to hyperglycemia and type 2 diabetes.

2.
Androgenetic Alopecia is the most prevalent form of alopecia in men having polygenic origin. Total testosterone levels were within normal levels did not change in cases and controls. Some of the cases had low levels of SHBG than the reference range and level were decreased significantly when compared with the controls (P = 0.007). Frequently lower levels of SHBG were attributed to the higher frequency of the polymorphism of D327N of the SHBG gene in these men.[14] While further studies have reported androgen receptor gene present on X chromosome as well as mutations in P2RY5 display variable expressivity was a factor underlying both hypotrichosis and alopecia.[15] Although testosterone levels were normal, FAI was significantly higher in cases than controls (P = 0.0006). Freetestosterone accelerates gradual transformation large terminal scalp follicles to tiny villous ones causing premature Androgenetic Alopecia in genetically predisposed person.[16] This shows that FAI is the best marker of a person's androgen status as it can bind to tissue receptors.

3.
Hormonal Profile in men with premature androgenic alopecia [Article in Czech]
Starka L, Hill M, Polacek V.
Endokrinologicky ustav a IPVZ, Praha, Czech Republic.
Androgenetic alopecia especially that with premature onset can be a cause of serious psychic trauma. As far as the treatment with antiandrogens, inhibitors of 5 alpha-reductase or hair transplantation represents a heavy economic burden for the patient, we tried to exclude other hormonal causes or to find a criterion for the apt candidates for the treatment in 15 young men with premature androgenetic alopecia. Hormonal analysis discovered a significantly lower plasma level of sexual binding globulin (SHBG) and FSH and nearly significantly higher concentration of 17 alpha-hydroxyprogesterone.



4.
Sex hormone-binding globulin and saliva testosterone levels in men with androgenetic alopecia.
Cipriani R, Ruzza G, Foresta C, Veller Fornasa C, Peserico A.
Sex hormone binding globulin (SHBG), plasma testosterone and saliva testosterone were measured in sixty-four men with androgenetic alopecia and in forty males within the same age range without alopecia. There was a significant reduction in SHBG levels in bald men, compared with controls. Plasma testosterone levels were not raised in bald men, but their salivary testosterone levels were significantly higher than in controls.

I think @menti gave a tip about metformin which is a mTOR suppressor as well.Perhaps mTOR suppresors can give something in terms of damage control with also adding a pure anti-oxidant? Truth being is I have my doubts how much of relevance they would have in healthy individuals who are already very active and on a balanced diet. But then again I have no doubt that when you carry Androgenetic Alopecia genes, you get fat and slobby and start to display things like insulin resistance your hair is going to get wrecked at a faster level. At the very least if mTOR had also a central role in Androgenetic Alopecia then, mTOR suppresors should at least considerably slow down Androgenetic Alopecia right?

Possibly. Minoxidil and estrogen are different though in that while minoxidil causes hair growth everywhere, estrogen has different effects on different hair types -- it promotes head hair growth but doesn't do the same for facial hair growth. Do you know why exactly?

I wish I knew . Response to female and male scalp hair follicles may be also different due to estrogen; http://elib.tiho-hannover.de/dissertations/conradf_ss04.pdf. Check page 108. Interestingly in the context of what I have just told CDKN1A is downregulated by estrogen stimulated hair follicles, more in male hair follicles actually. If you look at " E2-responsive genes regulated sex-dependent different in human HF" you can also see that FOSL2 is upregulated in male HF and downregulated in female HF.

What I said was something like "I don't think Shh agonists would work miracles for Androgenetic Alopecia", but I could be wrong of course. I thought it might initiate anagen but not reverse miniaturization at best, but if Shh is what causes dermal sheath proliferation, it's a lot more interesting. However, I thought people had tried Shh agonists with good, but not spectacular results?

Yes, well I don't know for sure either. I just think it's a interesting pathway. Well yes a specific compound was tried by a couple of very bold people, but that was as non-scientific as it can get. Might have been of a too low dosage (0.02%) and it was applied only once a or twice a week. It was total nuts though and highly dangerous imo. I mean it's not like we have data of any SHH agonist in vivo on humans. It's playing Russian roulette. Perhaps in this sense the compound wasn't used in a desired concentration/frequency.

 

[kuba197]

Maybe you could cure baldness??

 

[InBeforeTheCure]

Indeed I was thinking of a similar feedback loop... Although I also look at it from just SHH being a very strong and stimulative signal for (stem)cells.



Funny, yeah I was having the same thoughts in the past (hyperproliferation) and it came back to me after your analysis. I read another study similarly to the one you show that aberrant signalling of X factor causes miniaturization. I can't find it though currently so perhaps it's the one you showed. Then again if it was due to WNT, wouldn't it be illogical to think this? I mean valproic acid... And take SM04450, I mean they don't really seem to damage hair but they do have weak hair growth activity. Shouldn't that then speed up hair growth?

True, true. Maybe they haven't used it for long enough to cause damage. Maybe negative feedback keeps it in check (one negative feedback mechanism is broken in hypotrichosis simplex) or for some other reason it's not a problem. I'm still inclined to be a little cautious about it, but maybe I'm being overly paranoid.

mTOR is interesting though. Insulin resistance and the likes of metabolic syndrome are associated with increased mTOR activity, right?

That's right.

Truth is, I have no doubt that insulin resistance, metabolic syndrome for instance might speed up Androgenetic Alopecia, or in general "living" extremely unhealthy. This might be indeed due to extra stress of mTOR for instance and downstream bad effectors that come with it. This will put extra stress on the cells.

On the other hands things like insulin resistance and metabolic syndrome decrease SHBG, which leads to a higher FAI, which leads to more DHT and less estrogen. Correlations have been made many times between low SHBG levels and (aggresive) Androgenetic Alopecia.. Some of them (but there are few more);

So is the association between Androgenetic Alopecia and things like metabolic syndrome the result of a common genetic background? Is it the metabolic syndrome that leads to more aggressive hair loss? Or aggressive hair loss drives them to eat out of despair?

I suppose you're suggesting the second, so do you know of any twin studies that show whether differences in lifestyle can contribute to speed of hair loss?

I think @menti gave a tip about metformin which is a mTOR suppressor as well.Perhaps mTOR suppresors can give something in terms of damage control with also adding a pure anti-oxidant? Truth being is I have my doubts how much of relevance they would have in healthy individuals who are already very active and on a balanced diet. But then again I have no doubt that when you carry Androgenetic Alopecia genes, you get fat and slobby and start to display things like insulin resistance your hair is going to get wrecked at a faster level. At the very least if mTOR had also a central role in Androgenetic Alopecia then, mTOR suppresors should at least considerably slow down Androgenetic Alopecia right?

The MTOR gene is close to rs12565727, a SNP significantly associated with Androgenetic Alopecia risk:

If MTOR is the gene in this region that confers risk to Androgenetic Alopecia, then we should expect inhibiting it to at least slow down hair loss on average. A further question is to what extent mTORC1 vs. mTORC2 might contribute.

We see upregulation of SGK1, a known AR target gene, in Androgenetic Alopecia. We also see downregulation of SOD2 and CAT, target genes of FOXOs that are ROS scavengers. AR is also known to activate the PI3K/AKT pathway through non-genomic signaling, and of course mTORC2 is a part of that axis as well. AFAIK, metformin inhibits mTORC1 or at least some aspects of the mTORC1 pathway, but not mTORC2. So maybe a dual mTOR inhibitor like AZD8055 would be able to slow Androgenetic Alopecia in some cases. An interesting study: Reversal of phenotypes of cellular senescence by pan-mTOR inhibition

Cellular senescence, a state of essentially irreversible proliferation arrest, serves as a potent tumour suppressor mechanism. However, accumulation of senescent cells with chronological age is likely to contribute to loss of tissue and organ function and organismal aging. A crucial biochemical modulator of aging is mTOR; here, we have addressed the question of whether acute mTORC inhibition in near-senescent cells can modify phenotypes of senescence. We show that acute short term treatment of human skin fibroblasts with low dose ATP mimetic pan-mTORC inhibitor AZD8055 leads to reversal of many phenotypes that develop as cells near replicative senescence, including reduction in cell size and granularity, loss of SA-β-gal staining and reacquisition of fibroblastic spindle morphology. AZD8055 treatment also induced rearrangement of the actin cytoskeleton, providing a possible mechanism of action for the observed rejuvenation. Importantly, short-term drug exposure had no detrimental effects on cell proliferation control across the life-course of the fibroblasts. Our findings suggest that combined inhibition of both mTORC1 and mTORC2 may provide a promising strategy to reverse the development of senescence-associated features in near-senescent cells.

Mitochondrial biomass increases as cells approach senescence [32] possibly as a compensatory mechanism for increasingly inefficient mitochondrial activity. We therefore used a mitochondrial-specific probe, Mitotracker Red, to label mitochondria in low and high CPD cells with acute mTORC inhibition. Mitochondria were detected as reticular networks throughout the fibroblasts, though at low population doublings the signal was relatively weak both without (Fig 2A) and with (Fig 2B) AZD8055 exposure. By contrast, a high Mitotracker signal was detected in near-senescent cells at CPD 73 (Fig 2C, E), consistent with increased ROS in the mitochondria of aged cells. This signal was dramatically reduced on AZD8055 treatment (Fig 2D, F), to levels similar to those detected in cells early in their proliferative lifespan (ie at low CPD (Fig 2A, B)).

We also find that levels of the replication clamp PCNA and the cell cycle regulator p27 are both diminished on AZD8055 treatment (Fig 6B).

Of course, this is replicative senescence rather than stress-induced senescence, but still very interesting. mTOR also plays a role in SASP:

Cellular senescence is often accompanied by the production of secreted proteins that mediate the diverse effects of senescence on the tissue microenvironment. The mammalian target of rapamycin (mTOR), a master regulator of protein synthesis, is now shown to control the senescence-associated secretory phenotype by modulating gene transcription and mRNA translation and stabilization.

Link: http://www.nature.com/ncb/journal/v17/n10/full/ncb3244.html?WT.feed_name=subjects_senescence

They talk a lot about IL1A in particular, which is 15 times higher in balding DPCs at the mRNA level.

I wish I knew . Response to female and male scalp hair follicles may be also different due to estrogen; http://elib.tiho-hannover.de/dissertations/conradf_ss04.pdf. Check page 108. Interestingly in the context of what I have just told CDKN1A is downregulated by estrogen stimulated hair follicles, more in male hair follicles actually. If you look at " E2-responsive genes regulated sex-dependent different in human HF" you can also see that FOSL2 is upregulated in male HF and downregulated in female HF.

Interestingly enough, FOSL2 is upregulated in balding DPCs and CDKN1A (p21) is 36 times lower. However, you would probably see increased p21 expression in the epithelial part of balding HFs due to upregulation of p53 there.

Yes, well I don't know for sure either. I just think it's a interesting pathway. Well yes a specific compound was tried by a couple of very bold people, but that was as non-scientific as it can get. Might have been of a too low dosage (0.02%) and it was applied only once a or twice a week. It was total nuts though and highly dangerous imo. I mean it's not like we have data of any SHH agonist in vivo on humans. It's playing Russian roulette. Perhaps in this sense the compound wasn't used in a desired concentration/frequency.

Oh okay, 0.02% sounds really damn low, but I guess it depends on potency as well. It's impressive that they got any results at all.

And a couple random points:
- The X2K program seems to have some systematic biases; therefore, I'm going to put together a new program for analyzing these networks which will be normalized to the Chew dataset. I'll also including miRNAs in the analysis if there's a good source for them.
- Here's a nice lecture on mTOR (focused on mTORC1) if anyone's interested:

 

[Swoop]

@InBeforeTheCure , you beast . Will reply tomorrow, bit tired now . Going to watch that lecture on mTOR now.

 

[Dench57]

 

[Swoop]

I suppose you're suggesting the second, so do you know of any twin studies that show whether differences in lifestyle can contribute to speed of hair loss?

Not anything aside from this one;

http://www.grimalt.net/wp-content/uploads/2013/06/Androgenetic Alopecia-in-twins.pdf

The study is a bit weird though...

Would that be purely environmental anyway @InBeforeTheCure?

I think generally it has influence but on a very low scale. Assuming you are living generally healthy. However if one really starts to display obesity with high insulin resistance then I assume you would shred your hair at a faster pace.

2 sets of twins;

 

[abcdefg]

Ha yeah 2 sets of twins. One guy balding badly and the other guy also balding just not as bad. Both are still balding.
Also there is a study on identical twins that found that even identical twins have different numbers of copies of the same genes so in a way identical twins are not really genetically identical. Not saying that accounts for the differences, but adds more variability into the outcomes. You still cant say for 100 percent its all life style causing that although it might contribute some

 

[Swoop]

Ha yeah 2 sets of twins. One guy balding badly and the other guy also balding just not as bad. Both are still balding.
Also there is a study on identical twins that found that even identical twins have different numbers of copies of the same genes so in a way identical twins are not really genetically identical. Not saying that accounts for the differences, but adds more variability into the outcomes. You still cant say for 100 percent its all life style causing that although it might contribute some

Good point. That's why I asked if it would be purely environmental, but indeed if twins are not genetically identical it's a different thing!

 

[Agent 47]

Wait, i'm not sure i understood your science mumbojumbo. Does this mean balding man are more resistant to cancer/tumors?
That would be a nice advantage to have, especially in our society where tumors are increasing by the day. Maybe baldness is the next step of evolution for fighting cancer?

 

[Swoop]

Wait, i'm not sure i understood your science mumbojumbo. Does this mean balding man are more resistant to cancer/tumors?
That would be a nice advantage to have, especially in our society where tumors are increasing by the day. Maybe baldness is the next step of evolution for fighting cancer?

Haha... Nah... We might be genetically inferior mate . Check; http://onlinelibrary.wiley.com/doi/10.1111/exd.12965/epdf

Read "Molecular genetic findings support the hypothesis that Androgenetic Alopecia is not an isolated trait" on the 4th page;

The identification of associations between Androgenetic Alopecia and other clinical phenotypes/diseases through genetic Androgenetic Alopecia research is a promising strategy to gain deeper insights into common pathophysiological mechanisms and may ultimately demonstrate that Androgenetic Alopecia is not an isolated trait but rather an early prognostic marker for later onset disorders, such as severe neurological or cardiovascular disease.

....

 

[Agent 47]

Haha... Nah... We might be genetically inferior mate . Check; http://onlinelibrary.wiley.com/doi/10.1111/exd.12965/epdf

Read "Molecular genetic findings support the hypothesis that Androgenetic Alopecia is not an isolated trait" on the 4th page;



....

Well, considering how many man bald these days, it means pretty much that the whole human race is becoming inferior.
I can't go outside my house without seeing man with thinning air, bald spots or slick bald.