Geranylgeraniol (GG) - Literature & Supplementation

DuggaDugga

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Not a lot of discussion related to geranylgeraniol (GG) yet on the forum so I am starting this thread to initiate discourse on available literature, supplementation strategies, and anecdotal experience.

Endogenously, geranylgeranyl-PP is produced through the mevalonate pathway, which most are aware of because it is how we produce cholesterol and CoQ10 and is the target of statins (ie, HMG-CoA reductase inhibitors).

Simple-schematic-of-the-mevalonate-pathway-showing-that-postranslational-modiications.png

( Figure 3. Simple schematic of the mevalonate pathway showing that... )

In I-10 cell lines (mouse; testis tissue) have been shown to have enhanced testosterone and progesterone production levels in response to GGOH.

"GGOH enhanced testosterone and progesterone (its precursor) levels in I-10 cells by activating adenylate cyclase via cAMP/PKA signaling, without altering phosphodiesterase activity. These findings highlight the potential benefits of GGOH as a therapeutic agent for low testosterone levels, such as late-onset hypogonadism in men."

1638128175359.png


( https://www.tandfonline.com/doi/pdf/10.1080/09168451.2017.1415129 )

GG is a precursor to CoQ10.

GG supplementation may hold some unique advantages to CoQ10 supplementation, given its relative ease of absorption and "loose" regulation of the ubiquinone synthesis pathway.

GG’s molecular weight is one-third of CoQ10’s, with a lipophilic hydrocarbon tail (see Fig. 3). GG is likely well absorbed in the GI tract since in vitro studies showed it diffuses inside cells with no need of adjuvants. This is in contrast with CoQ10, which needs to be solubilized and emulsified for absorption in the intestine, for skin topicals or inside cells in-vitro.

Supplementation of cells with GG upregulates enzymatic reactions downstream from mevalonate, by mass action, resulting in increased synthesis of ubiquinone and other essential cell-signaling mediators (see Fig. 2).24,25 Fortunately, the ubiquinone synthesis pathway is not tightly regulated, as is that of cholesterol, thus it can be upregulated by increased substrate concentration (Fig. 4). This opens the possibility to correct age-related decline in COQ10 and other metabolites derived from GG, in all tissues.


453-Geranylgeraniol-figure-4-1024x638.jpg


( Geranylgeraniol (GG) Boosts Endogenous Synthesis of Coenzyme Q10 (CoQ10) and Cell Essential Metabolites, Overcoming CoQ10 Supplementation Limitations)



GGOH apparently has a unique/complementary pathway from MK-4 on osteoclast inhibition.

MK-4 and its isolated geranyl-geraniol side chain was also able to suppress the synthesis of prostaglandin E2, which is a potent bone resorption catalyst.

( X. Fu, S.L. Booth, in Encyclopedia of Human Nutrition (Third Edition), 2013 )
( Geranylgeraniol - an overview | ScienceDirect Topics)


GGOH improves the side effects of bisphosphonate therapy by regulating the MVP and inhibiting osteoclast formation

( https://www.tandfonline.com/doi/pdf/10.1080/09168451.2017.1415129 )

Overall, GG seems like an interesting "flex" player -- inhibiting soft tissue calcification, promoting testosterone, and promoting CoQ10, among other things.

I am considering supplementing GG with the goal of increasing my testosterone, improving recovery from weight training, and inhibiting soft tissue calcification (with the scalp of highest interest). I intend to take before and after labs.

More to come - curious what others have to say.
 

High_Prob

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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.
 

Grapelander

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Pharmacological Properties of Geraniol - A Review
Geraniol is an acyclic isoprenoid monoterpene isolated from the essential oils of aromatic plants including Cinnamomum tenuipilum, Valeriana officinalis, and several other plants.
The potential application of geraniol as a drug is discussed based on its pharmacological properties, including antitumor, anti-inflammatory, antioxidative, and antimicrobial activities, and hepatoprotective, cardioprotective, and neuroprotective effects.
 

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