Understanding Androgenetic Alopecia

[Swooping]

As a side note, I remember reading a study where researchers attempted to keep hair follicles alive in vitro for as long as possible. The maximum length of time they eventually were able to keep the follicles alive was around 44 days, if memory serves me. They tried a variety of solutions and along the way discovered that oxygen actually killed the follicles.

With that in mind I think it's wise that hair transplant patients avoid hyperbaric chambers post-op.

35YrsAfter also posts as CITNews and works at Dr. Cole's office - forhair.com - Cole Hair Transplant, 1045 Powers Place, Alpharetta, Georgia 30009 - Phone 678-566-1011 - email 35YrsAfter at chuck@forhair.com
The contents of my posts are my opinions and not medical advice
Please feel free to call or email me with any questions. Ask for Chuck

Interesting 35YrsAfter, thanks. Dermal papilla cells in culture thrive way better too in culture under hypoxic conditions than normoxic conditions. This is a good read too about hypoxia and stem cells; http://www.cell.com/cell-stem-cell/p...10)00341-3.pdf

Oxygen in Stem Cell Biology: A Critical Component of the Stem Cell Niche
The defining hallmark of stem cells is their ability to self-renew and maintain multipotency. This capacity depends on the balance of complex signals in their microenvironment. Low oxygen tensions (hypoxia) maintain
undifferentiated states of embryonic, hematopoietic, mesenchymal, and neural stem cell phenotypes and also influence proliferation and cell-fate commitment. Recent evidence has identified a broader spectrum
of stem cells influenced by hypoxia that includes cancer stem cells and induced pluripotent stem cells. These findings have important implications on our understanding of development, disease, and tissue-engineering
practices and furthermore elucidate an added dimension of stem cell control within the niche.

[35YrsAfter]

Yes you hear that right, the cells like a hypoxic environment in the hair follicle, they like to bath in low oxygen. Especially the connective tissue which consists of the dermal papilla's too. HIF-1A is a regulator which protects this hypoxia state , thus loss of HIF-1A in your hair follicle would completely shred your hair follicle because your cells wouldn't cope with a higher oxygen environment. There are several studies which show this a good short summary;

As a side note, I remember reading a study where researchers attempted to keep hair follicles alive in vitro for as long as possible. The maximum length of time they eventually were able to keep the follicles alive was around 44 days, if memory serves me. They tried a variety of solutions and along the way discovered that oxygen actually killed the follicles.

With that in mind I think it's wise that hair transplant patients avoid hyperbaric chambers post-op.

35YrsAfter also posts as CITNews and works at Dr. Cole's office - Cole Hair Transplant, 1045 Powers Place, Alpharetta, Georgia 30009 - Phone 678-566-1011
The contents of my posts are my opinions and not medical advice

[Swooping]

"The consensus about what stress signal(s) after activation of the androgen receptor lead to premature senescence in AGA is not completely known. However literature points much to ROS or DNA damage or a intertwining effect of them both. This stress is to much for the cells to handle and then major pathways get activated which lead to senescence."

This is indeed a pretty big question at the moment, however if you look at the previous study we can perhaps dig a bit further into why the cells get stressed and senescence pathways like P53/pRB/P16ink4a set in. This is the study I'm talking about; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164265/

Microarray analysis of androgenetic and senescent alopecia: Comparison of gene expression shows two distinct profiles

Hair/skin development and function is the most significant physiological function altered in both AGA and SA (senescent alopecia), however, the DEGs (differentially expressed genes) in this category differed in the two diseases. Table 1 shows the 34 genes in this category that are differentially regulated in AGA that contribute to hair follicle development, morphology and cycling (BARX2, EGFR, INHBA, MSX2, OVOL1, KRTs, KRTAPs, RUNX3 and TIMP3). Many of these genes required for hair follicle homeostasis are significantly under expressed in AGA but not in SA compared to normal scalp tissue (Table 1 and Figure S1). Our data (Table 1 & Figure S1) showed that the Androgen Receptor (AR) is up regulated in AGA, but not in SA. Previous studies [4] have shown that genetic variability in AR is a prerequisite for the development of early-onset AGA. A novel AGA susceptibility locus has been identified at 17q21.31 [5]. In our dataset, the DEAD box polypeptide 5 (DDX5), a transcriptional regulator of AR [6] is down regulated in AGA and maps to this locus. The most significant pathway altered in AGA is Notch Signaling which consists of 29 genes (Table 1) including HES1, Notch2, Notch4 and PROX1 that are known to play a role in cell fate determination [7]. The down regulated genes in this pathway in AGA include CNTN1, JAG1, NOTCH2 and PSEN1 and the genes that are up regulated include DTX3, HES and NOTCH4. The expression patterns of Notch signaling pathway genes including Notch 2 and JAG1 were validated by real-time PCR (Figure S1). Jagged1 (JAG1) gene which encodes a ligand for Notch receptor maps to chromosome 20p a susceptibility locus for male-pattern baldness [8]. A reciprocal negative feedback regulation exists between Notch and AR-dependent pathways in the prostate [9]. The activation of AR and the concomitant loss of Notch signaling may be contributing factors to hair follicle miniaturization and may serve as the mechanistic link between prostate cancer and AGA. Thus, modulating the Notch signaling pathway in AGA may lead to future therapies.

This is the table with differentially expressed genes in androgenetic alopecia with changes of -2 or +2 , basically the ones that stand out the most; http://www.ncbi.nlm.nih.gov/pmc/arti...ort=objectonly



Obviously as said there is evidence again that the androgen receptor is fcked in AGA, they found a 2.46 fold increase of this compared to control as you can see in the link just above and in the picture here above where I underlined it in purple. I underlined the Aryl hydrocarbon receptor nuclear translocator-like 2 because that one is the most differentially expressed in this research paper with a fold change of -12.13. This gene encodes a protein that is a co-factor in transcriptional regulation by hypoxia-inducible factor 1 (HIF-1A). We'll come back to this later.

Now they say that the most significant pathway altered in androgenetic alopecia is NOTCH signalling which consists of 29 genes. Furthermore they refer to a other study which found a suspectibility locus for AGA at chromosome 20p, and JAGGED1 (JAG1) gene is a ligand for the NOTCH receptor and maps to this. They propose that activation of the androgen receptor leads to loss of NOTCH signalling which results in miniaturization;

In conclusion, we found that canonical Notch signaling is required for late-stage granular layer differentiation and correct filaggrin processing in the epidermis. Importantly, Notch signaling loss in hair follicle lineages leads to DNA damage response and loss of stem cell characteristics, which is possibly due to aberrant activation of bulge stem cells.

Remember DNA damage? Obviously a signal which can lead very well to senescence by pathways like P53/P16/P21 etc like described in this thread.

Nonetheless, let's dig a bit further and connect the dots a bit further ourself from the information in this study. We have;

- Altered androgen receptor 2.46 fold
- Altered Aryl hydrocarbon receptor nuclear translocator-like 2 -12.13 fold
- NOTCH signalling most significant pathway altered (29 genes)

Let's propose a hypothesis and try to connect those 3 together. First we are going to look at if NOTCH and the androgen receptor have interactions with each other as proposed;

.The AR and Notch receptors play essential roles in the regulation of prostate development and homeostasis. Notch signaling initiates when receptor-bearing cells interact with Notch ligands present in neighboring cells. Notch activation causes an increase in HEY1 expression and HEY1 accumulates in the nucleus repressing AR transcriptional activity. In a reciprocal way, the activation of AR upon androgen binding downregulates the expression of Notch1 receptor and its ligand Jagged1, and upregulates Sel1L, a negative regulator of Notch.

NOTCH is also expressed abundantly in hair follicles. I underlined here evidence that the activation of AR upon androgen binding can for instance downregulate NOTCH signalling and the ligand JAGGED1 which maps to a suspectible locus in AGA. I'm not going to go to deep into this, but there are many studies which show androgen receptor interaction with NOTCH, you can look them up yourself if you want.

So yes perhaps in AGA because of an overexpressed androgen receptor there is loss of NOTCH signalling. Now we go to the second point , can NOTCH signalling be connected to the Altered Aryl hydrocarbon receptor nuclear translocator-like 2 with a -12.13 fold gene expression in AGA? As I this gene encodes a protein that is a co-factor in transcriptional regulation by hypoxia-inducible factor 1 (HIF-1A). HIF-1A is also abundantly expressed in the hair follicle.

Let's look up what HIF-1A is ;

The protein encoded by HIF1 is a bHLH - PAS transcription factor found in mammalian cells growing at low oxygen concentrations. It plays an essential role in cellular and systemic responses to hypoxia.[5] This is one of the class of hypoxia inducible factors, a family that includes Hif1a, Hif2a, and Hif3a. HIF-1 functions as a master regulator of cellular and systemic homeostatic response to hypoxia by activating transcription of many genes, including those involved in energy metabolism, angiogenesis, apoptosis, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia.

Now what many people don't really know is that the hair follicle is in a moderately to severe hypoxia state. Yes you hear that right, the cells like a hypoxic environment in the hair follicle, they like to bath in low oxygen. Especially the connective tissue which consists of the dermal papilla's too. HIF-1A is a regulator which protects this hypoxia state , thus loss of HIF-1A in your hair follicle would completely shred your hair follicle because your cells wouldn't cope with a higher oxygen environment. There are several studies which show this a good short summary;

Hypoxia is believed to promote an undifferentiated state in several stem and precursor cell populations (Mohyeldin et al., 2010) and our results suggest that the lower stem cell niche of human hair follicles may also be in hypoxic environment. As a portion of CD34+ stem/progenitor cells is located in this hypoxic environment and have been demonstrated to disappear during androgenetic alopecia, we hypothesized that the induction of hypoxia signaling in suboptimal conditions would help maintain hair follicle stem cell functionality and hence prevent alopecia or at least favor neogenesis. Hypoxia signaling is mediated by the hypoxia-inducible transcription factor 1 (HIF1), composed of an αβ heterodimer. The α subunit was reported to be abundantly expressed in human hair follicles (Rosenberger et al. 2007) and is regulated in an oxygen-dependent manner through prolyl-4-hydroxylase-mediated hydroxylation, which mediates proteosomal degradation (Jaakkola et al., 2001).[B]

So we know that androgen receptor activation can lead to loss of NOTCH signalling. Does NOTCH signalling have something in common with HIF-1a?

Jup.. It does; http://www.ncbi.nlm.nih.gov/pubmed/16256737

Hypoxia requires notch signaling to maintain the undifferentiated cell state.
In addition to controlling a switch to glycolytic metabolism and induction of erythropoiesis and angiogenesis, hypoxia promotes the undifferentiated cell state in various stem and precursor cell populations. Here, we show that the latter process requires Notch signaling. Hypoxia blocks neuronal and myogenic differentiation in a Notch-dependent manner. Hypoxia activates Notch-responsive promoters and increases expression of Notch direct downstream genes. The Notch intracellular domain interacts with HIF-1alpha, a global regulator of oxygen homeostasis, and HIF-1alpha is recruited to Notch-responsive promoters upon Notch activation under hypoxic conditions. Taken together, these data provide molecular insights into how reduced oxygen levels control the cellular differentiation status and demonstrate a role for Notch in this process.

That's right there is evidence in several studies that HIF-1A needs NOTCH signalling to maintain a hypoxia state.

So we could propose now and take this study further that there is a correlation between the 3 of them,

AR> LOSS NOTCH SIGNALLING > LOSS HIF-1A > SENESCENCE PATHWAYS

What will that do? Well HIF-1A has major interactions with senescence and P53 etc there are many studies about this;

http://www.nature.com/jid/journal/v133/n8/full/jid2013113a.html

An interesting corollary to this is that within tissues, oxygen gradients often exist with stem cells residing in the most hypoxic regions (83). It is tempting to think then that these cells, which are known to be more resistant to oxidative stress as a mechanism of self-preservation (84, 85), benefit from their hypoxic environments by avoiding senescence, which would be detrimental to the regenerative capacity of the tissue.

So yes, perhaps loss of notch signalling due to activation of the androgen receptor leads to loss of HIF-1A in the hair follicle if this would happen, your cells would get stressed as hell (Insane ROS/oxidative stress and possibly DNA DAMAGE) and pathways related to senescence would get activated which would trigger SASP again, an inflammatory response.

[35YrsAfter]

Yes I definitely agree with you on that. I very doubt that it would be possible to have a drug short term which will cure AGA. Something like estrogen that doesn't go systematic would be of great help indeed, would use immediately! I would already if it wouldn't bring boobs with it .

I'm surprised I don't hear of men derma rolling estrogen.

Chuck

[Swooping]

Totally agree with that statement. I think the key to long term prevention is simultaneously combat dht using drugs working by those two mechanisms.


Thats why cb/ru + dut is the best combo for long term maintenance.


Swooping, do you see something on the horizon regarding all these fascinating research about the strong connection between cellular senescence and aga? Therapeutically speaking, of course

Yes I agree, prevention is your best bet by doing these things to keep those cells in a healthy condition. I don't see anything on the horizon for a full reversal cure, at least not from a drug form whatsoever. Ultimately a cell based therapy or genetic engineering would be the perfect answer for AGA in my opinion.

[Tenma]

your best bet is currently to lower DHT or antagonize the androgen receptor

Totally agree with that statement. I think the key to long term prevention is simultaneously combat dht using drugs working by those two mechanisms.


Thats why cb/ru + dut is the best combo for long term maintenance.


Swooping, do you see something on the horizon regarding all these fascinating research about the strong connection between cellular senescence and aga? Therapeutically speaking, of course

[Swooping]

Swooping, why don't you think this can be reversed through supplementations of acetyl cysteine and acetyl glutathione.

On N-acetyl cysteine:



Source: Wiki

Good question. Because when senescence has set in it can't be reversed that easily. It's sort of like a protective lock. NAC is used often in vitro studies to prevent or counteract apoptosis, ROS, senescence and such. Perhaps it may aid in slowing/preventing AGA but from practical practice we see that anti-oxidants don't cut it. The signals which lead to senescence are very strong and your best bet is currently to lower DHT or antagonize the androgen receptor.

You could try to reverse senescence by brute overriding signals which mediate senescence like P53/P16ink4a/pRB/P21 etc. However the problem with that is that you don't know if it is going to work and too much knockdown of these pathways is pretty dangerous and may lead to increased cancer risk for example.

A other way to get rid of senescent cells would be to actually try to destroy them (apoptosis) or to induce autophagy and get rid of them. I'll make a post later about this.




Btw minoxidil in vitro is able to reduce P53/P21 ;

The effects of minoxidil and ATRA (retinoic acid) on the expressions of P53 and P21 protein in DPCs (dermal papilla cells) and NHK (normal human epidermal keratonicytes). (A) Minoxidil alone and minoxidil plus ATRA significantly suppress the expression of P53 protein in DPCs. (B) In NHK, minoxidil plus ATRA decreases P53 expression significantly. (C) In DPCs, Minoxidil significantly decreases the expression of P21. Minoxidil plus ATRA reduces the expression of P21 more significantly. (D) P21 expression is significantly downregulated with minoxidil plus ATRA. The bands are the representative of triplicate experiments. *, p<0.05 compared with the vehicle-treated control. The data are shown as the means±SEM of % elevation compared with controls from three different DPC and NHK cultures. M, minoxidil.

[inbrugge]

Swooping, why don't you think this can be reversed through supplementations of acetyl cysteine and acetyl glutathione.

On N-acetyl cysteine:

Supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increased tumor progression and reduced survival in mouse models of B-RAF and K-RAS induced lung cancer[citation needed]. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes[citation needed]. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells[citation needed]. High levels of ROS or prolonged stress upregulates p53 and provokes a pro-oxidant response to further increase ROS, which subsequently elicits the p53-dependent apoptotic processes to eliminate damaged cells.[43][44][45] Thus, antioxidants can accelerate tumor growth by disrupting the ROS-p53 axis apoptosis, and autophagy, processes. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production.[46] It is not clear what dose(s) induced these effects. Additionally, it is important to reiterate that NAC does not cause cancer, it counteracts ROS accumulation caused by p53 and down-regulates p53, which in turn prevents p53-induced apoptosis and promotes autophagy.[47] in all cells; it is a dose dependent response, and the ability to manipulate cellular apoptosis and autophagy has many therapeutic benefits.

Source: Wiki

[Swooping]

It is also worthy to note that even though they are not the majority, there are millions of elderly men with still a full head of hair.

You are right, sorry bald wasn't the correct word. A "decline of hair quality" would be more appropriate indeed.

[Swooping]

That study is interesting too actually in relation to this. Let's break it up on a superficial level;

Hair/skin development and function is the most significant physiological function altered in both AGA and SA, however, the differential expressed genes in this category differed in the two diseases. Table 1 shows the 34 genes in this category that are differentially regulated in AGA that contribute to hair follicle development, morphology and cycling (BARX2, EGFR, INHBA, MSX2, OVOL1, KRTs, KRTAPs, RUNX3 and TIMP3). Many of these genes required for hair follicle homeostasis are significantly under expressed in AGA but not in SA compared to normal scalp tissue (Table 1 and Figure S1). Our data (Table 1 & Figure S1) showed that the Androgen Receptor (AR) is up regulated in AGA, but not in SA. Previous studies [4] have shown that genetic variability in AR is a prerequisite for the development of early-onset AGA. A novel AGA susceptibility locus has been identified at 17q21.31 [5]. In our dataset, the DEAD box polypeptide 5 (DDX5), a transcriptional regulator of AR [6] is down regulated in AGA and maps to this locus.

Ok this study shows that the androgen receptor in AGA is 2.46 fold changed

Whats more interesting is the bold part I underlined. A previous study has shown as you see that a suspectible locus (spot) had been identified in this study they found a -2 fold of DDX5 which maps to this locus.

Let's take a look at DDX5 now;

http://en.wikipedia.org/wiki/DDX5#cite_note-pmid15660129-10

DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which is an RNA-dependent ATPase, and also a proliferation-associated nuclear antigen, specifically reacting with the simian virus 40 tumor antigen. This gene consists of 13 exons, and alternatively spliced transcripts containing several intron sequences have been detected, but no isoforms encoded by these transcripts have been identified.[1]

With what protein does DDX5 interact? Ahh yes that's right P53; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC548656/. Hmm isn't P53 implicated in senescence..

Let's take another gene from that study which is altered in AGA ; Aryl hydrocarbon receptor nuclear translocator-like 2 ; by -12.13 fold

Let's look it up what that thing is exactly;

he ARNT gene encodes the aryl hydrocarbon receptor nuclear translocator protein that forms a complex with ligand-bound aryl hydrocarbon receptor (AhR), and is required for receptor function. The encoded protein has also been identified as the beta subunit of a heterodimeric transcription factor, hypoxia-inducible factor 1 (HIF1). A t(1;12)(q21;p13) translocation, which results in a TEL-ARNT fusion protein, is associated with acute myeloblastic leukemia. Three alternatively spliced variants encoding different isoforms have been described for this gene.

Hmm how does HIF1 relate to the hair follicle again?

Hypoxia is believed to promote an undifferentiated state in several stem and precursor cell populations (Mohyeldin et al., 2010) and our results suggest that the lower stem cell niche of human hair follicles may also be in hypoxic environment. As a portion of CD34+ stem/progenitor cells is located in this hypoxic environment and have been demonstrated to disappear during androgenetic alopecia, we hypothesized that the induction of hypoxia signaling in suboptimal conditions would help maintain hair follicle stem cell functionality and hence prevent alopecia or at least favor neogenesis. Hypoxia signaling is mediated by the hypoxia-inducible transcription factor 1 (HIF1), composed of an αβ heterodimer.

Something with ROS/Oxidative stress.. Wasn't that a stress related signal which may lead to premature senescence?

[Swooping]

I was just going to ask what about the minority of men that have NW 1 at like 50+ years old? There are guys that lose minimal if any hair even into very old age. Why do so many women at old age not go bald at all verses men then? Women dont express the bald genes but should still experience this senescence that you speak of right?

We have a genetic profile that just speed things up for these cells to go senescent. However even the cells of people who don't have the genetic profile of androgenetic alopecia will eventually go bald, it's just not "premature" senescence.

Sure those men don't have AGA genetics, simple as that. If you would have castrated yourself before puberty, you would be NW1 now too. You know pseudo-hermaphrodites and people suffering from androgen insensitivity syndrome have literally luxurious scalp hair throughout their life. But they will definitely notice some hair thickness decrease, density lose and obviously graying of the hair when they get really old.

AGA = Premature senescence
NON-AGA = Senescence varies, some might experience quality decrease of their hair in their 50's some might only show signs of hair decline in their 80's etc. (although may not even be to a great extent and only minor)

Just look at this study;

Microarray analysis of androgenetic and senescent alopecia: Comparison of gene expression shows two distinct profiles

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164265/#!po=16.6667

The differences in gene expression profiles suggest that AGA and SA may represent two independent hair disorders and that non-androgen pathways may also contribute to hair loss. This study provides novel therapeutic targets for the prevention or treatment of two common hair disorders.

Although I wouldn't call senescent alopecia a real "balding" problem. AGA is a balding problem. Who the hell would care some hair decline of quality when you are almost a grandpa.

[burtandernie]

I was just going to ask what about the minority of men that have NW 1 at like 50+ years old? There are guys that lose minimal if any hair even into very old age. Why do so many women at old age not go bald at all verses men then? Women dont express the bald genes but should still experience this senescence that you speak of right?

We have a genetic profile that just speed things up for these cells to go senescent. However even the cells of people who don't have the genetic profile of androgenetic alopecia will eventually go bald, it's just not "premature" senescence.

[inbrugge]

The people who suffer from AGA suffer from premature senescence. Your genetics are to blame for this. The activation of the androgen receptor in AGA does this located at the dermal papilla cells. Remember AGA is a polygenic inheritance so everyone will differ in his balding progression. We have a genetic profile that just speed things up for these cells to go senescent. However even the cells of people who don't have the genetic profile of androgenetic alopecia will eventually go bald, it's just not "premature" senescence. They have a different genetic profile in which these cells don't get stressed like a bitch by activation of the androgen receptor. Hope that makes sense.

The consensus about what stress signal(s) after activation of the androgen receptor lead to premature senescence in AGA is not completely known. However literature points much to ROS or DNA damage or a intertwining effect of them both. This stress is to much for the cells to handle and then major pathways get activated which lead to senescence.

It is also worthy to note that even though they are not the majority, there are millions of elderly men with still a full head of hair.

[Swooping]

Ironically we might be seeing a cure or something close to this not emerging out of the hair loss related field. That is a positive side. Senescence is implicated in many diseases but also general aging.

I found this one to have a general good explanation of senescence too;

[Swooping]

So AGA activations varies from age with people depending on when one's DNA get damaged?

The people who suffer from AGA suffer from premature senescence. Your genetics are to blame for this. The activation of the androgen receptor in AGA does this located at the dermal papilla cells. Remember AGA is a polygenic inheritance so everyone will differ in his balding progression. We have a genetic profile that just speed things up for these cells to go senescent. However even the cells of people who don't have the genetic profile of androgenetic alopecia will eventually go bald, it's just not "premature" senescence. They have a different genetic profile in which these cells don't get stressed like a bitch by activation of the androgen receptor. Hope that makes sense.

The consensus about what stress signal(s) after activation of the androgen receptor lead to premature senescence in AGA is not completely known. However literature points much to ROS or DNA damage or a intertwining effect of them both. This stress is to much for the cells to handle and then major pathways get activated which lead to senescence.