Understanding Androgenetic Alopecia

[Swooping]

Hey Swooping, this is a great post. I rarely post on this forum, just lurk from time to time, but I think you know your stuff so I guess I can ask you this. I think you mentioned something about it in your post but I didn't quite get it though.

Question: I've always heard that stress can cause and accelerate hairloss. I've seen some people say it hasn't been proven, but what I wanna know is if it can cause AGA and then if it can accelerate it, or does it only cause something like telogen effluvium (which I think is reversible/temporary)?

Whenever I see stuff on the internet about stress causing hairloss it's usually articles from stupid magazines that have no scientific facts to back up their claims. Thanks so much for this post!

Thanks. Stress can definitely not cause AGA. However indeed AGA ain't the only cause which can bring on hairloss. Outside of that there can be many causes too. Let me give you a theoretical example of stress could possibly bring on hairloss. Stress can cause thyroid problems. We know thyroid problems on itself can cause hairloss. If you look at the literature then;

http://www.ncbi.nlm.nih.gov/pubmed/25066729

http://www.ncbi.nlm.nih.gov/pubmed/19825978

http://www.ncbi.nlm.nih.gov/pubmed/21956127

http://www.ncbi.nlm.nih.gov/pubmed/20302576

You can see that thyrotropin releasing hormone and the thyroid have a prominent role in hair follicle cycling too. So if things start to go wrong with your thyroid which can be induced by stress, your hair may suffer too. This is just a example obviously. Stress won't cause AGA though. Hope that helps you. Why by the way are you not sure if you are suffering from AGA?

[woodnor]

Thanks. Stress can definitely not cause AGA. However indeed AGA ain't the only cause which can bring on hairloss. Outside of that there can be many causes too. Let me give you a theoretical example of stress could possibly bring on hairloss. Stress can cause thyroid problems. We know thyroid problems on itself can cause hairloss. If you look at the literature then;

http://www.ncbi.nlm.nih.gov/pubmed/25066729

http://www.ncbi.nlm.nih.gov/pubmed/19825978

http://www.ncbi.nlm.nih.gov/pubmed/21956127

http://www.ncbi.nlm.nih.gov/pubmed/20302576

You can see that thyrotropin releasing hormone and the thyroid have a prominent role in hair follicle cycling too. So if things start to go wrong with your thyroid which can be induced by stress, your hair may suffer too. This is just a example obviously. Stress won't cause AGA though. Hope that helps you. Why by the way are you not sure if you are suffering from AGA?

No, I was asking because i wanted to know if my stress ws a contributing factor to my aga. So basically stress can be the root of other problems which cause hair loss, but can this type of hairloss (like the one caused by thyroid problems) be irreversible?
Thanks for answering by the way

[Swooping]

No, I was asking because i wanted to know if my stress ws a contributing factor to my aga. So basically stress can be the root of other problems which cause hair loss, but can this type of hairloss (like the one caused by thyroid problems) be irreversible?
Thanks for answering by the way

Well I was just giving an example how stress might contribute to hairloss. A good thing to be sure would to do a blood test and measure the following things; B12, cortisol, Iron, Ferritin, Iodine, TSH. If that is alright then you don't have anything to worry about I think. That is obviously if you don't suffer from alopecia areata or a worse form of alopecia, but if that were the case you would know.

[Swooping]

Another study which relates to this (on mice though this one);



Overview of major pathways implicated in AGA in relation to senescence and an overview about how they work in general;

Senescence-inducing signals, including those that trigger a DNA-damage response (DDR), as well as many other stresses (Fig. 1), usually engage either the p53 or the p16–retinoblastoma protein (pRB) tumour suppressor pathways. Some signals, such as oncogenic RAS, engage both pathways. p53 is negatively regulated by the E3 ubiquitin-protein ligase HDM2 (MDM2 in mice), which facilitates its degradation, and HDM2 is negatively regulated by the alternate-reading-frame protein (ARF). Active p53 establishes the senescence growth arrest in part by inducing the expression of p21, a cyclin-dependent kinase (CDK) inhibitor that, among other activities, suppresses the phosphorylation and, hence, the inactivation of pRB. Senescence signals that engage the p16–pRB pathway generally do so by inducing the expression of p16, another CDK inhibitor that prevents pRB phosphorylation and inactivation. pRB halts cell proliferation by suppressing the activity of E2F, a transcription factor that stimulates the expression of genes that are required for cell-cycle progression. E2F can also curtail proliferation by inducing ARF expression, which engages the p53 pathway. So, there is reciprocal regulation between the p53 and p16–pRB pathways. Interactions among ARF, HDM2, p53, p21, CDKs, pRB and E2F also occur in other cell contexts — for example, during the DDR and reversible or transient growth arrest — so it not yet clear how senescence, as opposed to quiescence or transient growth arrest, is established. It is noteworthy, however, that at least in cell-culture studies, upregulation of p16 is not part of the immediate DDR and does not occur during transient growth arrests or quiescence.

[Atum]

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

[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.

[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;

[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.

[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.

[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.

[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]

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.

[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]

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 meansąSEM of % elevation compared with controls from three different DPC and NHK cultures. M, minoxidil.

[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