Geranylgeraniol As A Supplement

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@Dave Clark mentioned Annatto-GG, a supplement made by Designs for Health that includes 150 mg of Geranylgeraniol in Kuinone - Liquid Vitamin K2 (MK-4)

Has anyone ever tried Geranylgeraniol as a supplement? Based on the studies that @haidut posted in the Gonadin thread, it clearly has a positive effect on Testosterone and Progesterone.

Any thoughts?
 
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I wonder how much of a dose of geranylgeraniol is contained in say 1 mg of MK4....
 
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Yeah, it was just a joke :) Btw, why you didn't put GGOH in it too, to make it more "complete". Did you considerate it and discarded the idea for some reason?

How much GGOH is in mk4, and how much would be the dose of mk4 to achieve 30μM of GGOH?

I did consider adding GGOH, but so far have not been able to find a vendor that can provide pure bulk amounts. I'll keep searching though as GGOH has a lot of studies behind it for various other benefits. The thing is though, GGOH is a precursor to squalene so using squalene probably accomplishes what GGOH would do. As far as the the dose required to reach 30uM/L, basically GGOH and POH have almost the same molar mass and the doses should be about the same. The first study with vitamin K2 (MK-4) used a HED of about 1mg/kg to replicate the 30uM in vitro concentration. I even sent them an email about it and the authors responses saying that indeed the 1mg/kg human dose should acheve 30uM/L vitamin K2 in tissues and that is how they chose the in vivo rat dose (~7mg/kg) Now, given that only a portion of the vitamin K2 molecule is actually GGOH (and taking into account the molar mass of the quinone portion and GGOH prtion) it means of those 30uM/L concentration vitamin K2 about 66% is GGOH. So, the effective concentration of GGOH in the vitamin K2 study was about 20uM/L, assuming it was only GGOH that had T boosting effects as the second study with GGOH and POH actually claims. Just to make sure, I went with 100mg per dose for both POH and squalene as it would achieve 30uM/L as the second study with GGOH and POH found 30uM/L to be optimal.
 
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Brain cholesterol turnover required for geranylgeraniol production and learning in mice


Brain cholesterol turnover required for geranylgeraniol production and learning in mice
Tiina J. Kotti, Denise M. O. Ramirez, Brad E. Pfeiffer, Kimberly M. Huber, and David W. Russell
PNAS March 7, 2006 103 (10) 3869-3874; https://doi.org/10.1073/pnas.0600316103

Abstract
The mevalonate pathway produces cholesterol and nonsterol isoprenoids, such as geranylgeraniol. In the brain, a fraction of cholesterol is metabolized in neurons by the enzyme cholesterol 24-hydroxylase, and this depletion activates the mevalonate pathway. Brains from mice lacking 24-hydroxylase excrete cholesterol more slowly, and the tissue compensates by suppressing the mevalonate pathway. Here we report that this suppression causes a defect in learning. 24-Hydroxylase knockout mice exhibit severe deficiencies in spatial, associative, and motor learning, and in hippocampal long-term potentiation (LTP). Acute treatment of wild-type hippocampal slices with an inhibitor of the mevalonate pathway (a statin) also impairs LTP. The effects of statin treatment and genetic elimination of 24-hydroxylase on LTP are reversed by a 20-min treatment with geranylgeraniol but not by cholesterol. We conclude that cholesterol turnover in brain activates the mevalonate pathway and that a constant production of geranylgeraniol in a small subset of neurons is required for LTP and learning.
 
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I will purchase this and report back. The only concern is that Annatto appears to cause allergenic symptoms in those that are susceptible.
 
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Have been taking this every day for 2 weeks. Nothing good or bad to report so far. Will be experimenting with Gonadin soon...
 

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I will purchase this and report back. The only concern is that Annatto appears to cause allergenic symptoms in those that are susceptible.
I have an e-mail in to Barrie Tan to find out whether any of these annatto based nutrients have allergy related issues, and if so, whether they are common or rare. Anybody can be allergic to anything at anytime, question is how common or rare or non existent (in record) is it. They are good to get back to me. They provided me the study that showed the liver damaging effects of tocotrienols was only a toxicology study.
 

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I have an e-mail in to Barrie Tan to find out whether any of these annatto based nutrients have allergy related issues, and if so, whether they are common or rare. Anybody can be allergic to anything at anytime, question is how common or rare or non existent (in record) is it. They are good to get back to me. They provided me the study that showed the liver damaging effects of tocotrienols was only a toxicology study.

Any new findings? Curious to hear back
 

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Any new findings? Curious to hear back
Oh yeah, forgot to follow up. Yes, they did get back to me and said that there was no particular studies done, but they have no reports from anyone regarding allergic reactions to annatto. I think it may be very rare, but anybody can be allergic to anything, especially in today's world where people's immune systems are so messed up. I think tocotrienols are more tolerated than vitamin E supplements, from what I've read. Any supplement can cause an allergy if the person using it is sensitive to the base ingredient, so if you know you are sensitive to annatto, then stay away from it, or try it and see what happens because sometimes when things are extracted and purified, the proteins that cause the reactions are left behind.
 

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I have been taking 300mg Squalene everyday for a week and haven't noticed anything significant except getting acnes on my face which is quite annoying.
 
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Geranylgeranyl pyrophosphate stimulates γ-secretase to increase the generation of Aβ and APP-CTFγ​



Geranylgeranyl pyrophosphate stimulates γ-secretase to increase the generation of Aβ and APP-CTFγ​

Yan Zhou, Anitha Suram, [...], and Kumar Sambamurti

Additional article information

Abstract​

Cleavage of the amyloid precursor protein (APP) by β- and γ-secretases results in the generation of the amyloid-β protein (Aβ), which is characteristically deposited in the brain of Alzheimer's disease (AD) patients. Inhibitors of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase (the statins) reduce the levels of cholesterol and isoprenoids such as geranylgeranyl pyrophosphate (GGPP). Previous studies have demonstrated that cholesterol increases and statins reduce Aβ levels, mostly by regulating β-secretase activity. In this study, we focused on the role of geranylgeranyl isoprenoids GGPP and geranylgeraniol (GGOH), in the regulation of Aβ production. Our data show that the inhibition of GGPP synthesis by statins plays an important role in statin-mediated reduction of Aβ secretion. Consistent with this finding, the geranylgeranyl isoprenoids preferentially increase the yield of Aβ of 42 residues (Aβ42), in a dose-dependent manner. Our studies further demonstrated that geranylgeranyl isoprenoids increase the yield of APP-CTFγ (a.k.a. AICD) as well as Aβ by stimulating γ-secretase mediated cleavage of APP-CTFα and APP-CTFβ in vitro. Furthermore, GGOH increases the levels of the active γ-secretase complex in the detergent insoluble membrane fraction along with its substrates: APP-CTFα and APP-CTFβ. Our results indicate that geranylgeranyl isoprenoids may be an important physiological facilitator of γ-secretase activity that can foster the production of the pathologically important Aβ42.

INTRODUCTION​

A large body of evidence suggests that APP metabolism is affected by the alteration of the lipid microenvironment (1). The genetic link between the risk of AD and the ε4 allele of apolipoprotein E (ApoE ε4), a protein involved in lipid homeostasis, was established more than a decade ago (2-5). Epidemiological studies suggest that high levels of cholesterol associated with ApoE ε4 may contribute to the pathogenesis of AD (6, 7). More recently, epidemiological studies by several groups have shown that statins, a group of cholesterol-lowering drugs, can markedly reduce the prevalence of AD (8, 9). However, prospective clinical trials of statins for the prevention of AD will be required to confirm these findings. Multiple studies have also shown that statins modulate APP processing and reduce Aβ generation both in vitro and in vivo(9-18), suggesting that the reduction of AD prevalence may be, at least partly, the result of decreased amyloidogenic APP processing by the treatment with statins.

As discussed in a well-articulated review, a large body of literature has concluded that Aβ42 levels are specifically increased by familial AD (FAD) mutations and the currently favored hypothesis is that oligomeric forms of Aβ are responsible for neurodegeneration in AD (19). As previously reviewed by us, Aβ42 is a minor metabolite of the larger precursor protein, APP, and is generated after cleavage of APP in the ectodomain by β-secretase into sAPPβ and APP-CTFβ, and within the membrane by γ-secretase to Aβ and APP-CTFγ (a.k.a. AICD) (20). Most APP is however cleaved inside the Aβ sequence by α-secretase to sAPPα and APP-CTFα making CTFβ, and therefore Aβ, a minor metabolite of APP. Moreover, most Aβ ends at residue V40 and only a small fraction of Aβ ends at residue A42. The ratio of Aβ42/Aβ40 is however increased in cells bearing FAD mutations, suggesting that Aβ42 is the more pathologically relevant species (21). Treatment of cells with a membrane cholesterol extracting reagent results in a drastic reduction of Aβ production by inhibition of β-secretase processing (22). In addition to total cellular cholesterol, cholesterol esters have also been reported to increase the generation of Aβ (23, 24). Studies using animal models of AD, including rabbits (25, 26), transgenic mice (27-29) and guinea pigs (14), further suggest a complex relationship between plasma cholesterol levels and Aβ generation. In addition, cholesterol appears to increase CTFγ, a metabolite whose role in AD pathogenesis has been poorly studied (30).

Although cholesterol homeostasis clearly plays a role in APP metabolism, whether the cholesterol-lowering effect of statins is the only mechanism by which statins lower Aβ levels is far from established. In this regard, the protective effect of statins was found to be independent of their effect on blood cholesterol levels by one of the early reports (8), suggesting that statins may protect against AD through an alternative mechanism besides their cholesterol lowering effect. It has also been shown that brain cholesterol levels and Aβ levels in the brain are not correlated in transgenic AD mouse model treated with atorvastatin (11) or in mice genetically engineered to have low blood cholesterol levels (31). Furthermore, γ-secretase activity in the detergent insoluble membranes (DIMs; a.k.a. rafts, TIMs, DRMs) is not affected by the reduction of cholesterol levels with cholesterol extracting reagent, suggesting that the γ-secretase activity in DIMs does not depend on cholesterol level per se (32). Statins inhibit HMG-CoA reductase, and thus reduce the synthesis of mevalonic acid and several of its important metabolites including cholesterol and isoprenoids (such as GGPP and farnesyl pyrophosphate; FPP). A recent report shows that GGPP plays an important role in modulating APP processing and Aβ production by statins (33). Other reports, including one from us, have also demonstrated that GGPP preferentially increases the levels of Aβ42 rather than total Aβ, suggesting that GGPP modulates γ-secretase activity or Aβ42 turnover (34, 35). In this study, we have demonstrated that geranylgeranyl isoprenoids stimulate the processing of APP-CTFα and APP-CTFβ by modulating γ-secretase. We have also provided evidence indicating that the active γ-secretase complex is increased in DIMs by treatment with GGOH.
 

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