GorillaHead
Member
I believe I truly elucidated the most likely mechanism for the genetic cause of balding. There are a lot of genes that are associated with AGA however many of these genes are not likely the cause but more like promoters. In fact the AR gene that was first implicated is likely just to be a promoter of balding and or sensitivity.
Lets talk about HDAC 4 it is not a new discovery its been discovered that this gene in particular places second or third on the highest association with AGA.
A lot of my research has focused on rare diseases that manifest AGA phenotypes and Adolescents phenotypes because these examples push against the puberty and androgen concepts being the cause as I have always said they are mediators.
Cue.
TRPS1 syndrome https://www.researchgate.net/public...ir_Loss_in_the_Trichorhinophalangeal_Syndrome
Myotonic Dystrophy type 1
Both of these diseases show very high association with Androgenetic alopecia and TRSP1 syndrome even shows association with prostate cancer.
Here is where things get interesting TRPS1 Syndrome is usually due to a mutation in the TRPS1 gene usually its not very well expressed, a full TRPS1 delete results in the Syndrome being more severe. But I found out that loss of TRPS1 also results in a significant loss in guess what HDAC4. This is a big deal because we see the AGA phenotype in TRPS1 and we know AGA has a huge hit on the HDAC4 gene.
www.ncbi.nlm.nih.gov
What does HDAC4 do, well it regulates bones, insulin and muscle. It has huge affects on calcification and many of us already theorized calcification being the cause and I have shown in other posts where bone calcification aka ossification was something some assistant noticed in the skulls of dead bald guys
Even more interesting is that there is a correlation that discovered that balding people tend to be shorter and have higher Bone mass densities. Science Has Found Out Why Shorter Men Go Bald More Often
Guess what happens if you do an HDAC4 delete on rats and mice, they end up shorter in length and their bones are thicker more density. Perhaps a coincidence but the connections and evidence are mounting. Go ahead and take a look at photos yourself in the links its very fascinating.
www.ncbi.nlm.nih.gov
Diving into more specific actions of HDAC4 it seems to inhibit the ossification of bone/and or hypertrophy of cartilage. Mice and Rats who have zero hdac4 end up with shorter fused limbs, the joints become bone. Cartilage usually turns into bone that's a normal process unless its suppose to stay cartilage and HDAC4 seems to ensure that joints and areas of cartilage that need to be cartilage stay as cartilage.
This lines up with the idea many of us have always thought of calcification. In fact if you search HDAC4 and calcification in google it seems to promote it in some cases and inhibit in others depending where it is in the cell, nucleus vs cytoplasm.
But wait there is even more connections I have discovered, HDAC4 seems to be regulated by PTH this isnt too crazy as we know that high pth can result in soft tissue calcification and even ossification bone spurs if my memory serves me right. JCI Insight - PTHrP targets HDAC4 and HDAC5 to repress chondrocyte hypertrophy.
pubmed.ncbi.nlm.nih.gov
Myotonic Dystrophy seems to show an association in studies where people have high PTH Validate User
PCOS often people bald, same scenario high pth Serum parathyroid hormone concentrations are increased in women with polycystic ovary syndrome - PubMed
Thing is in the studies I cited above some say PTH stimulates HDAC4, and PTHr does the opposite, actually I am very confused on this part and anyone with knowledge I would appreciate if you enlighten us. Its possible that HDAC4 location is what matters.
I also discovered SIK1 pushed HDAC4 in cytoplasm and causes aortic calcification yet if we inhibit SIK1 then HDAC4 goes to the nucleus and inhibits the calcification. SIK1 is noteworthy as its induced by high salt and Aldosterone has been shown I believe in two studies to be extremely elevated in AGA. Salt-inducible kinase induces cytoplasmic histone deacetylase 4 to promote vascular calcification - PubMed
This all is connected to PTH, Calcium and Prolactin, if the antibody Hope medicine is working on is the holy grail then it would make sense because their prolactin antibody caused reversal of AGA in monkeys which is a better model than rats 100 times over. We know calcium intake reduces Prolactin , vitamin D increases calcium intake, k2 removes calcification only from soft tissue not bone which may actually be the issues calcification of the bone making this a hard condition to reverse but perhaps easier to halt. and vitamin D reduces aldosterone and on top of that there is a very old weak study that saw the more salt was consumed the more hairfall.
Now it seems like I am implying we just need to lower PTH and this should solve the problem and maybe that's true because funny enough studies show that irrelevant of calcium, phosphate and vitamin D intake PTH goes up in age ten percent or so every 8-10 years which could explain why this AGA disease is progressive with age
In the end I am not sure on what the solution is but I am practically 10000% confident it has all to do with HDAC4. the fact its related to bone, muscle and insulin signaling lines up with all the epidemiological studies that have observed phenotypes.
IF anyone who has reduced their PTH with higher calcium intake has actually seen their balding halt, say something, thing is people do bald when PTH is high but I could not find studies to show if it was in an AGA fashion although it does look like it. And funny enough one study saw that body hair got thicker in hyperparathyroidism which would add to the fact it could truly be the issue here cause alot of us see increased body hair thickening as we age concurrent with our balding. Then there are studies that show Thailand has the lowest calcium intake of any country on average around 300mg a day which is crazy because they have the least balding of any country according to an old japanese study, doesn't invalidate the idea because it could just have to do with lower food consumption smaller sized individuals etc but does throw a bit of shade.
If I were to theorize a solution I would reccomend very low doses of retinol (funny enough there is more than enough data to show it accelerates balding and or kickstarts it in men) vitamin K and Vitmain D, 600mg of calcium daily and Topical vitamin C as vitamin C potentiates the anti prolactin effect on the receptor by dopamine assuming prolactin and PTH are directly related here. One guy found topical vitamin C completely halted his hairloss even though he was on minoxidil for 8 months with zero results. Not to mention there is publication that shows an ascorbic analog protects hair from androgen mediated hairloss.
Everything points to bone issues, insulin, metabolic syndrome and HDAC4 I assure you is at the center of it all.
Lets talk about HDAC 4 it is not a new discovery its been discovered that this gene in particular places second or third on the highest association with AGA.
A lot of my research has focused on rare diseases that manifest AGA phenotypes and Adolescents phenotypes because these examples push against the puberty and androgen concepts being the cause as I have always said they are mediators.
Cue.
TRPS1 syndrome https://www.researchgate.net/public...ir_Loss_in_the_Trichorhinophalangeal_Syndrome
Myotonic Dystrophy type 1
Both of these diseases show very high association with Androgenetic alopecia and TRSP1 syndrome even shows association with prostate cancer.
Here is where things get interesting TRPS1 Syndrome is usually due to a mutation in the TRPS1 gene usually its not very well expressed, a full TRPS1 delete results in the Syndrome being more severe. But I found out that loss of TRPS1 also results in a significant loss in guess what HDAC4. This is a big deal because we see the AGA phenotype in TRPS1 and we know AGA has a huge hit on the HDAC4 gene.
The multi zinc-finger protein Trps1 acts as a regulator of histone deacetylation during mitosis
TRPS1, the gene mutated in human "Tricho-Rhino-Phalangeal syndrome," encodes a multi zinc-finger nuclear regulator of chondrocyte proliferation and differentiation. Here, we have identified a new function of Trps1 in controlling mitotic progression in ...
www.ncbi.nlm.nih.gov
What does HDAC4 do, well it regulates bones, insulin and muscle. It has huge affects on calcification and many of us already theorized calcification being the cause and I have shown in other posts where bone calcification aka ossification was something some assistant noticed in the skulls of dead bald guys
Even more interesting is that there is a correlation that discovered that balding people tend to be shorter and have higher Bone mass densities. Science Has Found Out Why Shorter Men Go Bald More Often
Guess what happens if you do an HDAC4 delete on rats and mice, they end up shorter in length and their bones are thicker more density. Perhaps a coincidence but the connections and evidence are mounting. Go ahead and take a look at photos yourself in the links its very fascinating.
Histone deacetylase 4 deletion results in abnormal chondrocyte hypertrophy and premature ossification from collagen type 2α1‑expressing cells
Histone deacetylase 4 (HDAC4) plays a vital role in chondrocyte hypertrophy and bone formation. To investigate the function of HDAC4 in postnatal skeletal development, the present study developed lineage‑specific HDAC4‑knockout mice [collagen type 2α1 (Col2α1)‑Cre, HDAC4d/d mice] by crossing...
www.spandidos-publications.com
The deletion of Hdac4 in mouse osteoblasts influences both catabolic and anabolic effects in bone
Histone deacetylase 4 (Hdac4) is known to control chondrocyte hypertrophy and bone formation. We have previously shown that parathyroid hormone (PTH) regulates many aspects of Hdac4 function in osteoblastic cells in vitro; however, in vivo confirmation ...
www.ncbi.nlm.nih.gov
Diving into more specific actions of HDAC4 it seems to inhibit the ossification of bone/and or hypertrophy of cartilage. Mice and Rats who have zero hdac4 end up with shorter fused limbs, the joints become bone. Cartilage usually turns into bone that's a normal process unless its suppose to stay cartilage and HDAC4 seems to ensure that joints and areas of cartilage that need to be cartilage stay as cartilage.
This lines up with the idea many of us have always thought of calcification. In fact if you search HDAC4 and calcification in google it seems to promote it in some cases and inhibit in others depending where it is in the cell, nucleus vs cytoplasm.
But wait there is even more connections I have discovered, HDAC4 seems to be regulated by PTH this isnt too crazy as we know that high pth can result in soft tissue calcification and even ossification bone spurs if my memory serves me right. JCI Insight - PTHrP targets HDAC4 and HDAC5 to repress chondrocyte hypertrophy.
Parathyroid hormone regulates histone deacetylase (HDAC) 4 through protein kinase A-mediated phosphorylation and dephosphorylation in osteoblastic cells - PubMed
Histone deacetylases (HDACs) are crucial regulators of gene expression in transcriptional co-repressor complexes. Previously, we reported that HDAC4 was a basal repressor of matrix metalloproteinase-13 (MMP-13) transcription and parathyroid hormone (PTH) regulates HDAC4 to control MMP-13...
pubmed.ncbi.nlm.nih.gov
Myotonic Dystrophy seems to show an association in studies where people have high PTH Validate User
PCOS often people bald, same scenario high pth Serum parathyroid hormone concentrations are increased in women with polycystic ovary syndrome - PubMed
Thing is in the studies I cited above some say PTH stimulates HDAC4, and PTHr does the opposite, actually I am very confused on this part and anyone with knowledge I would appreciate if you enlighten us. Its possible that HDAC4 location is what matters.
I also discovered SIK1 pushed HDAC4 in cytoplasm and causes aortic calcification yet if we inhibit SIK1 then HDAC4 goes to the nucleus and inhibits the calcification. SIK1 is noteworthy as its induced by high salt and Aldosterone has been shown I believe in two studies to be extremely elevated in AGA. Salt-inducible kinase induces cytoplasmic histone deacetylase 4 to promote vascular calcification - PubMed
This all is connected to PTH, Calcium and Prolactin, if the antibody Hope medicine is working on is the holy grail then it would make sense because their prolactin antibody caused reversal of AGA in monkeys which is a better model than rats 100 times over. We know calcium intake reduces Prolactin , vitamin D increases calcium intake, k2 removes calcification only from soft tissue not bone which may actually be the issues calcification of the bone making this a hard condition to reverse but perhaps easier to halt. and vitamin D reduces aldosterone and on top of that there is a very old weak study that saw the more salt was consumed the more hairfall.
Now it seems like I am implying we just need to lower PTH and this should solve the problem and maybe that's true because funny enough studies show that irrelevant of calcium, phosphate and vitamin D intake PTH goes up in age ten percent or so every 8-10 years which could explain why this AGA disease is progressive with age
In the end I am not sure on what the solution is but I am practically 10000% confident it has all to do with HDAC4. the fact its related to bone, muscle and insulin signaling lines up with all the epidemiological studies that have observed phenotypes.
IF anyone who has reduced their PTH with higher calcium intake has actually seen their balding halt, say something, thing is people do bald when PTH is high but I could not find studies to show if it was in an AGA fashion although it does look like it. And funny enough one study saw that body hair got thicker in hyperparathyroidism which would add to the fact it could truly be the issue here cause alot of us see increased body hair thickening as we age concurrent with our balding. Then there are studies that show Thailand has the lowest calcium intake of any country on average around 300mg a day which is crazy because they have the least balding of any country according to an old japanese study, doesn't invalidate the idea because it could just have to do with lower food consumption smaller sized individuals etc but does throw a bit of shade.
If I were to theorize a solution I would reccomend very low doses of retinol (funny enough there is more than enough data to show it accelerates balding and or kickstarts it in men) vitamin K and Vitmain D, 600mg of calcium daily and Topical vitamin C as vitamin C potentiates the anti prolactin effect on the receptor by dopamine assuming prolactin and PTH are directly related here. One guy found topical vitamin C completely halted his hairloss even though he was on minoxidil for 8 months with zero results. Not to mention there is publication that shows an ascorbic analog protects hair from androgen mediated hairloss.
Everything points to bone issues, insulin, metabolic syndrome and HDAC4 I assure you is at the center of it all.
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