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Exploiting the Gaba > Klotho path

gaba klotho

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#1 OP2040

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Posted 14 May 2018 - 09:16 PM


MikeDC, in one of the rare moments when he wasn't shilling for Chromadex, alerted me to the following study, and for that I am grateful.

 

https://www.ncbi.nlm...pubmed/28993191

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

 

 

The gist of the study is that GABA increases Klotho in several mouse and tissue cultures, thus ameliorating both T1DM  and T2DM.  Plasma Klotho and a couple other tissues were seen to have Klotho levels that were returned to normal via GABA.

 

It's true that this study is not exactly directly translatable.  But given how cheap GABA supplements are, and how expensive and obnoxious trying to obtain soluble Klotho is, this may work.  I won't review the benefits of Klotho, suffice to say it is possibly the most promising anti-aging substance, with the only downside being that there is no efficient way to get it into your system regularly.

 

One of the benefits of this pathway might be that GABA shouldn't need to cross the BBB to increase Klotho.  GABA does cross in small amounts, but given it's neurotransmitter status, it's probably good that it doesn't.  Even for those of us that could use some GABA neur-upregulation, there would most likely be tolerance issues.

 

I really, really wish there was an easy (non-ELISA) way to measure serum Klotho levels.  The more interventions I do, the more I'm seeing the necessity for accurate measurement.  You are literally flying blind without it.


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#2 hazy

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Posted 14 May 2018 - 11:09 PM

hmm interesting. i never thought of the connection between klotho and gaba. so benzos and alcohol would lower klotho long term and cause shorter lives? it makes sense



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#3 OP2040

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Posted 15 May 2018 - 02:14 PM

Ya, the alcohol thing would make sense on a couple different levels.  It would explain why moderate alcohol intake is good (raises GABA and Klotho) whereas over-drinking is bad because it would dysregulate the GABA system, just like Benzos.

 

Of course, this opens up a huge can of worms for this potential intervention.  The GABA system seems to be notoriously easy to screw up, so how do you increase it in a permanent and stable manner?  At the end of the day, it may be easier just to pursue a direct Klotho intervention, rather than risk GABA habituation. 

 

I'm curious now if even Klotho is subject  to habituation.  And if it were, why would those with the good Klotho genes, or the mice injected with it, gain a lifelong benefit?  The implication is that there is no serious habituation with Klotho.  Lots of questions...


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#4 OP2040

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Posted 16 May 2018 - 02:48 PM

Is there any way to change the thread title.  I would like to see it as a general thread "targeting the Klotho pathway", mainly due to the study I'm going to post now.

 

https://www.ncbi.nlm...pubmed/28657902  

"Induction of anti-aging gene klotho wi th a small chemical compound that demethylates CpG islands"

 

The gist of this is that it's another strong inductive pathway for Klotho.  In this case it is based on the following relatively inexpensive and mysterious "Compound H", also known as:

 

N-(2-chlorophenyl)-1H-indole-3-caboxamide

 

There are lots of labs selling it for anywhere from ~$100-300/G  and the HED should only be around 1.2 mg/kg so around 100mg for 185lb person. Sop this makes it a relatively inexpensive intervention.

 

Compound H increases serum Klotho levels, but not cell surface, which is fine because lots of other studies show that the serum level is just as effective, if not more so. 

 

There's another study by the same group where this compound basically cures hypertension and arterial stiffness in aged (not genetically modified) mice.  This is exactly what Klotho supplementation should be expected to do.  But also, intriguingly they map one of the other upregulated pathways, which was Srt1-AMPK-eNOS.  It also effectively changed the collagen/elastin balance to a more favorable ration with more elastin and less collagen in the aorta.  And finally, the mechanism of action was determined to be activation of DNA demethylases, thus showing that it targets a major anti-aging pathway. 

 

https://www.ncbi.nlm...pubmed/29659128

 

All very exciting stuff!

 

 



#5 orion22

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Posted 16 May 2018 - 03:33 PM

whats optimal dose of gama to take



#6 Nate-2004

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Posted 16 May 2018 - 05:50 PM

There are a number of ways to upregulate klotho listed here. Even statins upregulate it. If youthspan increases or rejuvenation is going to be seen it's probably not going to be just klotho, as it will just be another one thing to target.

 

https://www.selfhack...e-it-rs9536314/



#7 YOLF

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Posted 16 May 2018 - 06:59 PM

PM Maxwatt if you want to change the title.

 

Sounds interesting. did they note whether the rodents were klotho deficient? Perhaps free klotho is the regulator for some FGFs? How did they deliver it? 

 

 

From the study:

 

 

We found that Compound H increased Kl expression via demethylation in CpG islands of the Kl gene. The demethylation was accomplished by activating demethylases rather than inhibiting methylases. Due to demethylation, Compound H enhanced binding of transcription factors, Pax4 and Kid3, to the promoter of the Kl gene. Pax4 and Kid3 regulated Kl promoter activity positively and negatively, respectively. Thus, our results show that demethylation is an important molecular mechanism that mediates Compound H-induced Kl expression. Further investigation is warranted to determine whether Compound H demethylates the Kl gene in vivo and whether it can serve as a therapeutic agent for repressing or delaying the onset of age-related diseases.

 

So this makes it look like we could restore klotho levels to our youthful maximum which may or may be sufficient to match the aging performance of those with the beneficial klotho mutation in anyone except young carriers?

 

Kid3 May not have a human equivalent. This calls it novel in mice:

https://www.wikigene...e/10786630.html

 

However, I did find human homologues for this repressor, though too little of it may also be problematic. I don't see a mention of what SNP it is though, so that's limiting me from figuring it out.


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#8 OP2040

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Posted 16 May 2018 - 10:57 PM

Nate, I like Self Hacked, but they do tend to throw everything in together, even if it is just a correlation or weak effect. This has a very strong effect and Klotho is definitely in the top 5 for potential anti-aging.

Yolf, I don’t have the study handy right now but I think it was at least partially based on naturally aged mice. I don’t like when they do studies where they make deficient mice, then docks the deficiency, and the mice become healthier. Those studies can be insightful, but they’re fairly useless otherwise.

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#9 OP2040

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Posted 18 May 2018 - 03:15 PM

Yolf,

To answer your question.  The study you posted did use transgenic mice, but it was still a nice study as it elucidated the mechanism by which Compound H works.  The second study I posted is the one that used just normally aged mice, something I really wish more studies would do.  To quote extensively from that study:

 

 

Aged mice (24–27 months) and adultmice (12 months) were used. Pulse wave velocity ( PWV), a direct measure of arterialstiffnes s, and blood  press ur e (BP) were increased significantly in aged mice. Notably, daily treatments with compound H (15 mg/kg, IP) for 2 weeks significantly attenuatedthe aging-related increases in PWV and BP. Compound H abolished aging associated downregulation of secreted Klotho (SKL) levels in both kidneys and serum likely by enhancing DNA demethylase activity and decreasing DNA methylation.
Aging-related arterial stiffness was associated with accumulation of stiffer collagen and degradation of compliant elastin which are accompanied by increased expression of MMP2, MMP9, TGF-b1, and TGF-b3. These changes were effectively attenuated by compound H, suggesting rejuvenation of aged arteries. Compound H also rescued downregulation of Sirt1 deacetylase, AMPKa, and eNOS activities in aortas of aged mice. In cultured smooth muscle cells (SMCc) Klotho-deficient serum upregulated expression of MMPs and TGFb which, however, was not affected by compound H. In conclusion, compound H attenuates aging-associated arterial stiffness and hypertension by activation of DNA demethylase which increases renal SKL
expression and consequently circulating SKL levels leading to activation of the Sirt1-AMPK-eNOS pathway in aortas of aged mice.

 

One of the newsworthy things about recent research into Klotho is that Serum Klotho is enough to provide all the benefits Klotho is thought to have.  This is great because it means using it as a target does not have to involve any genetic engineering.

 

Here is another study showing that even a fragment of Serum a-Klotho has beneficial activity in the brains of young, old and transgenic alzheimer mouse models.  So it effects the brain w/o necessarily crossing the BBB.

 

https://www.cell.com...1247(17)30990-7

 

There are innumerable other studies out there.  They didn't name it after t his lady for no reason:

 

 

 

 

 


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