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Stimulation of Hair Growth by Small Molecules that Activate Autophagy

autophagy metabolite hair loss hair regeneration rapamycin metformin mtor ampk α-ketoglutarate α-ketobutyrate

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#1 Engadin

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Posted 20 June 2019 - 06:04 PM


S O U R C E :   Cell Reports

 

 

 

ABSTRACT

 

  • mTOR and AMPK modulation by rapamycin, metformin, and α-KG induces anagen hair growth
  • Autophagy induction is necessary and sufficient for anagen entry and hair growth
  • Autophagy is increased during anagen phase of the natural hair follicle cycle
  • Aged mice fed the autophagy-inducing metabolite α-KB are protected from hair loss

 

 

Summary

 

Hair plays important roles, ranging from the conservation of body heat to the preservation of psychological well-being. Hair loss or alopecia affects millions worldwide, but methods that can be used to regrow hair are lacking. We report that quiescent (telogen) hair follicles can be stimulated to initiate anagen and hair growth by small molecules that activate autophagy, including the metabolites α-ketoglutarate (α-KG) and α-ketobutyrate (α-KB), and the prescription drugs rapamycin and metformin, which impinge on mTOR and AMPK signaling. Stimulation of hair growth by these agents is blocked by specific autophagy inhibitors, suggesting a mechanistic link between autophagy and hair regeneration. Consistently, increased autophagy is detected upon anagen entry during the natural hair follicle cycle, and oral α-KB prevents hair loss in aged mice. Our finding that anagen can be pharmacologically activated in telogen skin when natural anagen-inducing signal(s) are absent has implications for the treatment of hair loss patients.
 
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Introduction

 

The biological and psychological importance of hair is well recognized. Hair loss affects millions worldwide and can occur because of aging, hormonal dysfunction, or autoimmunity or as a side effect of cancer treatment. Mammalian hair growth consists of cyclic repetitions of telogen (quiescence), anagen (regeneration), and catagen (degeneration) phases of the hair follicle. This hair follicle cycle is regulated by both intrinsic and extrinsic signals that control quiescence and activation of hair follicle stem cells (HFSCs). Inadequate hair follicle stem cell activation and proliferation underlie alopecia in numerous biological and pathological conditions, including aging. Molecules that can promote hair follicle stem cell activation and anagen initiation have been intensely searched for, as they may both help reveal how hair regeneration is regulated and provide therapeutic and cosmetic interventions. Here, we postulate that telogen hair follicles may be induced to enter anagen by pharmacologically triggering autophagy.

 

As a fundamental process for degrading and recycling cellular components, autophagy is critical for adaptation to nutrient starvation and other adverse environmental conditions, and it is regulated by such signals. Autophagy is also important for quality control of proteostasis through the elimination of misfolded or damaged proteins and damaged organelles. The loss of autophagy may be causally related to neurodegeneration and other diseases. Autophagy declines with age, likely contributing to the higher prevalence of autophagy-related diseases (e.g., cancer, neurodegenerative diseases) in the elderly. Autophagic clearing of active, healthy mitochondria in hematopoietic stem cells is required to maintain quiescence and stemness

, and autophagy fulfills the nutrient demand of quiescent muscle stem cell activation. In the skin, autophagy is required for self-renewal and differentiation of epidermal and dermal stem cells, but its role in hair follicle stem cells has remained controversial. On one hand, autophagy may be required for hair growth as skin grafts from the autophagy-related gene 7 (Atg7)-deficient mice exhibit abnormal hair growth. On the other hand, Atg7 deficiency in epithelial cells of the skin and hair was reported to be compatible with growth of hair, although sebaceous glands were affected, and male mutant mice developed an oily coat when they aged. It was also reported that psychological stress induced autophagy and delay of hair cycle.

 

Previously, alterations in intrinsic signaling, gene expression, and circadian function were implicated to prevent anagen entry in aged hair follicle stem cells and result in alopecia. The unforeseen finding that supplementation of a metabolite α-ketobutyrate (α-KB) in old mice can increase longevity and prevent alopecia suggests that rejuvenating aging or aging associated deficiencies may restore hair follicle stem cell function and hair growth in skin. We report herein that autophagy is increased during anagen phase of the natural hair follicle cycle and demonstrate that specific small molecules that induce autophagy can be used to promote anagen entry and hair growth from quiescent telogen phase.

 

...../.....


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#2 Mind

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Posted 20 June 2019 - 08:10 PM

Nice to see some investigation into hair loss, although this seems like a prevention strategy rather than rejuvenation.

 

Hair loss and greying are one of the surest signs of the failure of all anti-aging or "rejuvenation" treatments/supplements to date. I suspect some of the things I am taking are slowing down the aging process, but nothing so far has restored my hair or slowed down my greying. When I look at all of the other people my age and older....same thing...same grey hair and same male pattern baldness. When my hair grows back, I will know that particular rejuvenation therapy is working at a root level.


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#3 Phoebus

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Posted 20 June 2019 - 08:25 PM

 

 

We report that quiescent (telogen) hair follicles can be stimulated to initiate anagen and hair growth by small molecules that activate autophagy, including the metabolites α-ketoglutarate (α-KG) and α-ketobutyrate (α-KB), and the prescription drugs rapamycin and metformin, 

 

 

could any of those compounds be used topically on the scalp? I doubt anyone has ever used rapamycin topically on the scalp but it might be an interesting experiment. 


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#4 Oakman

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Posted 20 June 2019 - 10:24 PM

could any of those compounds be used topically on the scalp? I doubt anyone has ever used rapamycin topically on the scalp but it might be an interesting experiment. 

 

Alpha-ketoglutarate (AAKG is a pre-metabolite form of arginine.) is readily available (Amazon) and not expensive, you could always give it a try topically. Although as mind mentions, the study states, "Our data show stimulation of hair regeneration in the telogen phase but have not been tested for hair regeneration in alopecia.", so anything is possible.


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#5 TMNMK

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Posted 24 September 2019 - 12:36 PM

Yeah I'll give it a shot, 2-ketoglutaric acid (328-50-7), 2-ketobutyric acid (600-18-0), metformin. So I'll perhaps make neapolitan desert on my arm and see how it goes with those three. I'm mid-forties (that might be important to know). I've never made a PLO before, so that'll be a fun gooey mess unless there are other suggestions on transdermal gels or creams - anything easy out there? I could try topical first. I can take some pictures as I go through the process and post here. There is of course the oral route as well.. shall I try that at the same time or different timing?


Edited by TMNMK, 24 September 2019 - 12:37 PM.

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#6 TMNMK

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Posted 03 October 2019 - 05:43 PM

So after some experimentation and trying my hand at manual pharmaceutical compounding (spread/mixed on glass with metal spatulas, geometric dilution, then luer-lock syringes connected spout to spout with a little luer-lock to luer-lock connector pushing back and forth between the syringes ~30 times until well mixed), it seems less of a task to try one compound at a time (and I don't have pure metformin yet anyway). So I've started with 2-ketoglutaric acid (99.1%) in Humco PLO20 base with just a smidge of DMSO to loosen it up a bit (this is a messy inexact science to be sure). I'm going to deviate somewhat from the paper though. Instead of 4.675mg/ml to achieve a 32mM concentration I've simply made it 1% as at least one other paper does this instead (in 7:3 H2O:ethanol in that case but the density of PLO20 is 0.97 g/ml and DMSO  1.1 g/ml so it's probably coming in just under 1). I am applying that topically every other day to various parts of the left side of my body (left arm, left hand, left face, left side of head where I have grey / missing hair. I'll do this for perhaps 6 months, I think that should be enough time before diving into the next compound (probably the 2-ketobutyric acid, but since I'm older-ish I may try that orally according to the paper).

 

Let me know if you see an issue with any part of the above.


Edited by TMNMK, 03 October 2019 - 06:00 PM.


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#7 TMNMK

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Posted 03 October 2019 - 08:26 PM

So I suppose my concentration is 68.44mM, there is a patent associated with this paper that utilizes 16mM, so the other consideration is that I dilute what I have now by 2x to get to approximately 17mM. If I see any negative consequences I may do that, or if others here recommend that.

 

And when I try the 2-ketobutyric acid I'll probably dissolve 10g in ~12.25 liters of dH2O for ~8mM and drink that over the course of.. some period of time, I guess mice drink ~4-7 ml of water daily whereas I drink quite a lot of coffee and tea every day... I guess I'll need a rather large stockpile of 2-ketobutyric acid to make this experiment work. Looking for cheaper sources than my supplier. Lord help me if I have to go to alibaba on this thing, that would be an ordeal I think - if anyone has a way to get maybe a kg or two of this stuff for a reasonable price let me know!


Edited by TMNMK, 03 October 2019 - 08:46 PM.


#8 TMNMK

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Posted 04 October 2019 - 04:02 PM

A good read, especially for those who supplement with amino acids: Amino acids in the regulation of aging and aging-related diseases


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#9 OP2040

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Posted 04 October 2019 - 04:31 PM

Nice to see some investigation into hair loss, although this seems like a prevention strategy rather than rejuvenation.

 

Hair loss and greying are one of the surest signs of the failure of all anti-aging or "rejuvenation" treatments/supplements to date. I suspect some of the things I am taking are slowing down the aging process, but nothing so far has restored my hair or slowed down my greying. When I look at all of the other people my age and older....same thing...same grey hair and same male pattern baldness. When my hair grows back, I will know that particular rejuvenation therapy is working at a root level.

 

 

Very true.  I usually discount things like this as "not all that important" in the grand scheme of things.  And I often get sidetracked away from aging in general toward some specific symptom of aging that I'm interested in.  But I do think the sea change in people's attitudes toward aging will happen when we give balding men back their hair and take wrinkles away from older women.  It just impacts us all in a way that lab tests, though far more impact, never will.

 

Having said all that, I've become convinced of the proposition that many of the answers are already out there and available.  It's just they they're largely ignored, misunderstood completely or a couple ingredients short of a full recipe. 

 

I've recently been sidetracked yet again with LLLT therapy.  My own biases meant that I basically ignored this because it's one of those "women beauty" things, or because it isn't hard science enough.  But my saving grace was that I always go by the studies.  And there are a lot of studies showing that red light therapy works for a lot of things.  You could argue that all of them are low quality studies but I would disagree.  And regrowing hair is prominent among the things that it is supposed to help.  I truly believe that something like this could be sitting out there, and working for a subset of people, yet totally ignored by the general population.  Going to try it myself, though I'm not quite balding just yet,  Maybe it will help with grey hair.

 

Apologies for my super-long post, they even annoy me as I'm vomiting them out onto the page lol. 


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#10 TMNMK

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Posted 08 October 2019 - 09:10 PM

So far my skin hasn't melted off and my hair hasn't fallen out. It would be too early to expect anything positive but a lack of negatives allows me to continue.



#11 TMNMK

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Posted 08 October 2019 - 10:03 PM

a-KG has some very interesting properties. It's used by NASA to neutralize hydrazine. It's apparently an option if you find yourself poisoned with cyanide, and besides those useful household chores it has some pretty cool physiological activities. There are quite a few papers out there on it. It tastes pretty good in my opinion if you swig 300mgs in a cup of water (it is very soluble in water), kind of like a tart drink. But if you do drink it wash it down with an extra glass of water would be my recommendation due to the low pH it could be bad for your teeth and also its absorption increases when diluted (don't have that reference on me but read that somewhere). Also there's a company out there Rejuvant that is selling it as a calcium salt 30g for $160-$200 (note the calcium salt would be heavier). I bought 100g of the free acid for a quarter of that price. To make the calcium salt would be easy but even that effort I don't think is terribly worthwhile based on what I've read.

 

Oh also I'm going to change my PLO protocol, I'm going to dissolve it in a minimum of DMSO, put that into the syringe, then back load the PLO20 base on top of that, then do the whole luer-lock to luer-lock shearing/mixing action between the two connected syringes. I think my particular formulation is probably not optimized due to the fact that I had previously mixed the a-KG first into the PLO base then added the DMSO (I think pharmacists out there would cringe hearing that - so sorry, I'll do a better job next time).


Edited by TMNMK, 08 October 2019 - 10:17 PM.

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#12 TMNMK

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Posted 16 October 2019 - 07:38 PM

Still going, nothing shocking in either direction yet. Possible reduction in some wrinkles in forehead but that may be a hydrating effect of the PLO. It makes for one hell of a hair gel though, having a lot of fun in the mirror making mohawks. If nothing, it's great for laughs  :)

 

When I get back from this trip I've been on next week I'll try out the aforementioned PLO mixing method and see if anything happens with that.


Edited by TMNMK, 16 October 2019 - 07:43 PM.






Also tagged with one or more of these keywords: autophagy, metabolite, hair loss, hair regeneration, rapamycin, metformin, mtor, ampk, α-ketoglutarate, α-ketobutyrate

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