Stimulation Of Hair Growth By Small Molecules That Activate Autophagy

[gonetoday]

https://www.sciencedirect.com/science/article/pii/S2211124719306990

I actually have some rapamycin laying around and would love to test it, but am confused how much i should add to my topical, if anyone understands the μm etc, it states

Rapamycin (1.6 μM)
Test compounds (in 25 μL DMSO, unless otherwise indicated) .

Anyone understand that?

Study seems to suggest that autophagy is required for cells to start anagen.

 

[sktboiboi]

there's no proof that autophargy grows hair in vivo. there are tons of molecules that does this, mostly flavonoids- resveratrol is 1 of them. so has resveratrol grown any hair?

 

[sktboiboi]

u see this conflicting results between huamns and mice:

Furthermore, as shown in Figures 3A–3D, anagen induction and hair regeneration were also stimulated by topical treatment with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMP analog. Metformin, another agonist of AMPK (Burkewitz et al., 2014), has been widely used as a diabetes drug and was the first drug approved for human anti-aging studies (Knowler et al., 2002, Barzilai et al., 2016). Here we show that topical metformin similarly induced autophagy and hair regeneration (Figures 3E–3H). Interestingly, although metformin has not been used to study hair growth or treat hair loss, decreased hair loss in polycystic ovary syndrome patients treated with metformin tablets has been documented (Ou et al., 2016, Shahebrahimi et al., 2016).

= AICAR grows hair in mice



Impaired keratinocyte and DP cell proliferation upon AICAR treatment
To investigate the mechanism of PGC1α in causing hair miniaturization, we then analyzed the impact of elevated PGC1α expression on immortalized epithelial keratinocytes and mesenchymal DP cell proliferation. To stimulate PGC1α expression in vitro, cells were treated with AICAR (1 mM), an AMPK stimulator well known to induce PGC1α in dermal fibroblasts and keratinocytes31,32. PGC1α expression was induced by 2 fold and 1.6 fold immortalized keratinocyte and DP cells respectively after AICAR treatment for 24 hours (Fig. 5A). AICAR-stimulation resulted in a significant decrease of cell proliferation from 11.36% (Untreated) to 5.185% (AICAR treated) in NTERTs and from 17.43% (Untreated) to 14.09% (AICAR treated) in DP cells as measured by DNA-incorporation of EdU label (Fig. 5B).



= AICAR decreases hair growth in balding scalps of humans

 

[Otis Mack]

AICAR does not stimulate autophagy in some studies though. I just found this one and quickly there are probably more:

https://www.ncbi.nlm.nih.gov/pubmed/30021848

We showed that AMPK activation significantly attenuated the progression of heart failure and improved cardiac function, which was accompanied by decreased autophagy levels in the failing hearts


Metformin has some studies where chronic use damage the mitochondria. I will find it/them when I have a chance...



I guarantee that autophagy inhibitors(chloroquinone) will cause hair loss.


Dht probably is in itself an autophagy inhibitor and acts through MiRNA-212 or 221(I will find the studies).

How ____effective___ are drugs at inducing autophagy is the real question and another study suggested stacking various pathways.

Two well known on the list of small molecule autophagy activators are minoxidil and verapamil(I posted that study).

 

[Otis Mack]

About metformin damaging mitochondria:

https://www.ncbi.nlm.nih.gov/pubmed/25667085

Several changes in oxidative stress-related genes following metformin treatment were detected by PCR arrays specific for the oxidative stress pathway. These effects of metformin were found to be antagonized by the addition of insulin, which reduced Aβ levels, oxidative stress, mitochondrial dysfunction and cell death. Similarly, antioxidant molecules, such as ferulic acid and curcumin, are able to revert metformin's effect.

 

[Otis Mack]

Upregulation of MiR- 221:
https://www.ncbi.nlm.nih.gov/pubmed/21967250

We detected the significant upregulation of miR-221, miR-125b, miR-106a and miR-410 in balding papilla cells.



Up-regulation of miRNA-221 inhibits hypoxia/reoxygenation-induced autophagy
https://www.ncbi.nlm.nih.gov/pubmed/27105917


MiR-221 significantly reduced H/R injury in association with inhibition of autophagy

 

[CastorTroy]

One of the main substances here that initiated growth was alpha ketoglutarate
Which is available in capsules on amazon
It also has low molecular weight so should absorb easy and it’s cheap

 

[whatevr]

One of the main substances here that initiated growth was alpha ketoglutarate
Which is available in capsules on amazon
It also has low molecular weight so should absorb easy and it’s cheap

Don't hold your breath. Tried both orally and topically for about a month, not even reduction in shedding, kept losing hair.

 

[sktboiboi]

One of the main substances here that initiated growth was alpha ketoglutarate
Which is available in capsules on amazon
It also has low molecular weight so should absorb easy and it’s cheap

Ya right bro, show your regrowth pls?


It didnt grow hair and instead, worsened it, worse still, it gave me idiopathic kidney pain.

 

[Otis Mack]

I'm wondering how much alpha-KG increases autophagy in human cells? In humans it appears to have the exact opposite effect on ATP synthase as what starvation does. Starvation is a proven way of inducing autophagy in humans.


Cellular Compound May Increase Lifespan Without the Need for Strict Dieting

https://www.sciencemag.org/news/201...increase-lifespan-without-need-strict-dieting

To figure out how α-KG works, Huang and colleagues used a technique they developed that identifies the proteins in human cells that α-KG interacts with. The results showed that the compound attaches to ATP synthase, an enzyme that makes ATP, the cell’s main energy-carrying molecule. ATP synthase resides in the energy-producing structures called mitochondria. By studying the mitochondria from cow heart cells, the researchers found that α-KG blocks ATP synthase, thus turning down the cell’s metabolism.


Mitochondrial biochemist Michael Ristow of the Swiss Federal Institute of Technology in Zurich says that the molecular mechanism for this effect took him by surprise. He notes that other studies have shown that calorie restriction boosts ATP synthesis by making mitochondria more efficient, so you’d predict that α-KG would do the same. “That’s what makes it interesting,” he says. “It’s unexpected.”

Dietary supplements that contain α-KG and allegedly build muscle are already on the market. The study drops a barbell on their use, however, by suggesting that α-KG inhibits TOR, thus thwarting muscle growth. “If people are taking this as a muscle builder, you would think it doesn’t cause the desired effect,” Mair says.

There’s no guarantee that α-KG will have the same effects on aging in people as it has in worm

 

[Otis Mack]

As they say...a picture is worth a 1000 words. These animals likely had higher autophagy levels than their well fed counterparts. Any guess who has the hair loss before looking at the pictures???

There have been some good arguments put forth about how CR works and many think it is from iron overload. Less food consumed = less iron consumed.

But remember there are adolescents who develop pattern balding too. Are we to blame iron overload as a cause so early in life? NO.

Iron overload increases with age as does Androgenetic Alopecia and that part makes perfect sense for the iron overload argument. But WHY so early in life does an does hair loss occur?

As far as gender goes, females have better autophagy and just generally look better physically than males even late in life.

What I think it is the menstrual cycle does equal loss of iron but it really is what iron fluctuations do to trigger autophagy.
Once menopause hits the iron fluctuations are less drastic and they pick up the same rate of aging and physical ailments of men.


We can see through out the years the use of metal ions that have been used in various hair growth topicals and studies.
Were we attempting to upregulate autophagy?

https://sci-hub.tw/10.1016/j.phrs.2017.01.009









https://pubsapp.acs.org/cen/science/87/8731sci2.html

 

[Otis Mack]

As they say...a picture is worth a 1000 words. These animals likely had higher autophagy levels than their well fed counterparts. Any guess who has the hair loss before looking at the pictures???

There have been some good arguments put forth about how CR works and many think it is from iron overload. Less food consumed = less iron consumed.

But remember there are adolescents who develop pattern balding too. Are we to blame iron overload as a cause so early in life? NO.

Iron overload increases with age as does Androgenetic Alopecia and that part makes perfect sense for the iron overload argument. But WHY so early in life does an does hair loss occur?

As far as gender goes, females have better autophagy and just generally look better physically than males even late in life.

What I think it is the menstrual cycle does equal loss of iron but it really is what iron fluctuations do to trigger autophagy.
Once menopause hits the iron fluctuations are less drastic and they pick up the same rate of aging and physical ailments of men.


We can see through out the years the use of metal ions that have been used in various hair growth topicals and studies.
Were we attempting to upregulate autophagy?

https://sci-hub.tw/10.1016/j.phrs.2017.01.009



I will mention about iron chelators which was discussed in the above link.

Some are aware of the IVIG treatments which reversed Androgenetic Alopecia.

While everyone jumped on the anti-inflammation bandwagon to why IVIG could have worked, I noticed that IVIG is an EXCEPTIONAL iron chelator. Normal chelation therapies are slow progress and can last for years. But check out the drastic change in the pictures of IVIG treatment on neo-natal iron overload.


https://www.ncbi.nlm.nih.gov/pubmed/25057417









https://pubsapp.acs.org/cen/science/87/8731sci2.html

 

[Otis Mack]

I will mention about iron chelators which was discussed in the above link.

Some are aware of the IVIG treatments which reversed Androgenetic Alopecia.

https://www.sciencedirect.com/science/article/pii/S2352241017300191

While everyone jumped on the anti-inflammation bandwagon to why IVIG could have worked, I noticed that IVIG is an EXCEPTIONAL iron chelator. Normal chelation therapies are slow progress and can last for years. But check out the drastic change in the pictures of IVIG treatment on neo-natal iron overload.


https://www.ncbi.nlm.nih.gov/pubmed/25057417

 

[Otis Mack]

One of the problems hindering autophagy is the build-up of lipofuscin which occurs with age.

https://medium.com/the-mission/the-garbage-catastrophe-of-aging-and-how-to-avoid-it-783fb2a795c5


"There have been a few reports of substances that can clear lipofuscin from cells. If these were to pan out, they could turn out to be potent anti-aging interventions.

One such substance is a form of cyclodextrin, which is a cheap safe molecule that is already used as an excipient in medicines."); background-size: 1px 1px; background-position: 0px calc(1em + 1px);">10

This form of cyclodextrin upregulates autophagy and clears cellular junk."); background-size: 1px 1px; background-position: 0px calc(1em + 1px);">11"

 

[Armando Jose]

But WHY so early in life does an does hair loss occur?

Good question....

 

[Armando Jose]

NAC (N Acetl Cystein) is good for mithrochondias and avoid lipofucsin

 

[Otis Mack]

This research paper strongly argues against histidine(dont supplement it) as it increases lipofuscin formation.


https://www.longdom.org/open-access...ofuscin-in-mitochondria-2161-1009-1000357.pdf

 

[Otis Mack]

Good question....

It is good to not avoid data which don't fit "our" model.

Avoiding data points which dont fit is just overfitting and everybody does it and I'm talking to myself here too.

 

[Armando Jose]

A data, very important, is if at 4 or 6 years old, we have sebum in our scalp hair.
If yes, then time to start study again at this interesting problem.
Which is your opinion?

 

[Otis Mack]

NAC (N Acetl Cystein) is good for mithrochondias and avoid lipofucsin

Such substances as cysteine, histidine and imidazole are not 100%- th antioxidants. Нe\ can act as pro-oxidants at high concentrations. Probably this is due to a reduction of iron atoms, which then come into the Fenton’s reaction. Нis reaction starts the lipid per-oxidation and, as a consequence, the quantity of LF increases.


Glutathione precursor cysteine also has a sufhydryll group. Нerefore, we suggested that cysteine could also be able to cleave the LF. Indeed, the amount of thermal-LF in mitochondria decreased by 25% aіer 1 hour incubation with 1 mM cysteine at 23°C. Dithiothreitol has two thiol groups with redox potential of −0.33 V at pH 7 [28]. It is a strong reducing agent, so it is also able to cleave the 6chiوٴ bases. Нe standard reduction potential of the 6chiوٴ bases is in the range of -1.5 V to -2.5 V [29]. Нe electromotive force of the reaction is directed towards the reduction of the 6chiوٴ bases. In our experiments, the LF concentration decreased by 15% aіer incubation of mitochondria with 1 mM dithiothreitol for 1 hour at 23°C.