The Most Important Essential Nutrient You’ve Never Heard Of

So why do statins cause SAMS? The answer comes down to coenzyme Q10, (CoQ10), which you’ve probably heard of since it’s a common dietary supplement. We’ve written about CoQ10 on The PricePlow Blog many times. Your body actually makes its own CoQ10, because this coenzyme is essential for healthy muscle function.

Unfortunately, statins interfere with the action of the enzymes your body uses to synthesize CoQ10.^[3] Logically, you might assume that CoQ10 supplementation is the solution – doctors often suggest patients take it alongside their statin drugs. Many researchers considered the same strategy, which led to a lot of research on the subject.

The bad news is that according to a 2015 meta-analysis, CoQ10 supplementation doesn’t prevent SAMS.^[3]

American River Nutrition’s GG-Gold (Geranylgeraniol), is an essential nutrient for functions like CoQ10 production, testosterone, and more!

The good news is that supplementation with geranylgeraniol does appear to prevent SAMS!^[4] As we’ll learn, GG is one of the substrates required for CoQ10 synthesis. And it turns out that the adverse muscular effects of statins are driven by their tendency to deplete the body’s reserves of GG, which, like CoQ10, is necessarily for healthy muscular function.^[4]

At this point, you could logically guess that geranylgeraniol plays a crucial role in several biological systems — not just the skeletomuscular system — since CoQ10 does — and that guess would be absolutely right.

The statin case is merely a good starting point for our discussion of the profound, wide-ranging potential of GG-Gold for human health and performance.

Geranylgeraniol’s Fundamental Mechanism of Action: Mevalonate Pathway

One big clue to geranylgeraniol’s fundamental importance is that it’s ubiquitous not only in the human body, but also throughout the entire biological world. It’s an essential building block not only for several phytochemicals like tocotrienol (vitamin E) and provitamin A carotenoids as well as CoQ10:

Because Geranylgeraniol (GG) participates in the mevalonate pathway, it plays an important role in the entire biological world – it’s present and used in a molecular building block in both prokaryotic and eukaryotic organisms.^[4]

For example, in plants, GG is a necessary component for the synthesis of phytol, a diterpene molecule that eventually gets converted into phylloquinone, the plant form of vitamin K (also known as vitamin K1).^[5,6]

But GG is also a building block for Menaquinone 4 (MK4), which is the biologically active form of vitamin K2 in the human body. Because of this, statin administration, which depletes GG, has been shown to inhibit the body’s endogenous K2 production.^[7]

The reason for GG’s biological ubiquity is its participation in the mevalonate pathway, an ancient, evolutionarily-conserved pathway that’s present not just in humans and plants, but also in microorganisms, including single-celled and prokaryotic organisms like bacteria.^[8]

The mevalonate (MVA) pathway begins with Acetyl-CoA (marked in orange at the top of this chart).^[9] We have circled/boxed the steps that are most relevant to our discussion of GG – the HMGR enzyme, cholesterol, ubiquinone (CoQ10), and geranylgeraniol (GG) itself.

As you can see from the inset image, GG’s participation in the MVA pathway is downstream of ubiquinone (CoQ10) synthesis, but upstream of cholesterol synthesis. This is why GG supplementation can help mitigate the harmful effects that statins have on CoQ10 production, without impairing the statins’ ability to decrease serum cholesterol.^[10]

In one study, researchers carried out an experiment in rats in which, predictably, statins decreased their muscular strength – but treatment with geranylgeraniol significantly decreased this effect, partially restoring the rat muscles’ ability to generate force.^[11]

Muscles from geranylgeraniol-treated rats (GG), particularly the gastrocnemius, were able to generate more force than muscles from non-GG-treated animals.^[11]

GG, CoQ10, and muscular function

The MVA pathway image shows us that restoring geranylgeraniol levels through supplementation can also help restore the activity of the GGPP, an intermediate isoprenoid that ultimately controls CoQ10 synthesis. This matters because CoQ10 appears to be necessary for muscle mass and strength – research has repeatedly linked CoQ10 deficiency to sarcopenia (age-related muscle loss),^[12] and one study found that in two independent human cohorts, an individual’s ratio of CoQ10 to cholesterol correlated significantly with hand grip strength.^[13]

An individual’s CoQ10-to-cholesterol ratio predicts muscular strength.^[13]

Remember – because geranylgeraniol’s participation in the MVA pathway is upstream of cholesterol synthesis, GG supplementation should increase a person’s CoQ10-to-cholesterol ratio, because it should increase ubiquinone synthesis while leaving cholesterol synthesis unchanged. We can logically deduce that if that weren’t the case, then GG would interfere with the statins’ ability to lower cholesterol.

But the benefits of GGPP upregulation aren’t limited to its impact on CoQ10 synthesis. One in vitro study using rat skeletal muscle fibers found that of all the mevalonate pathway metabolites tested, a list that included farnesylpyrophosphate (FPP), coenzyme Q9, and coenzyme Q10, only GGPP prevented statin-induced cellular energy deficits in muscle cells, as measured by adenosine triphosphate (ATP) concentrations.^[14]

This suggests that GG’s effect on GGPP levels, besides just indirectly upregulating CoQ10, is directly rescuing muscle tissue from death due to lack of cellular energy.

Anti-catabolic effect via prenylation

One 2018 in vitro study looked at geranylgeraniol’s ability to protect muscle cells from statin-induced myotoxicity.^[15]

In this study, mouse muscle stem cells (AKA murine myoblasts) were treated with one of three statins – atorvastatin (ATR), simvastatin (SIM), and methyl-beta-cyclodextrin (MβCD) – and then co-treated with mevalonate (MEV), farnesol (FOH), geranylgeraniol (GG), or water-soluble cholesterol (Chol-PEG).^[15]

The researchers then analyzed how each co-treatment affected the muscle cells’ viability during statin treatment.^[15]

The viability of proliferating murine myoblasts increased significantly following co-treatment with geranylgeraniol (GG).^[15]

This study found that GG co-treatment completely reversed the statin-associated decrease in muscle stem cell viability.^[15]

The mechanism of action here was super interesting – according to the authors of the study, the best explanation for this result is GG’s ability to restore myoblasts’ capacity for autophagy,^[15] a process of cellular self-renewal in which damaged cellular components are broken down and recycled into new, healthy replacements. GG does this by restoring protein prenylation, which is a function of the GGPP isoprenoid we discussed above.^[16]

In order to confirm that GGPP upregulation was the mechanism here, the researchers also cultured some cells with GGTI-286, which inhibits the geranylgeranyltransferase (GGTase) enzyme that catalyzes the transfer of isoprenoids like GG and GGPP to target proteins.^[17] The study found that in the presence of GGTI-286, GG did not have any effect on muscle cell viability, which strongly implies that GGPP is the mechanism behind GG’s anti-catabolic effect.^[15]

At this point, we believe that this effect goes beyond statin-treated muscle cells — mainly because an enzyme that controls autophagy in skeletal muscle cells (RAP GTPase) is known to be prenylated exclusively by GG.^[15] More research is needed to confirm this, though.

You’ve probably heard that vitamin K2 is great for bone health. There are actually two sides to this story – the first is that K2 does, as you’d probably expect, stimulate the creation of new osteoblasts, the bone cells that are responsible for synthesizing new bone tissue.^[18]

The other side is that K2 inhibits the formation of new osteoclasts, which do the opposite – whereas osteoblasts synthesize new bone, osteoclasts break it down and resorb it.^[18]

As it turns out, GG also inhibits osteoclast formation.^[19]

This is interesting because geranylgeraniol is a side chain of the vitamin K2 molecule – basically, it’s one component of K2.

The chemical structure of geranylgeraniol (GG), vs. that of MK-4 (vitamin K2).^[20] As you can see, GG accounts for a large part of the MK-4 molecule.

Interestingly, one study found that MK-4 and GG inhibit osteoclast by different mechanisms – while MK-4 downregulates prostaglandin (PGE2) production via cyclooxygenase 2 (COX-2) inhibition, GG downregulates the RANKL pathway, which is ordinarily activated in response to PGE2.^[19]

In other words, GG inhibits osteoclast formation by a mechanism that’s downstream of COX-2/PGE2, whereas MK-4 does it by decreasing COX-2-driven PGE2 production.^[19]

Impact on endogenous MK-4 synthesis

Although human clinical trials on this subject remain to be seen, science has identified the specific gene that’s responsible responsible for the human body’s endogenous synthesis of the MK-4 form of vitamin K2.^[21] The mechanism here is, once again, prenylation – a gene called UbiA prenyltransferase containing 1 (UBIAD1) regulates an enzyme that prenylates either phylloquinone or its intermediary, vitamin K3, by adding GGPP, thus creating MK-7 K2.^[21]

In theory, GG should increase MK-7 biosynthesis in humans by generating additional GGPP for phylloquinone-to-MK-7 conversion. This idea is backed up by a 2022 study in mice, which found that basically all forms of dietary vitamin K get converted, once ingested, into MK-7.^[22]

Another factor that will come into play is how MK-4 has been shown to enhance testosterone production in rats^[23] — we’ll be exploring this critical hormone lower in this article.

One of the reasons we want lots of healthy muscle tissue is that muscle tissue uses glucose. The more lean mass you have relative to fat mass, the less likely you are to be insulin resistant.^[24]

In fact, the statins’ potential to compromise metabolic health is related to SAMS. This is because when the body’s geranylgeraniol reserves get depleted, muscle tissue becomes less insulin sensitive,^[25] which triggers the pancreas to create extra insulin in an attempt to compensate. This is, unfortunately, the beginning of a vicious cycle that can eventually lead to full-blown metabolic despair.

By now, we’ve all heard about how important the microbiome is, not only for gastrointestinal health, but for virtually all other aspects of health as well.

With that in mind, some intrepid researchers got the idea to test whether the benefits of GG could be explained in terms of its impact on gut flora.

Microbiome study – Shen et al. (2021)

They randomized 36 mice to one of three groups:

Mice in the high-fat diet+geranylgeraniol group (marked GG on the graphs) showed significant improvements on a glucose tolerance test (GTT) and insulin tolerance test (ITT).^[26]

1. a low-fat diet (LFD group, 10% of calories from fat)
2. high-fat diet (HFD group, 60% of calories from fat)
3. HFD supplemented with GG at 800 mg/kg

For 14 weeks, animals in all three groups had unrestricted access to water and food, during which time the researchers performed weekly measurements of the animals’ body weight, food intake, and water consumption.^[26] What’s particularly interesting about this study is that it was performed using American River Nutrition’s GG-Gold.

The study found that GG treatment significantly increased the mice’s levels of B. pullicaecorum, which is linked to anti-inflammatory effects, while decreasing the prevalence of D. longicatena, which is linked to inflammation and metabolic dysfunction.^[26]

Although the size of GG’s effect on the microbiome wasn’t huge, the researchers did observe pretty much exactly what they expected to see from favorable alterations to microbiome composition:^[26]

Geranylgeraniol treatment (GG) brought the mice’s carboxy-terminal collagen crosslink (CTX) levels down dramatically compared to the high-fat diet (HFD) group – almost back in line with the low-fat diet (LFD).^[26]

• Improved glucose homeostasis,
• Better bone tissue architecture and greater bone strength, and
• decreased inflammatory cytokine production.^[26]

Adipose (fat) tissue is notorious for producing inflammatory cytokines, which have the potential to cause metabolic derangement when elevated. So it’s very interesting to note that while the LFD group showed roughly 4 pg/mg of interleukin-6 (IL-6) in their adipose tissue, and the HFD group had about 8 pg/mg, the geranylgeraniol-treated group (GG) had only 3 pg/mg – lower than both the HFD group and the LFD group.^[26]

But perhaps the most striking result in this study was the impact that GG treatment had on carboxy-terminal collagen crosslinks (CTX), which is a measure of osteoclast activity.^[26] Recall from the previous section that osteoclasts are the bone cells responsible for breaking down and resorbing bone tissue – less CTX, and hence less osteoclast activity, implies stronger bones.

As you can see from the inset image, GG treatment caused a very large reduction in serum CTX, from roughly 22 ng/mL to 14 ng/mL.^[26] The fact that GG can reduce CTX activity this powerfully in animals shows the incredible potential of this supplement for improving bone health.

Followup study – Shen et al. (2022)

Since the 2021 study revealed potential for GG to modulate the microbiome, a followup study was conducted a year later, featuring many of the same scientists on the research team.^[27]

In this study, 48 mice were randomized to one of four groups:

1. Placebo (control) group
2. 400 mg GG/kg body weight in food
3. 0.5% weight/volume green tea polyphenols (GTPs) in water
4. 400 mg GG/kg and 0.5% weight/volume GTPs in water

The mice received their group’s prescribed treatment for 14 weeks, at which point the researchers collected samples of the mice’s intestinal and skeletal muscle tissue.^[27]

Both Geranylgeraniol (GG) and GTP had a positive impact on the mice’s microbiome, as did a combination of both substances.^[27]

This study found a much more robust effect of GG on the microbiome – as you can see from the inset image, GG administration caused statistically significant increases in the abundance of probiotic bacteria from the Bacteroidetes and Verrucomicrobia phyla.^[27]

While the GTPs were better at increasing the Verrucomicrobia population, this basically came at the expense of the Bacteroidetes and Firmicutes populations.^[27] In other words, this study showed that GG had a more balanced beneficial effect on the mouse microbiome.

Supplementation with GG also decreased the relative abundance of dysbiotic (bad) bacteria.^[27]

Of course, achieving microbiome health isn’t just about increasing the amount of good bacteria present. We also want to minimize the propagation of bad bacteria where possible. Fortunately, the study found that GG administration decreased the relative abundance of Sporobacter termitidis, which synthesizes fatty acids from cellulose,^[28] and Dorea longicatena, which is positively associated with clinical obesity.^[29]

Geranylgeraniol administration, like GTP administration, caused improvements in metabolic function and body composition that are probably related to its microbiome-modulating effect.^[27]

Given the importance of the microbiome for metabolic function, it’s not surprising that this study also found significant improvements in body composition from GG administration. Again, while GTPs had similar effects, GG pulled significantly ahead when it came to decreasing the mice’s amount of white adipose tissue (WAT), which is basically metabolically inactive fat tissue, the type we want to minimize (as opposed to brown adipose tissue or BAT, which is loaded with mitochondria and has the potential to create a significant daily calorie burn.^[27]

Note – this study also specifically used American River Nutrition’s GG-Gold geranylgeraniol supplement.

With the knowledge that supplemental Vitamin K (as MK-4) enhances testosterone production in rats,^[23] researchers used cultured mouse testicular cells to test GG’s ability to increase sex steroid hormone synthesis in a 2016 vitro study.^[30]

Exposure to varying concentrations of geranylgeraniol (here abbreviated GG) dose-dependently and time-dependently increased the production of both testosterone and progesterone, a testosterone precursor.^[30]

After being incubated overnight, these cells were then refreshed with a medium containing varying concentrations of geranylgeraniol, and incubated for another 24 hours. After that, the researchers lysed (broke open) the cells and measured the concentration of progesterone and testosterone in each culture.

The results show clearly that the longest exposure to GG, and the highest concentration, produced the biggest increase in testicular cell synthesis of both testosterone and progesterone, which is a testosterone precursor.^[30]

This is an interesting result because progesterone and testosterone are both cholesterol-derived hormones. And since, as we discussed earlier, GG isn’t affecting the body’s synthesis of cholesterol, there must be some other mechanism, implicated in both progesterone and testosterone synthesis, that GG is affecting.

Steroid synthesis pathway chart.^[31] Given that Geranylgeraniol doesn’t affect the body’s synthesis of cholesterol, how can we explain the fact that it upregulates both progesterone and testosterone, which are both cholesterol-derived hormones?

According to the authors of this study, GG increases the synthesis of progesterone and testosterone by upregulating the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway. Ultimately, stimulating the cAMP/PKA upregulates the steroidogenic acute regulatory protein (StAR), which potentiates the conversion of cholesterol into pregnenolone.^[30]

In simple terms, this means that GG helps your body turn more of its existing circulating cholesterol to the task of steroid hormone synthesis. It’s not increasing the amount of cholesterol your body produces, but it is helping testicular cells turn that cholesterol into hormones — and the hormones we generally want, at that.

Importantly, GG increases cAMP signaling without activating an enzyme called phosphodiesterase,^[30,32] which is responsible for breaking down cAMP. This is unusual – what we typically see with other testosterone-boosting ingredients such as forskolin is upregulation of both cAMP and phosphodiesterase, a dual mechanism that blunts the overall upregulation of cAMP. Since GG does not affect phosphodiesterase,^[32] it should upregulate cAMP to a far greater extent.

A follow-up study by that same team again found that GG enhanced cellular testosterone levels by activating adenylate cyclase via cAMP/PKA signaling, without altering phosphodiesterase activity. They concluded the following:

“These findings highlight the potential benefits of GGOH as a therapeutic agent for low testosterone levels, such as late-onset hypogonadism in men.”^[32]

These are exciting results — so now it’s time to put it to the test in real humans:

Human study – GG-Gold supplementation increases testosterone levels in lower tertile of men

Perhaps the most compelling human data we’ve seen on geranylgeraniol comes from another GG-Gold-specific study. This study, published in 2023, set out to establish the impact that GG could have on serum hormone levels in both men and women, as well as to evaluate GG’s safety profile.^[33]

This was an 8-week-long dose-escalation study, meaning the subjects didn’t take the same dose for the entire study period – they took 150 mg geranylgeraniol for the first 4 weeks, and 300 mg for the last 4 weeks.^[33]

While the study population as a whole didn’t show a significant sex hormone response to GG supplementation, the researchers found something interesting hidden in the data. When they stratified the male participants by serum testosterone levels, and then performed an exploratory analysis on the bottom third, a subgroup with total testosterone under 700 ng/dl, they found that GG-Gold supplementation had caused a significant increase in this subgroup’s testosterone levels.^[33]

GG-Gold supplementation (geranylgeraniol) improved every measure of serum testosterone, compared to placebo. Here, delta refers to the magnitude of the change in the variable, e.g. a delta of +33.93 means GG-Gold increased total testosterone by 33.93 ng/dl on average.^[33]

Compared to the placebo, GG-Gold caused large and statistically significant increases in total, free, and bioavailable testosterone levels in the lower-tertile subgroup of male study participants.^[33]

While it should be considered preliminary, this is strong evidence that GG supplementation – and GG-Gold in particular – has the potential to restore testosterone production in hypogonadal men, and increase testosterone production in men on the lower end of the reference range. The average testosterone level of this lower tertile subgroup was about 450 ng/dl, which is below average, but not technically hypogondal.^[33]

For decades, Dr. Barrie Tan has been the universal expert on all things annatto — including geranylgeraniol and tocotrienols

We’ve been talking about GG-Gold, the world’s first geranylgeraniol ingredient, but haven’t properly introduced its backstory. It all begins with Dr. Barrie Tan, the scientific community’s foremost expert on vitamin E, who discovered a form of vitamin E called tocotrienol. Dr. Tan found that the best source was Annatto, a tree with orange-red fruits and seed also known as the achiote tree.

Dr. Tan started American River Nutrition to sell DeltaGold, the world’s first tocopherol-free tocotrienol product extracted from annatto.

But along the way, he also found something else in annatto — geranylgeraniol! His knowledge of this plant, ability to make world-class extracts, scientific research funding, and existing business reach led to GG-Gold, the industry’s most trusted, naturally-sourced GG extract.

We’ll have Dr. Barry Tan on the PricePlow Podcast to tell his story, and this section will be updated when it goes live.

In recent years, there’s been a lot of controversy about statins, with some arguing that while the drugs do reduce cholesterol, the anti-hyperlipidemic effect doesn’t necessarily confer a net health benefit due to the adverse effects outweighing the positive effects.

Some researchers argue that cholesterol reduction itself doesn’t necessarily reduce the risk of cardiovascular disease,^[34] and there’s evidence that the drugs can increase the risk of type 2 diabetes and liver dysfunction,^[2] on top of the muscle-related issues discussed in this article.^[2]

We’re not here to take a side in this controversy, but given that a 2022 meta-analysis found clinically and statistically significant benefits from statin therapy,^[1] we don’t expect these drugs to go anywhere anytime soon.

Given that patients will continue taking statins, what we want is some way to continue enjoying the benefits of statin therapy, while minimizing the adverse effects of these drugs. And fortunately, Dr. Barrie Tan and his team at American River Nutrition have identified a promising strategy for doing just that.