Reversal of hair loss in Mice with “sugar gel”

[Mauritio]

@Hearthfire I have used it orally.

I think heavy metals can cause fungus overgrowth since they bind and incorporate heavy metals. And we're certainly getting heavy metals from all kinds of angles.

[Mauritio]

@AinmBeo said in Reversal of hair loss in Mice with “sugar gel”:

Or getting the hair wet and making "rows" and applying it to the scalp at the base of each row?

This without making it wet. I apply it to the scalp, massage it and spread it with my fingers and after that comb my hair to spread it and increase circulation.

[Gaston]

@CrumblingCookie said in Reversal of hair loss in Mice with “sugar gel”:

I've been wondering whether BHB or butyrate would be better energy substrates to hair follices rather than dextrose.

Possible role of β-hydroxybutyrate in inducing inflammation in alopecia areata

https://onlinelibrary.wiley.com/doi/full/10.1111/exd.15117

[CrumblingCookie]

@Gaston said:

Possible role of β-hydroxybutyrate in inducing inflammation in alopecia areata

https://onlinelibrary.wiley.com/doi/full/10.1111/exd.15117

• Serum BHB levels were found to be significantly elevated in patients with AA compared with healthy controls, with higher levels correlating with severity of hair loss. BHB treatment increased inflammatory cytokine production in outer root sheath (ORS) cells, mimicking the inflammatory conditions seen in AA.

Hmm. That's a flip side. So the BHB seems to be strongly immunostimulative. Not necessarily merely proinflammatory per se. That leads us down to question the possibilities of what is underlying such (auto)immunological responses in alopecia areata, which may be due to specific or indistinct pathogen infection. And whether tackling such infection is possible rather than feeding or suppressing the immune response against it.

I can't find BHB serum measurements at the standard labs. Knowing those before would of course be nice to figure out which scenario one's in.

@Gaston said:

https://www.bulksupplements.com/products/potassium-bhb

Those are good offers for BHB. Unfortunately they don't sell butyrate or a-KG yet.

@Hearthfire said:

I've seen some stuff about how potassium may be a key to reversing hair loss.

https://www.hairloss-research.org/carnitine-and-hairloss/

Thanks. If I'm grasping it correctly the effects of the potassium only replaces the use of minoxidil: So in all cases where minoxidil proves to be of no benefit there would be no benefits from potassium either.
That and the AA/BHB-connection really points to wanting to first figure out the underlying mechanism of one's hair loss. Or to at least set up a plan of one's own trials as in "if not AA, then...", "if minoxidil, then K" or "if not minoxidil/K, then..."

[Hearthfire]

@CrumblingCookie The potassium bicarbonate at least is anti-fungal as well, so it could have multiple pathways to regrow hair. While also being much healthier/safer than minoxidil (even though minoxidil is pretty proven as a safe drug in correct doses and application)

[Gaston]

@CrumblingCookie What about ornithine a-ketoglutarate? I'm leaning towards trying this rather than BHB.

https://www.bulksupplements.com/products/l-ornithine-a-ketoglutarate-okg-powder

[AinmBeo]

@Mauritio
I put it on this morning.
Is there any reason to wash it off?
It does not seem leave a mess on the hair, after it dries.

[Mauritio]

@AinmBeo No I just leave it in. This should increase absorption .
It's surprisingly practical. Even the sugar version is growing on me. Its sticky first, but after drying it works a little like a hair gel.

Which version are you using ?

Im gonna add sodium butyrate this weekend .

[CrumblingCookie]

@Gaston said:

What about ornithine a-ketoglutarate?

Good find. I can't wrap my head around it all atm so maybe someone else may elucidate.
I remember ornithine works for scavenging/converting ammonia to urea and that less ammonia spares a-KG for more energy from the TCA. Then ornithin-aKG could be doubly beneficial.

It would be great if anyone can find the equivalent study to this study Intermediary metabolism of the human hair follicle but done on the dermal papilla.
According to this ex vivo/in vitro study the human hair follicles (and skin) mainly rely on

1. aerobic glycolysis of glucose, i.e. predominantly foregoing mitochondrial oxphos which only accounts to about 10% of all the glucose used up.
2. energy from glutamine by peripheral consumption of circulating amino acids or protein catabolism.

So glutamine and glucose seem to be an equally important energy substrates for hair follicles.
Replacing the 1% glucose with 1% L-glutamine may be an option. Or using both L-Glut and glucose in combination, which in the study above lead to much higher follicle ATP content than only glucose (in case that higher ATP content is a good thing and not sign of a backlog).

Yet I'm thinking that feeding other substrates (like a-KG) directly into the mitochondrial TCA of skin or hair follicles could unleash significant, additional metabolic energy capacities.

[AinmBeo]

@Mauritio
I am doing:
• Dextrose: 1 g
• B3 niacinamide: 1 g
• Vodka/Ethanol: 1 oz
• Distilled h2o: 2.3 oz
By the way, is there any reason not to do this every day?

[Mauritio]

@CrumblingCookie I discussed the hair metabolism in this post
https://bioenergetic.forum/post/41937

I've read the study you linked.
And I'm not sure glutamine is necessary . It gives a small energy boost, but maybe it also has it's draw backs (ammonia, inflammation?) .

It does increase total ATP content, but it also inhibits glucose utilization, indicating that they're competing for oxidation. Maybe glutamine is an emergency fuel.

Also glutamine is being converted to a ketoglutarate, which can feed the TCA cycle . But as we know this is a minor source of energy in the HF so I wouldn't focus on it too much . And it's partially taken care of by the current formula already.
But I'm gonna look into it more.

In wondering what other more benign amino acids do for the hair, like glycine ?

[Mauritio]

@AinmBeo I'd use NMN if possible.

Topical niacinamide does not stimulate hair growth based on the existing body of evidence
https://pubmed.ncbi.nlm.nih.gov/31955438/

Sure that's kind of the point.

[Mauritio]

Glutamic acid.
Not exactly glutamine, but related .

Has very impressive hair boosting effects in this study, especially the 1% and 10% solution .

https://www.nature.com/articles/s41598-021-94816-y/figures/3

@CrumblingCookie I haven't fully read it, but I feel like this study explains a lot of what we're wrestling with.

It seems that glutamine drives hair follicle growth from stem cells (HFSC) to outer root shaft cells which support the growing hair in the anagen phase. Interestingly this process is triggered by glutamine inhibiting aerobic glycolisis and boosting TCA cycle. So generally this could be achieved by substances that supress glycolisis and boost TCA cycle.

On the other hand they show that excessive glutamine or blocking mtorc2, long term depletes the HFSC pool, and I guess over long time frame that would lead to impaired regeneration and thinning hair.

This is also explains why they saw such drastic effects in the study above, but I'm not sure if that would be the same long term.

So, maybe cyclic addition of glutamine would be best. Between 1-10% , maybe 1 month on 2 months off or sth like that ?

https://pubmed.ncbi.nlm.nih.gov/32905798/

[CrumblingCookie]

@Mauritio said:

I discussed the hair metabolism in this post
https://bioenergetic.forum/post/41937

Sorry I had missed this post. It's essentially the same study and authors we both dug out there.

@Mauritio said:

On the other hand they show that excessive glutamine or blocking mtorc2, long term depletes the HFSC pool, and I guess over long time frame that would lead to impaired regeneration and thinning hair.

This is also explains why they saw such drastic effects in the study above, but I'm not sure if that would be the same long term.

So, maybe cyclic addition of glutamine would be best. Between 1-10% , maybe 1 month on 2 months off or sth like that ?

The "spatiotemporal" effects really open up a different angle to determine suitable combinations and timings of different topical substrates. We wouldn't want a limited phase of fully engaged "hair growth bloom" followed up by depletion of the underlying stem cells and exacerbated balding.

It's very important that when I think of true hair loss reversal I am thinking of reactivated dermal papilla. Whereas feeding preexisting hair follicles only impacts hair thickness and rate of growth.
Of course outer sheath and hair thickness and follicle formation are crucial for robustness and rootedness of the hair follicle and for distinguishing proper head hair from vellus hair.
So we do need stimulation of both. Maybe in cyclic variation of topical regiments.

I've discovered a metabolic study in which the authors set up a 3D sphere culture to generate hair follicles from dermal papilla (DP) activating skin epithelial stem cells:
Glucose metabolism regulates expression of hair-inductive genes of dermal papilla spheres via histone acetylation

• "Here we show that active DP exhibit robust aerobic glycolysis. We observed decrease of signature genes associated with hair induction by DP in presence of low glucose (2 mM) and glycolysis inhibitors. Moreover, hair shaft elongation was attenuated by glycolysis inhibitors. Interestingly, excessive glucose is able to increase the expression of hair inductive genes and elongation of hair shaft. We also observed glycolysis-mediated histone acetylation is increased and chemical inhibition of acetyltransferase reduces expression of the signature genes associated with hair induction in active DP. "

• "energy metabolism has been shown to be one of the major cues during hair follicle formation. Especially, lactate dehydrogenase (LDHA), an enzyme involved in anaerobic glycolysis is required for hair follicular stem cell activation."

• "To determine whether sDP exhibit anaerobic or aerobic glycolysis, we measured pyruvate and lactate levels. sDP showed higher pyruvate levels but not lactate levels, which indicating aerobic glycolysis is activated by sDP (Fig. 1e,f)."

-->DP also rely on aerobic glycolysis. So no obvious contradictions between HF and DP so far.
Yet I am wondering what happens with all that excess pyruvate in HF and DP:
@Mauritio said:

...Aerobic glycolisis leads to copious amounts of intermediate generation like lactate and pyruvate . Which can be used to build nucleotides and keratin for new hair . In OxPhos the carbon goes towards CO2.

• "In addition to ATP production, SCs utilize glucose-derived carbons for lipid synthesis and for production of hexosamines, ribose, glycerol, serine, and glycine." *

Anyway, (excessive, 10-20mM) glucose concentrations (/extra energy) go hand-in-hand with histone acetylation and epigenetic activation of (dormant) DP under assumed normal circumstances:

• "Expression of DP signature genes including BMP4, LEF1, WNT5A, VCAN and FGF7 were decreased from sDP in presence of low glucose (2 mM) compared with physiological of glucose (5.5 mM) without alteration in cellular viability (Fig. 2a–f)."

• "Interestingly, excessive glucose (10 mM) supplement increased expression of the signature genes associated with hair induction (Fig. 2p-t). [...] We also found that hair shaft elongation was enhanced by increased glucose concentration (Fig. 2w,x).

Which seems to underscore the first and foremost importance of energy substrates but also makes me wonder under what (sick or altered) conditions and toeholds and auxilliary cells non-energy-subtrate HDACi or DNMTi or HMTi or LSD/KDM and coriander and apple phenols etc exert their action in this context.
If the extent of glycolysis directly drives histone acetylation in DP and HFs then more isolated benefits can be expected by reducing histone or DNA methylation back to prior physiologically states. Topical EGCG, decursin, apigenin?
The reducing qualities of plant phenols may be necessary whenever increasing the small proportion of OXPHOS in HF and DP, e.g. by NMN? Or generally for the larger proportions of OXPHOS in the afferent capillaries?

Interestingly, feeding ketones/fatty acids to hair follicles inhibits the PPP synthesis of ribonucleotides (your 1991 HF study. Don't know what the actual effects of this will be):

• "Both palmitate and beta-hydroxybutyrate inhibited glucose flux through the pentose phosphate pathway. "

@Mauritio said:

In wondering what other more benign amino acids do for the hair, like glycine ?

• "The suggestion that glutamine may be an important metabolic substrate in skin is strengthened by one further observation: the concentration of most amino acids in sweat reflect, largely, their concentration in blood; but the concentration of glutamine in sweat is only 3% of that of blood, 18"

which is taken from a 1974 study on healthy subjects during sauna bathing, i.e. an increase of metabolism surely met by increased tissue perfusion yet probably not by sufficiently increased glucose utilization. Are excessive sauna-goers and endurance sportsmen balding more widely and quickly?

Leucine and (sources of) sulfate may be worth a look because of biglycan as a significant messenger to Wnt activation for hair follicle renewal:
Dermal papilla cell-secreted biglycan regulates hair follicle phase transit and regeneration by activating Wnt/β-catenin
Activated VDR is an important factor for Wnt/β-catenin activation. So any of the numerous pathogens which express antagonizing ligands will suppress Wnt/β-catenin, as would excessive D3 and 25-OH-D3.

For dermal papilla functions, activating the Akt pathway and increasing the
level of Bcl-2 as well as VEGF and IGF-1 all seem important. DP also excrete powerful exosomes which induce their own activation via Wnt/β-catenin in neighbouring tissues. Reminds me quorum sensing in bacterial cultures. The more adjacent hair you have, the more hair you keep/get:

• "A growth factor cocktail of keratinocyte-conditioned media such as VEGF and IGF-1 was found to significantly increase the proliferation of DPCs and induce hair follicles in mouse models [13]. The results of experimental studies showed that Wnt1a- and BM-MSC-conditioned media stimulate the conversion of hair follicles from the telogen to anagen phase. This cocktail was also found to significantly increase the number of hair follicles in mice [45]"

Maintaining Hair Inductivity in Human Dermal Papilla Cells: A Review of Effective Methods

[AinmBeo]

@Mauritio
Thanks.
I'm a wee bit confused.
I was partly going on this post, in which you mentioned glucose+niacinamide+ apple polyphenols for hair.
https://bioenergetic.forum/topic/1205/niacinamide-as-effective-as-minoxidil-at-treating-androgenic-hair-loss?_=1743946469122

[Mauritio]

@CrumblingCookie said in Reversal of hair loss in Mice with “sugar gel”:

Sorry I had missed this post. It's essentially the same study and authors we both dug out there.

No problem .

@CrumblingCookie said in Reversal of hair loss in Mice with “sugar gel”:

The "spatiotemporal" effects really open up a different angle to determine suitable combinations and timings of different topical substrates. We wouldn't want a limited phase of fully engaged "hair growth bloom" followed up by depletion of the underlying stem cells and exacerbated balding.

Totally agree. Gotta look more into LONG term studies on these substances , although they're probably scarce.

@CrumblingCookie said in Reversal of hair loss in Mice with “sugar gel”:

We also observed glycolysis-mediated histone acetylation is increased and chemical inhibition of acetyltransferase reduces expression of the signature genes associated with hair induction in active DP. "

Good one! Another reason to use butyrate and other HDACs.
The study even cited 2 other studies showing beneficial effects of HDACs on hair.

https://pubmed.ncbi.nlm.nih.gov/30814580/
https://pubmed.ncbi.nlm.nih.gov/22506014/

@CrumblingCookie said in Reversal of hair loss in Mice with “sugar gel”:

DP also rely on aerobic glycolysis. So no obvious contradictions between HF and DP so far.

But they study cited another one showing that HFSC rely on ANaerobic glycolisis, generating large amounts of lactate (not pyruvate)
So lactate itself might be wanted and needed for hair (stem cells).. something I never thought I'd say.
Or at least less lactate = less hair stem cells

But is their a cost?
Meaning more stem cells = less actively growing hair.
I think the glutamine study hinted at outer root sheath (ORS) cells reverting back to HFSC, which should reduce the hairs in anagen phases.

Then we're running into the glutamine problem again.
Short term vs. long term effects.

https://pubmed.ncbi.nlm.nih.gov/28812580/#:~:text=Furthermore%2C lactate generation appears to,(Ldha)%20prevented%20their%20activation.

Although this study suggests there is no difference in lactate between people with hair loss vs. No hair loss.
Which at least suggests high lactate there is normal and not necessarily a sign of a broken metabolism .

Squalene, a major component of sebum, was higher in people with hair loss, suggesting higher sebum production.
https://pubmed.ncbi.nlm.nih.gov/37760935/

[Mauritio]

@Mauritio said in Reversal of hair loss in Mice with “sugar gel”:

So lactate itself might be wanted and needed for hair

Here's an interesting review. Under 3.4.3 they talk about lactate and hair loss.

Lactate increases VEGF, leading to new blood vessels and better nutrients supply.
Also, lactate can increase glycogen levels, which increases anagen phase.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11879785/

[Mauritio]

@AinmBeo haidut always says NMN is basically niacinamide, which I don't think is true. Not in hair and not in all of the rest of the body . He's very pro niacinamide so maybe he's a bit biased there.
Not saying Niacinamide doesn't have benefits , hope I'm clear on that.

[AinmBeo]

@Mauritio said in Reversal of hair loss in Mice with “sugar gel”:

Total Liquids:
Water: 70 mL
Ethanol: 20 mL
Propylene Glycol: 10 mL
Total: 100 mL

Does the "Ethanol" listed here imply pure alcohol (no water in the mix)?
I am asking because, if I use 100 proof vodka instead, that is half water, so I would have to adjust the ratio.

[CrumblingCookie]

@Mauritio said:

But they study cited another one showing that HFSC rely on ANaerobic glycolisis, generating large amounts of lactate (not pyruvate)
So lactate itself might be wanted and needed for hair (stem cells).. something I never thought I'd say.
Or at least less lactate = less hair stem cells

But is their a cost?
Meaning more stem cells = less actively growing hair.

• "To assess the role of anaerobic glycolysis and lactate on 3C-HFSC proliferation in our system, we inhibited lactase dehydrogenase using FX11 (Flores et al., 2017) and observed that inhibiting lactate production attenuated proliferation of both HFSCs and ORS progenitors (Figure S4H), but did not affect the proportions of the two populations (Figure 4D). This indicated that, consistent with Flores et al., anaerobic glycolysis is required for HFSC activation, but it does not influence HFSC to ORS lineage progression."

Oh wow. HFSC do require lactate for their own proliferation. But on average it doesn't seem to hinder their absolute differentiation, it seems.

@Mauritio said:

The study even cited 2 other studies showing beneficial effects of HDACs on hair.

https://pubmed.ncbi.nlm.nih.gov/30814580/
https://pubmed.ncbi.nlm.nih.gov/22506014/

Nice follow up on this! I am unsure, however, whether these effects are mediated through HDACi or whether they are separate effects on Akt activation->GSK3beta inhibition->Wnt activation. It may be a distinct mechanism? But indeed why do they list 4-phenyl-butyrate (HDACi) as having the same effects? And trichostatin A (TSA) in the other study (which increased the acetylation level of histone H3K19 and H3K14).
They say VPA inhibits GSK-3beta "indirectly by an as-yet-unknown pathway" but that's info back from 2002. There seem to have been later studies in which HDAC activity was blocked or irrelevant and yet VPA directly inhibited GSK3β enzymatic activity. TSA on the other hand, as in the linked study, doesn't seem to act through Wnt/β-catenin but through increasing bone morphogenetic proteins (BMPs) which sound odd in the context of skin and hair.
(Topical) lithium will also do the Akt activation->GSK3beta inhibition->Wnt activation, but directly.

Even in conditions of sufficient glycolysis the activation of the Wnt/β-catenin pathway apparently lies at the very beginning at DP activation and HF induction because of the presence of overriding other adverse, inhibitory influences.
Which matches my experiences with topical glucose yielding strenghtened hair roots yet no proliferation.

@Mauritio said:

Here's an interesting review. Under 3.4.3 they talk about lactate and hair loss.

Lactate increases VEGF, leading to new blood vessels and better nutrients supply.

... so, topical lactate? If the topical solution remains at pH <5 we may even use benzoic acid or benzoate at 0.5-0.9% as a preservative instead of the high 35% ethanol. Maybe combined with an equimolar amount of glycine to allow for its enzymatic conversion to hippuric acid once applied and absorbed.

@Mauritio said:

haidut always says NMN is basically niacinamide, which I don't think is true. Not in hair and not in all of the rest of the body .

I've ditched all my NAM. I find its effects outright antimetabolic beyond the very short term yet those of nicotinic acid much more agreeable and I've been wanting to source NMN.