The Anti-aging Protein Klotho Induced By Gaba

[High_Prob]

The anti-aging protein Klotho is induced by GABA therapy and exerts protective and stimulatory effects on pancreatic beta cells. - PubMed - NCBI

The anti-aging protein Klotho is induced by GABA therapy and exerts protective and stimulatory effects on pancreatic beta cells.
Prud'homme GJ, et al. Biochem Biophys Res Commun. 2017.
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Abstract
Systemic gamma-aminobutyric acid (GABA) therapy prevents or ameliorates type 1 diabetes (T1D), by suppressing autoimmune responses and stimulating pancreatic beta cells. In beta cells, it increases insulin secretion, prevents apoptosis, and induces regeneration. It is unclear how GABA mediates these effects. We hypothesized that Klotho is involved. It is a multi-functional protein expressed in the kidneys, brain, pancreatic beta cells, other tissues, and is cell-bound or soluble. Klotho knockout mice display accelerated aging, and in humans Klotho circulating levels decline with age, renal disease and diabetes. Here, we report that GABA markedly increased circulating levels of Klotho in streptozotocin (STZ)-induced diabetes. GABA also increased Klotho in the islet of Langerhans of normal mice, as well as the islets and kidneys of STZ-treated mice. In vitro, GABA stimulated production and secretion of Klotho by human islet cells. Knockdown (KD) of Klotho with siRNA in INS-1E insulinoma cells abrogated the protective effects of GABA against STZ toxicity. Following KD, soluble Klotho reversed the effects of Klotho deficiency. In human islet cells soluble Klotho protected against cell death, and stimulated proliferation and insulin secretion. NF-κB activation triggers beta-cell apoptosis, and both GABA and Klotho suppress this pathway. We found Klotho KD augmented NF-κB p65 expression, and abrogated the ability of GABA to block NF-κB activation. This is the first report that GABAergic stimulation increases Klotho expression. Klotho protected and stimulated beta cells and lack of Klotho (KD) was reversed by soluble Klotho. These findings have important implications for the treatment of T1D.

PMID
28993191 [Indexed for MEDLINE]

 

[bdawg]

nice one

What is the GABA 'therapy' they used in the study?

 

[Sobieski]

Is this to say people with low gaba levels age faster?

 

[High_Prob]

nice one

What is the GABA 'therapy' they used in the study?

Here is the full study: https://www.researchgate.net/public..._stimulatory_effects_on_pancreatic_beta_cells

Under 'Animal Handling' it explains that mice were treated with GABA in drinking water. So it appears that they used the straight amino acid.

Under 'Cell Culture' it explains that cultured cells were treated with Muscimol for Gaba A receptors and Baclofen for Gaba B receptors.

 

[bdawg]

Here is the full study: https://www.researchgate.net/public..._stimulatory_effects_on_pancreatic_beta_cells

Under 'Animal Handling' it explains that mice were treated with GABA in drinking water. So it appears that they used the straight amino acid.

Under 'Cell Culture' it explains that cultured cells were treated with Muscimol for Gaba A receptors and Baclofen for Gaba B receptors.

Thanks

I thought GABA by itself is poorly absorbed - you need a phenibut like structure to get it past the BB barrier

 

[haidut]

Here is the full study: https://www.researchgate.net/public..._stimulatory_effects_on_pancreatic_beta_cells

Under 'Animal Handling' it explains that mice were treated with GABA in drinking water. So it appears that they used the straight amino acid.

Under 'Cell Culture' it explains that cultured cells were treated with Muscimol for Gaba A receptors and Baclofen for Gaba B receptors.

Finally, some good studies coming out to expose the pharma fraud that convinced the public oral GABA is useless. The dose was minuscule, and the HED was 0.48mg/kg. So, for most humans that means 30mg-50mg GABA daily. For comparison, most supplements on the market sell GABA in 500mg pills. The duration was 11 weeks, so kind of long but I think the same effects can be seen in much shorter timeframes with higher doses of GABA. Human studies with 100mg+ have shown lower insulin and blood sugar, as well as lower cortisol, so we know it definitely has an effect when taken orally.
In my opinion, the "ineffectiveness" of oral GABA ranks right up there with serotonin being a "happiness" hormone in the hall of fame of scientific fraud.
Btw, vitamin D is a another potent inducer of Klotho and so is thyroid (T3).

 

[managing]

Finally, some good studies coming out to expose the pharma fraud that convinced the public oral GABA is useless. The dose was minuscule, and the HED was 0.48mg/kg. So, for most humans that means 30mg-50mg GABA daily. For comparison, most supplements on the market sell GABA in 500mg pills. The duration was 11 weeks, so kind of long but I think the same effects can be seen in much shorter timeframes with higher doses of GABA. Human studies with 100mg+ have shown lower insulin and blood sugar, as well as lower cortisol, so we know it definitely has an effect when taken orally.
In my opinion, the "ineffectiveness" of oral GABA ranks right up there with serotonin being a "happiness" hormone in the hall of fame of scientific fraud.
Btw, vitamin D is a another potent inducer of Klotho and so is thyroid (T3).

is GABA best taken with food, or empty stomach?

 

[haidut]

Thanks

I thought GABA by itself is poorly absorbed - you need a phenibut like structure to get it past the BB barrier

Not true, it was a well-orchestrated fraud by Pharma in order to sell benzodiazepines like Xanas, Klonopin, etc and other GABA agonists like Pregabalin (Lyrica), Topiramate, etc.
See my comment above in response to Prob. Also, Google for "GABA oral bioavailability Pubmed". Tons of studies have come out lately and exposed the fraud perpetrated for decades. Unfortunately, generations of doctors went through the system indoctrinated that oral GABA is useless, so Pharma will have another decade or so of good sales before the public finally catches on.

 

[haidut]

is GABA best taken with food, or empty stomach?

Empty stomach, and combines great with BCAA/phenylalanine/tyrosine to lower serotonin and cortisol, even though it would have decent effects on those even by itself. GABA increase serotonin degradation and GABA agonists are used to treat Cushing syndrome.

 

[bdawg]

Not true, it was a well-orchestrated fraud by Pharma in order to sell benzodiazepines like Xanas, Klonopin, etc and other GABA agonists like Pregabalin (Lyrica), Topiramate, etc.
See my comment above in response to Prob. Also, Google for "GABA oral bioavailability Pubmed". Tons of studies have come out lately and exposed the fraud perpetrated for decades. Unfortunately, generations of doctors went through the system indoctrinated that oral GABA is useless, so Pharma will have another decade or so of good sales before the public finally catches on.

Great to hear

I also found this, GABA is not only absorbed but beneficial for type 1 diabetes, human study:

Study of GABA in Healthy Volunteers: Pharmacokinetics and Pharmacodynamics

Our data show that GABA is rapidly absorbed and tolerated in human beings; its endocrine effects, exemplified by increasing islet hormonal secretion, suggest potential therapeutic benefits for diabetes.

 

[benaoao]

Quick google search

Natural Ways to Increase GABA

I’m very much fond of coconut too, since MCTs seem to raise ketones and ketones seem to increase GABA whilst decreasing glutamate for a double positive. I don’t really see issues with coconuts to be honest, besides the occasional allergic person.

 

[bdawg]

What would be a good dosing? I notice pharmagaba (synthesized from bacteria) is quite expensive compared to plain powder.

The study I posted used 2g doses up to 3 times a day

 

[griesburner]

interesting. i started a thread about gaba supplementation a while ago, too:

GABA As A Supplement?

But i was a bit sceptical that there are so many threads on different forums in the internet concerning side effects like: shortness of breath and heart rate stuff. Any ideas why gaba could cause this? I think gaba should be really safe substance but that sounds very dangerous if its true and i would like to know by with mechanism that could be caused in some people.

 

[haidut]

interesting. i started a thread about gaba supplementation a while ago, too:

GABA As A Supplement?

But i was a bit sceptical that there are so many threads on different forums in the internet concerning side effects like: shortness of breath and heart rate stuff. Any ideas why gaba could cause this? I think gaba should be really safe substance but that sounds very dangerous if its true and i would like to know by with mechanism that could be caused in some people.

These sounds mostly like allergic reactions. Unless you are taking multi-gram amounts in a single dose it should not have an effect on heart rate. Excess GABA gets converted to succinic acid, which is yet another beneficial substance Peat has spoken about.

 

[griesburner]

sounds good. maybe i will try to take it again soon. anyone else has experience with pure gaba as a supplement?

 

[MissRed]

I have been (nervously) taking 1G daily for a couple of years. It is very helpful for my insomnia, anxiety and depression. I haven't taken any breaks , which are recommended.

 

[managing]

should GABA be spread out throughout the day? Or taken only on waking or just before bed? I've only tried it once so far and it seemed to have a somewhat sedative effect at about 300mg. Need to try again to confirm. Just looking for data points.

 

[ddjd]

Finally, some good studies coming out to expose the pharma fraud that convinced the public oral GABA is useless. The dose was minuscule, and the HED was 0.48mg/kg. So, for most humans that means 30mg-50mg GABA daily. For comparison, most supplements on the market sell GABA in 500mg pills. The duration was 11 weeks, so kind of long but I think the same effects can be seen in much shorter timeframes with higher doses of GABA. Human studies with 100mg+ have shown lower insulin and blood sugar, as well as lower cortisol, so we know it definitely has an effect when taken orally.
In my opinion, the "ineffectiveness" of oral GABA ranks right up there with serotonin being a "happiness" hormone in the hall of fame of scientific fraud.
Btw, vitamin D is a another potent inducer of Klotho and so is thyroid (T3).

this is very interesting. have you heard of this 'gaba shunt' effect

"Supplementing with GABA is a popular suggestion among many practitioners. However, I frequently work with people who get a stimulating effect from supplementation. GABA itself can be converted back into glutamine, which is then converted back into glutamate through a metabolic pathway called the GABA shunt. So GABA supplementation can end up increasing glutamate in some people as well."

 

[haidut]

this is very interesting. have you heard of this 'gaba shunt' effect

"Supplementing with GABA is a popular suggestion among many practitioners. However, I frequently work with people who get a stimulating effect from supplementation. GABA itself can be converted back into glutamine, which is then converted back into glutamate through a metabolic pathway called the GABA shunt. So GABA supplementation can end up increasing glutamate in some people as well."

It is possible in theory but in my experience GABA raises succinic acid more than anything else. Also, if GABA is taken with a B-complex then the risk of raising glutamate is much lower as vitamins like thiamine, B6 and biotin increase synthesis of GABA from glutamate and thus keep the pathway in favor of GABA.

 

[ddjd]

Btw, vitamin D is a another potent inducer of Klotho and so is thyroid (T3).

isnt this article suggesting T3 actually lowers GABA?:

https://www.cell.com/biophysj/fulltext/S0006-3495(12)04768-6?code=cell-site

"Disorders of the thyroid cause a multitude of neurological dysfunctions including depression, anxiety, and psychosis. Thyroid hormones have been primarily thought to act via genomic mechanisms throughout the organism; however, recently another mechanism has been proposed for the adult brain. We hypothesize that the thyroid hormone triiodothyronine (T3) acts directly on GABA(A) receptors via a mechanism similar to that of neurosteroids. Previous electrophysiology experiments on expressed recombinant GABA(A) receptors demonstrated an inhibition of GABA responses in the presence of T3, and, at much higher concentrations of T3 alone, a direct stimulation of receptor activity. Current experiments are being conducted to investigate stereoselective effects and interactions with other compounds known to bind directly to the GABA(A) receptor. using a GABA(A) receptor homology model based on the crystal structure of the related Glutamate-gated chloride channel, atomic resolution molecular dynamics simulations were conducted to analyze the possible interaction of T3 and the GABA(A) receptor. In simulations, T3 is stable in binding sites in the transmembrane domain of the GABA(A)receptor in a region that is associated with the activation by neurosteroids. Alchemical free energy perturbation calculations are underway to test the affinity of T3 for the binding site in the GABA(A) receptor. Our results provide strong evidence supporting earlier experimental findings indicating a role of T3 in regulating the activity of GABA(A) receptors in brain, while bringing additional insight into both the molecular binding mode and the mechanism of modulation."