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Exploring Geranylgeraniol's Therapeutic Potential
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Our goal is to advance understanding of geranylgeraniol's mechanisms, including cell cycle regulation and anti-inflammatory pathways, to unlock its potential in treating various systemic diseases effectively and to share with people interested in their health.
Explore health benefits of geranylgeraniol through curated references and studies for various conditions.
Geranylgeraniol (GG) demonstrates significant therapeutic potential across multiple disease states through diverse mechanisms including cell cycle regulation, anti-inflammatory pathways, mitochondrial protection, and metabolic modulation. Below is an extensively researched collection of evidence-based benefits organized by disease category, supported by peer-reviewed studies.
Geranylgeraniol health benefits
Overview of Geranylgeraniol Mechanisms
Geranylgeraniol (GGOH) is a C20 diterpene alcohol and critical intermediate in the mevalonate pathway. It exerts diverse therapeutic effects through several interconnected molecular mechanisms:
Mevalonate pathway activation and protein prenylation
Wang, Y., & Hekimi, S. (2016). Understanding Ubiquinone. Trends in Cell Biology, 26(5), 367–378.
https://pubmed.ncbi.nlm.nih.gov/26827090/
Geranylgeraniol acts as an obligatory substrate in the mevalonate pathway, serving as a precursor for geranylgeranyl pyrophosphate (GGPP), the activated form required for protein prenylation of Rho and Rab GTPases. This prenylation is crucial for normal cellular viability, membrane trafficking and protein signalling. GG also supports CoQ10 synthesis, critical for mitochondrial electron transport and cellular energy metabolism.
Anti-inflammatory effects via NF-κB inhibition
Giriwono, P. E., Shirakawa, H., et al. (2013). Dietary supplementation with geranylgeraniol suppresses lipopolysaccharide-induced inflammation via inhibition of nuclear factor-κB activation in rats. European Journal of Nutrition, 52(3), 1191–1199.
https://pubmed.ncbi.nlm.nih.gov/22847643/
GG exerts potent anti-inflammatory effects by interfering with the NF-κB signalling pathway through suppression of IRAK1 and TRAF6, reducing pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6) across multiple tissue types and disease contexts.
Apoptosis induction through caspase-3 and JNK signalling
Masuda, Y., Nakaya, M., Nakajo, S., & Nakaya, K. (2000). The mechanism of geranylgeraniol-induced apoptosis involves activation by a caspase-3-like protease, of a c-Jun N-terminal kinase signaling cascade and differs from that of apoptosis induced by conventional chemotherapeutic drugs. Cell Biology International, 24(8), 647–657. https://doi.org/10.1006/cbir.2000.0667
https://www.sciencedirect.com/science/article/abs/pii/S0145212600000667
GG triggers programmed cell death in tumour cells by activating a caspase-3-like protease, which in turn triggers a c-Jun N-terminal kinase (JNK) signalling cascade. This mechanism is distinct from conventional chemotherapy, providing a unique approach to cancer cell elimination.
Statin-induced myotoxicity prevention through RAP1 prenylation
Jaśkiewicz, A., Pająk, B., Litwiniuk, A., Urbańska, K., & Orzechowski, A. (2018). Geranylgeraniol Prevents Statin-Dependent Myotoxicity in C2C12 Muscle Cells through RAP1 GTPase Prenylation and Cytoprotective Autophagy. Oxidative Medicine and Cellular Longevity, 2018, Article ID 6463807.
https://pmc.ncbi.nlm.nih.gov/articles/PMC5987243/
GG supplementation reverses statin-induced muscle damage by restoring prenylation of RAP1 GTPase and activating cytoprotective autophagy, thereby preserving muscle cell viability. This demonstrates GG's role in rescuing cells from mevalonate pathway inhibition.
Bone cell rescue and mevalonate pathway restoration
Fliefel, R. M., Entekhabi, S. A., Ehrenfeld, M., & Otto, S. (2019). Geranylgeraniol (GGOH) as a Mevalonate Pathway Activator in the Rescue of Bone Cells Treated with Zoledronic Acid: An In Vitro Study. Stem Cells International, 2019, Article ID 4351327. https://doi.org/10.1155/2019/4351327
https://pmc.ncbi.nlm.nih.gov/articles/PMC6343170/
GG effectively rescues bone cells treated with mevalonate pathway inhibitors (like zoledronic acid) by restoring protein prenylation and improving cellular viability, suggesting a promising therapeutic strategy for medication-related osteonecrosis of the jaw (MRONJ).
Geranylgeraniol Activity in Systemic Disease - Clickable index
Bone Disease
Bisphosphonate-related complication
Zafar, S., Coates, D. E., Cullinan, M. P., Drummond, B. K., Milne, T., & Seymour, G. J. (2016). Effects of zoledronic acid and geranylgeraniol on the cellular behaviour and gene expression of primary human alveolar osteoblasts. Clinical Oral Investigations, 20(8), 2023–2035.
https://pubmed.ncbi.nlm.nih.gov/26795621/
Zoledronic acid decreased cell viability and migration and induced apoptosis in primary human mandibular alveolar osteoblasts, with transmission electron microscopy revealing ultrastructural signs of apoptosis. Co-administration of GGOH ameliorated ZA's cytotoxic effects and partially restored cells to control state, with significant modulation of 28 osteogenic and 27 angiogenic genes. The reversal of ZA toxicity by GGOH suggests therapeutic potential for preventing bisphosphonate-related osteonecrosis of the jaw (BRONJ).
Topical GG counteracts bisphosphonate-induced osteonecrosis of the jaw.
Fliefel, R. M., Entekhabi, S. A., Ehrenfeld, M., & Otto, S. (2019). Geranylgeraniol (GGOH) as a Mevalonate Pathway Activator in the Rescue of Bone Cells Treated with Zoledronic Acid: An In Vitro Study. Stem Cells International, 2019, Article ID 4351327.
https://pmc.ncbi.nlm.nih.gov/articles/PMC6343170/
This study demonstrates that geranylgeraniol effectively rescues bone cells treated with zoledronic acid by restoring protein prenylation and improving cellular viability, suggesting a promising therapeutic strategy for medication-related osteonecrosis of the jaw (MRONJ).
GG rescues bone cells treated with zoledronic acid by restoring protein prenylation.
Osteoblast/osteoclast restoration
Coxon, F. P., Helfrich, M. H., Van't Hof, R., Sebti, S., Ralston, S. H., Hamilton, A. D., & Dunford, J. E. (2000). Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. Journal of Bone and Mineral Research, 15(8), 1467–1476.
https://pubmed.ncbi.nlm.nih.gov/10934645/
GG supplementation restores viability in human osteoblasts and osteoclasts suppressed by nitrogen-containing bisphosphonates like zoledronate through restoration of protein geranylgeranylation, demonstrating that protein prenylation is essential for normal osteoclast formation, function, and survival.
GG rescues normal function and viability in osteoclasts suppressed by bisphosphonates.
Dunford, J. E., Thompson, K.et al.. (2001). Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. Journal of Pharmacology and Experimental Therapeutics, 296(2), 235–242.
https://pubmed.ncbi.nlm.nih.gov/11160603/
This study demonstrates the mechanistic basis for bisphosphonate-induced bone cell toxicity through farnesyl diphosphate synthase inhibition, highlighting the potential for GG supplementation to restore normal bone cell function by replenishing downstream isoprenoid products in the mevalonate pathway.
Vitamin K2 pathway
Schumacher, M. M., Jun, D. J., et al.. (2016). Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi. Journal of Lipid Research, 57(7), 1286–1299.
https://pmc.ncbi.nlm.nih.gov/articles/PMC4918857/
This study demonstrates that geranylgeraniol (GGOH) regulates the transport of UBIAD1 prenyltransferase between endoplasmic reticulum and Golgi membranes, a mechanism critical for vitamin K2 (menaquinone-4) synthesis. The research reveals that UBIAD1 continuously cycles between organelles based on geranylgeranyl pyrophosphate (GGPP) levels, and that mutations in UBIAD1 associated with Schnyder corneal dystrophy block this geranylgeranyl-regulated transport, leading to ER sequestration and impaired cholesterol homeostasis in corneal tissue.
Bone Health
Bisphosphonate-related complications
Chen, X., Zhu, W., Xu, R., Shen, X., Fu, Y., Cheng, J., Liu, L., & Jiang, H. (2021). Geranylgeraniol Restores Zoledronic Acid-Induced Efferocytosis Inhibition in Bisphosphonate-Related Osteonecrosis of the Jaw. Frontiers in Pharmacology, 12, 775846.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8595285/
This study demonstrates that zoledronic acid impairs efferocytosis in bone marrow-derived macrophages, contributing to the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Geranylgeraniol supplementation restores efferocytosis capacity, reduces inflammatory cytokine levels, and alleviates BRONJ lesions in a mouse model, highlighting GG’s potential as a restorative strategy for bisphosphonate-inhibited bone cell function.
Fliefel, R. M., Entekhabi, S. A., Ehrenfeld, M., Otto, S. (2019). Geranylgeraniol (GGOH) as a Mevalonate Pathway Activator in the Rescue of Bone Cells Treated with Zoledronic Acid: An In Vitro Study. Stem Cells International, 2019, Article ID 4351327.
https://pmc.ncbi.nlm.nih.gov/articles/PMC6343170/
This study demonstrates that geranylgeraniol effectively rescues bone cells treated with zoledronic acid by restoring protein prenylation and improving cellular viability, suggesting a promising therapeutic strategy for medication-related osteonecrosis of the jaw (MRONJ).
Chin, K. Y., Ekeuku, S. O., & Trias, A. (2022). The Role of Geranylgeraniol in Managing Bisphosphonate-Related Osteonecrosis of the Jaw. Frontiers in Pharmacology, 13, 878556. https://doi.org/10.3389/fphar.2022.878556
Comprehensive review demonstrating geranylgeraniol's promise as a topical treatment to mitigate bisphosphonate-related ONJ by supporting the bone healing process through restoration of GTPase prenylation, though further research is needed to establish effective delivery methods and validate clinical use.
Mungpayabarn, H., & Patntirapong, S. (2021). Timing of geranylgeraniol addition increases osteoblast activities under alendronate condition. BMC Oral Health, 21, 285.
https://pubmed.ncbi.nlm.nih.gov/34026481/
This study demonstrates that geranylgeraniol (GG) counteracts alendronate-induced suppression of osteoblast viability and function. The timing of GG addition significantly increased cell viability, alkaline phosphatase activity, and mineralization in osteoblast cultures under alendronate treatment, indicating GG’s restorative potential for bisphosphonate-impaired bone cells and suggesting optimal supplementation strategies.
Di Vito, A., Chiarella, E., et al., (2020). Dose-dependent effects of zoledronic acid on human periodontal ligament stem cells: An in vitro pilot study. Pharmaceuticals, 13(12), 463.
https://pmc.ncbi.nlm.nih.gov/articles/PMC7784504/
This in vitro pilot study evaluates the cytotoxic and reparative effects of zoledronic acid (ZA) at varying concentrations on human periodontal ligament stem cells (hPDLSCs). ZA exposure leads to dose-dependent decreases in viability and proliferation, and induces apoptosis, implicating mevalonate pathway inhibition in bisphosphonate-related oral complications and targeting stem cell function. Findings support the clinical relevance of ZA’s effects on oral bone and highlight the need for regenerative strategies to mitigate bisphosphonate-related adverse events.
Osteoblast/osteoclast restoration
Fraser P. Dr. Coxon, Miep H. Helfrich,, et al. (2000). Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. Journal of Bone and Mineral Research, 15(8), 1467–1476.
https://doi.org/10.1359/jbmr.2000.15.8.1467
GG supplementation restores viability in human osteoblasts and osteoclasts suppressed by nitrogen-containing bisphosphonates like zoledronate through restoration of protein geranylgeranylation.
van Beek, E., et al., (1999). The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: A clue to the mechanism of action of nitrogen-containing bisphosphonates. Journal of Bone and Mineral Research, 14(5), 722–729. https://pubmed.ncbi.nlm.nih.gov/10320520/
Landmark study demonstrating that protein geranylgeranylation, but not farnesylation, is essential for osteoclast-mediated bone resorption and that nitrogen-containing bisphosphonates exert their antiresorptive action by affecting enzymes generating geranylgeranyl pyrophosphate. GG fully reverses bisphosphonate-inhibited bone resorption.
Fisher, J. E., Rogers, M. J., Halasy, J. M.,et al. (1999). Alendronate mechanism of action: Geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proceedings of the National Academy of Sciences, 96(1), 133–138. https://doi.org/10.1073/pnas.96.1.133
Demonstrates that geranylgeraniol prevents alendronate-induced inhibition of osteoclast formation and bone resorption by restoring mevalonate pathway intermediates, establishing GG's mechanistic role in countering bisphosphonate effects.
Van Beek, E. R., Löwik, C. W. G. M., & Papapoulos, S. E. (2002). Bisphosphonates suppress bone resorption by a direct effect on early osteoclast precursors without affecting the osteoclastogenic capacity of osteogenic cells: the role of protein geranylgeranylation in the action of nitrogen-containing bisphosphonates on osteoclast precursors. Bone, 30(1), 64–70.
https://pubmed.ncbi.nlm.nih.gov/11792566/
Establishes that bisphosphonates suppress bone resorption by directly targeting early osteoclast precursors through inhibition of protein geranylgeranylation and that GG can partly reverse these effects, providing mechanistic foundation for therapeutic interventions.
Vitamin K2 pathway
Schumacher, M. M., et al., (2016). Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi. Journal of Lipid Research, 57(7), 1286–1299.
https://pmc.ncbi.nlm.nih.gov/articles/PMC4918857/
This study demonstrates that geranylgeraniol (GGOH) regulates the transport of UBIAD1 prenyltransferase between endoplasmic reticulum and Golgi membranes, a mechanism critical for vitamin K2 (menaquinone-4) synthesis. The research reveals that UBIAD1 continuously cycles between organelles based on geranylgeranyl pyrophosphate (GGPP) levels, and that mutations in UBIAD1 associated with Schnyder corneal dystrophy block this geranylgeranyl-regulated transport, leading to ER sequestration and impaired cholesterol homeostasis in corneal tissue.
Cancer
Apoptosis induction in tumour cells
Ohizumi, H., Masuda, Y., Nakajo, S., Sakai, I., Ohsawa, S., & Nakaya, K. (1995). Geranylgeraniol is a potent inducer of apoptosis in tumor cells. The Journal of Biochemistry, 117(1), 11–13.
https://academic.oup.com/jb/article-abstract/117/1/11/871497
Screening of various isoprenoids identified GG as having the most potent apoptosis-inducing activity in human leukemia HL-60 cells. GG induced concentration and time-dependent apoptosis in multiple tumour cell lines, including human myeloid leukemia K562, lymphoblastic leukemia Molt3, and colon adenocarcinoma COLO320 DM, while selectively inhibiting DNA synthesis.
Masuda, Y., Nakaya, M., et al., (2000). The mechanism of geranylgeraniol-induced apoptosis involves activation by a caspase-3-like protease, of a c-Jun N-terminal kinase signaling cascade and differs from that of apoptosis induced by conventional chemotherapeutic drugs. Cell Biology International, 24(8), 647–657.
https://www.sciencedirect.com/science/article/abs/pii/S0145212600000667
Geranylgeraniol triggers apoptosis via a caspase-3-like enzyme and JNK cascade, showing unique cell death mechanisms beyond standard chemotherapy.
Masuda, Y., et al., (2007). Increase in intracellular Ca(2+) concentrations and the corresponding intracellular acidification are early steps for induction of apoptosis by geranylgeraniol in HL60 cells. Biological & Pharmaceutical Bulletin, 30(5), 880–884.
https://pubmed.ncbi.nlm.nih.gov/17473429/
GG prompts early intracellular calcium rise and acidification, driving apoptosis in HL60 leukemia cells.
Breast cancer - Mitosis disruption
Wei, J., Xia, S., et al., (2022). Geranylgeranylation signaling promotes breast cancer cell mitosis via the YAP-activated transcription of kinetochore/centromere genes. Am J Cancer Res, 12(3), 1143–1155.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8984885/
This research demonstrates that geranylgeranylation signalling supports mitosis in breast cancer cells through YAP-driven transcriptional activation of key kinetochore/centromere genes, uncovering new pathways for tumour progression and offering mechanistic insights for targeted therapies.
Prostate cancer - Cell cycle arrest
Fernandes, N. V., Yeganehjoo, H., et al., (2013). Geranylgeraniol suppresses the viability of human DU145 prostate carcinoma cells and the level of HMG CoA reductase. Experimental Biology and Medicine, 238(11), 1265–1274.
https://pmc.ncbi.nlm.nih.gov/articles/PMC4010193/
This study demonstrates that geranylgeraniol induces G1-phase cell cycle arrest and apoptosis in DU145 prostate carcinoma cells, with a concentration-dependent reduction in HMG CoA reductase protein, supporting GG's potential as a chemopreventive and therapeutic agent in prostate cancer.
Yeganehjoo, H., et al., (2017). Synergistic impact of d-δ-tocotrienol and geranylgeraniol on the growth and HMG CoA reductase of human DU145 prostate carcinoma cells. Journal of Nutritional Biochemistry, 45, 94–100. https://doi.org/10.1016/j.jnutbio.2017.03.001
https://pubmed.ncbi.nlm.nih.gov/28362175/
This study demonstrates that d-δ-tocotrienol and geranylgeraniol synergistically suppress the growth of human DU145 prostate carcinoma cells and decrease cellular HMG-CoA reductase levels. The findings suggest a potential combinatorial nutraceutical strategy targeting the mevalonate pathway in prostate cancer therapy.
Leukemia apoptosis induction
Okada, S., Yabuki, M., et al., (1999). Geranylgeranylacetone induces apoptosis in HL-60 cells. FEBS Letters, 454(1–2), 215–2
https://pubmed.ncbi.nlm.nih.gov/10462178/
This study shows that geranylgeranylacetone induces apoptosis in HL-60 human leukemia cells, providing evidence for its potential antitumor effects via caspase activation and mitochondrial membrane disruption. The findings highlight the relevance of geranylgeranyl derivatives in cancer cell death mechanisms.
Masuda, Y., Aiuchi, T., et al., (2007). Increase in intracellular Ca(2+) concentrations and the corresponding intracellular acidification are early steps for induction of apoptosis by geranylgeraniol in HL60 cells. Biological & Pharmaceutical Bulletin, 30(5), 880–884.
https://pubmed.ncbi.nlm.nih.gov/17473429/
This study demonstrates that geranylgeraniol induces apoptosis in human leukemia HL60 cells through early increases in intracellular calcium and subsequent intracellular acidification, highlighting the mechanisms involved in its cytotoxic action
Similar articles
Masuda Y, Yoda M, Ohizumi H, Aiuchi T, Watabe M, Nakajo S, Nakaya K.Int J Cancer. 1997 May 16;71(4):691-7. doi: 10.1002/(sici)1097-0215(19970516)71:4<691::aid-ijc29>3.0.co;2-d.PMID: 9178828
Kobayashi D, Ahmed S, Ishida M, Kasai S, Kikuchi H.Toxicology. 2009 Apr 5;258(1):25-32. doi: 10.1016/j.tox.2009.01.002. Epub 2009 Jan 9.PMID: 19167453
Comparison of tBuBHQ with chemotactic peptide and phorbol ester in O2- production in HL-60 cells.
Tsukii K, Nakahata N, Watanabe K, Tsurufuji S, Ohizumi Y.Eur J Pharmacol. 1996 Feb 29;298(1):87-95. doi: 10.1016/0014-2999(95)00787-3.PMID: 8867924
Ca2+-independent synergistic augmentation of O2- production by FMLP and PMA in HL-60 cells.
Tsukii K, Nakahata N, Tsurufuji S, Ohizumi Y.Can J Physiol Pharmacol. 1998 Oct-Nov;76(10-11):1024-32. doi: 10.1139/cjpp-76-10-11-1024.PMID: 10100885
The Pivotal Role of Ca2+ Homeostasis in PBDE-47-Induced Neuronal Apoptosis.
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Cardiovascular Disease
CoQ10 synthesis and heart health
Wang, C., & Hekimi, S. (2016). Understanding Ubiquinone. Trends in Cell Biology, 26(5), 367-378. https://pubmed.ncbi.nlm.nih.gov/26827090/
As a precursor to CoQ10, GG supports heart muscle function, improves circulation, and helps maintain healthy blood pressure through enhanced mitochondrial energy production.
Statin myopathy prevention
Irwin, J., Fenning, A., Vella, R. (2019). Geranylgeraniol prevents statin-induced skeletal uscle fatigue without causing adverse effects in cardiac or vascular smooth muscle performance. Translational Research, 215, 17–30. Elsevier, USA.
https://acquire.cqu.edu.au/articles/journal_contribution/Geranylgeraniol_prevents_statin-induced_skeletal_muscle_fatigue_without_causing_adverse_effects_in_cardiac_or_vascular_smooth_muscle_performance/13454714
This peer-reviewed rodent study demonstrates that geranylgeraniol supplementation completely prevents statin-induced muscle fatigue in fast-twitch glycolytic muscle and improves muscle performance in both affected and control animals, without causing adverse changes in heart or vascular function. The results support GGOH's potential to mitigate statin-associated muscle symptoms (SAMS) without cardiovascular risk.
Eye Disease (Schnyder Corneal Dystrophy)
UBIAD1 regulation and cholesterol metabolism
Schumacher, M. M., Elsabrouty, R., Seemann, J., Jo, Y., & DeBose-Boyd, R. A. (2015). The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase. eLife, 4, e05560.
https://pmc.ncbi.nlm.nih.gov/articles/PMC4374513/
This landmark study identifies UBIAD1 as the molecular target of geranylgeraniol in the sterol-accelerated degradation of HMG CoA reductase. GG disrupts the binding of UBIAD1 to reductase, facilitating enzyme degradation and UBIAD1 translocation from the ER to the Golgi. Mutations in UBIAD1 associated with Schnyder corneal dystrophy prevent this geranylgeraniol-mediated displacement, leading to impaired reductase degradation and abnormal cholesterol accumulation in corneas, a hallmark of SCD pathogenesis.
Fredericks, W. J., McGarvey, T., Wang, H., Lal, P., et al. (2011). The bladder tumor suppressor protein TERE1 (UBIAD1) modulates cell cholesterol: implications for tumor progression. DNA and Cell Biology, 30(11), 851–864.
https://pubmed.ncbi.nlm.nih.gov/21740188/
Demonstrates that UBIAD1 (also known as TERE1) modulates cellular cholesterol metabolism through interactions with HMG CoA reductase, with implications for understanding SCD pathogenesis and cholesterol-related disorders.
Glycemic Disease (Diabetes)
PPARγ activation
Matsubara, T., Takakura, N., Urata, M., Muramatsu, Y., Tsuboi, M., Yasuda, K., Addison, W. N., Zhang, M., Matsuo, K., Nakatomi, C., Shigeyama-Tada, Y., Kaneuji, T., Nakamichi, A., & Kokabu, S. (2018). Geranylgeraniol induces PPARγ expression and enhances the biological effects of a PPARγ agonist in adipocyte lineage cells. Scientific Reports, 8, 15997.
https://pubmed.ncbi.nlm.nih.gov/30348686/
This study shows that geranylgeraniol (GG) upregulates PPARγ expression in adipocyte lineage cells and potentiates the effects of the PPARγ agonist rosiglitazone. GG enhances adipogenic differentiation and PPARγ-dependent gene expression, suggesting a regulatory role for GG in metabolic and adipose tissue health.
Metabolic improvement in obesity
Chung, E., Elmassry, M. M., Cao, J. J., Kaur, G., Dufour, J. M., Hamood, A. N., & Shen, C. L. (2021). Beneficial effect of dietary geranylgeraniol on glucose homeostasis and bone microstructure in obese mice is associated with suppression of proinflammation and modification of gut microbiome. Nutrition, 88, 111243.
https://www.sciencedirect.com/science/article/abs/pii/S0271531721000439
This study demonstrates that dietary geranylgeraniol supplementation improves glucose homeostasis and bone microstructure in obese mice through mechanisms involving suppression of proinflammatory responses and beneficial modulation of gut microbiome composition, highlighting GG's multi-system metabolic benefit..
Glucose Homeostasis
Chung, E., Elmassry, M. M., Cao, J. J., Kaur, G., Dufour, J. M., Hamood, A. N., & Shen, C. L. (2021). Beneficial effect of dietary geranylgeraniol on glucose homeostasis and bone microstructure in obese mice is associated with suppression of proinflammation and modification of gut microbiome. Nutrition, 88, 111243.
https://www.sciencedirect.com/science/article/abs/pii/S0271531721000439
This study demonstrates that dietary geranylgeraniol supplementation improves glucose homeostasis and bone microstructure in obese mice through mechanisms involving suppression of proinflammatory responses and beneficial modulation of gut microbiome composition, highlighting GG's multi-system metabolic benefit..
Hormonal Health
Steroidogenesis enhancement
Ho, H. J., Shirakawa, H., Yoshida, R., Ito, A., Maeda, M., Goto, T., & Komai, M. (2016). Geranylgeraniol enhances testosterone production via the cAMP/protein kinase A pathway in testis-derived I-10 tumor cells. Bioscience, Biotechnology, and Biochemistry, 80(4), 791–797.
https://pubmed.ncbi.nlm.nih.gov/26757775/
GG enhances testosterone and progesterone production in testis-derived cells through cAMP/PKA signalling pathway activation, demonstrating its role in steroidogenesis regulation with potential applications for testosterone enhancement in ageing men.
Clinical trial evidence - Testosterone enhancement
Gheith, R., Sharp, M., Stefan, M., Ottinger, C., Lowery, R., & Wilson, J. (2023). The Effects of Geranylgeraniol on Blood Safety and Sex Hormone Profiles in Healthy Adults: A Dose-Escalation, Randomized, Placebo-Controlled Trial. Nutraceuticals, 3(4), 590–607.
https://www.mdpi.com/1661-3821/3/4/43
Eight-week randomised trial (n=66, ages 30-49) demonstrated GG supplementation (150-300mg daily) significantly increased total testosterone (7.5%), free testosterone (15%), and bioavailable testosterone (14.8%) in males with baseline levels <700ng/dL, while placebo group showed decreases. No significant alterations in blood chemistry, hematology, or sex hormone profiles in healthy adults, confirming excellent safety profile.
American River Nutrition. (2024). Geranylgeraniol supplementation may benefit males with low testosterone - Clinical study. Research Summary.
https://americanrivernutrition.com/geranylgeraniol-supplementation-may-benefit-males-with-low-testosterone-clinical-study/
Clinical study summary highlighting GG's ability to increase usable forms of testosterone (free and bioavailable) in males with low baseline testosterone, supporting its potential as a natural alternative to testosterone replacement therapy.
Related Compounds
Geraniol (C10 Monoterpene)
Geraniol is a C10 monoterpene alcohol structurally related to geranylgeraniol (C20 diterpene). While shorter in chain length, geraniol shares similar biological properties and therapeutic potential in certain conditions.
Antiarthritic activity
Malik, M. N. H., et al. (2023). Geraniol Suppresses Oxidative Stress, Inflammation, and Interstitial Collagenase to Protect against Inflammatory Arthritis. ACS Omega, 8(40), 37128–37139.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10568708/
Geraniol significantly reduced paw edema (comparable to methotrexate), restored joint structure with minimal inflammation and normalised inflammatory markers (RF, CRP, ESR) in complete Freund's adjuvant-induced arthritis models. Downregulates pro-inflammatory cytokines (TNF-α, IL-1β, NF-κB1), COX-2, mPGES-1, PTGDS, and matrix metalloproteinase-1 (MMP-1) through direct molecular interactions confirmed by docking studies.
Acute lung injury protection
Jiang, K., et al. (2017). Geraniol alleviates LPS-induced acute lung injury in mice through TLR4-mediated NF-κB and MAPK signaling pathways. International Immunopharmacology, 50, 208–217.
https://pubmed.ncbi.nlm.nih.gov/29050341/
Geraniol alleviates LPS-induced acute lung injury through TLR4-mediated NF-κB pathway inhibition, reducing pulmonary inflammation, apoptosis, and neutrophil infiltration. This related monoterpene demonstrates protective effects in acute respiratory models comparable to those being investigated for geranylgeraniol in ARDS.
Farnesol (C15 Sesquiterpene)
Farnesol is another isoprenoid alcohol in the mevalonate pathway, structurally between geraniol (C10) and geranylgeraniol (C20). While farnesol has been studied for its antimicrobial and anti-inflammatory properties, geranylgeraniol demonstrates superior efficacy in rescuing statin-induced myopathy and supporting skeletal muscle protein synthesis.
Research Note: Current evidence suggests that while farnesol shares some biological activities with geranylgeraniol, only GG specifically reverses statin-associated muscle damage through restoration of protein geranylgeranylation required for skeletal muscle maintenance.
Liver Disease and Hepatic Protection
Anti-inflammatory effects and LPS-induced inflammation
Giriwono, P. E., et al. (2013). Dietary supplementation with geranylgeraniol suppresses lipopolysaccharide-induced inflammation via inhibition of nuclear factor-κB activation in rats. European Journal of Nutrition, 52(3), 1191–1199.
https://pubmed.ncbi.nlm.nih.gov/22847643/
A 10-day high-dose GGOH-supplemented diet significantly suppressed LPS-induced liver inflammation and NF-κB activation in rats. Treatment reduced plasma inflammatory cytokines (TNF-α, IL-1β, IL-6) and hepatic damage markers (ALT/AST activities). GGOH substantially decreased mRNA expression of signal transducer genes upstream of the IκB kinase complex, with Western blotting demonstrating significant reductions in total IRAK1 and TRAF6 protein levels, leading to inhibited NF-κB signal transduction and hepatic protection.
Lung Disease
Acute lung injury - Geranylgeranylation pathway importance
Zhao, X., Qi, L., et al. (2021). Geranylgeranyl diphosphate synthase deficiency hyperactivates macrophages and aggravates lipopolysaccharide-induced acute lung injury. Frontiers in Immunology, 12, 627885.
https://pubmed.ncbi.nlm.nih.gov/33729030/
Myeloid-specific GGPPS knockout (the enzyme that synthesizes GGPP, the active form of GG) in mice significantly increased mortality and aggravated LPS-induced acute lung injury, with increased inflammatory cell accumulation and cytokine production (IL-6, IL-1β, TNF-α) in bronchoalveolar lavage fluid. Mechanistically, GGPPS deficiency increased Rac1-GTP levels and NF-κB p65 phosphorylation/nuclear translocation, suggesting that maintaining adequate geranylgeranyl pyrophosphate levels through GG supplementation may protect against acute respiratory distress syndrome (ARDS).
Muscle Disease and Myopathy
Statin-associated muscle symptoms
Jaśkiewicz, A., et al. (2018). Geranylgeraniol Prevents Statin-Dependent Myotoxicity in C2C12 Muscle Cells through RAP1 GTPase Prenylation and Cytoprotective Autophagy. Oxidative Medicine and Cellular Longevity, 2018, Article ID 6463807.
https://pmc.ncbi.nlm.nih.gov/articles/PMC5987243/
GG reverses statin-induced myotoxicity in muscle cells via RAP1 GTPase prenylation and autophagy activation.
Tan, B., & Chin, K. Y. (2023). Potential role of geranylgeraniol in managing statin-associated muscle symptoms: a COVID-19 related perspective. Frontiers in Physiology, 14, 1246589.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10691100/
This comprehensive opinion paper proposes geranylgeraniol as a pharmacological solution to statin-associated muscle symptoms (SAMS), arguing that GG is superior to CoQ10 supplementation in reversing statin-induced myopathy. The review presents evidence that GG prevents statin-induced skeletal muscle fatigue, protects against muscle atrophy and restores muscle protein synthesis through restoration of protein geranylgeranylation and mitochondrial function, with particular relevance to expanded statin use in COVID-19 management.
Diabetic muscle atrophy
Jiwan, S., et al. (2021). Geranylgeraniol Alleviates Diabetic Skeletal Muscle Atrophy by Improving Mitochondrial Quality Control and Enhancing Autophagy. International Journal of Molecular Sciences, 22(19), 10543. https://digitalcommons.wku.edu/ijesab/vol2/iss14/107/#:~:text=With%20diabetes%2C%20skeletal%20muscle%20mitochondrial%20quality%20control%20(mitochondrial%20fusion%2C%20fission%20&%20macro%2Dautophagy)%20is%20impaired.
This study demonstrates that geranylgeraniol supplementation mitigates diabetic skeletal muscle atrophy in animal models by improving mitochondrial function, enhancing autophagy and reducing muscle fiber loss, supporting its role as a promising intervention for diabetes-associated muscle degeneration.
Jiwan, N. C., et al. (2022). Geranylgeraniol Supplementation Mitigates Soleus Muscle Atrophy via Changes in Mitochondrial Quality in Diabetic Rats. In Vivo, 36(6), 2638–2649.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9677755/
This study demonstrates that GGOH supplementation mitigates soleus muscle atrophy in diabetic rats through decreased mitochondrial fragmentation (reduced DRP1), improved autophagy (reduced LC3A/LC3B), and preservation of muscle cross-sectional area while reducing pro-inflammatory cytokine IL-1β.
Nervous System Disease (Dementia & Alzheimer's)
Microglial activation and neuroinflammation
Hooff, G. P., Peters, I., Wood, W. G., Müller, W. E., Eckert, G. P. (2010). Modulation of cholesterol, farnesyl-pyrophosphate, and geranylgeranyl-pyrophosphate in neuroblastoma SH-SY5Y cells by statins. Biochemical Pharmacology, 79(12), 1729–1738. PMCID: PMC2859886
https://pmc.ncbi.nlm.nih.gov/articles/PMC2859886/
This study investigates how statins modulate levels of cholesterol and the isoprenoids farnesyl-pyrophosphate and geranylgeranyl-pyrophosphate in neuroblastoma SH-SY5Y cells, revealing mechanistic insights into protein prenylation, cellular signalling, and neuroprotection relevant to nervous system disease models.
Mitochondrial protection in neurons
Izumi, Y., et al, T. (2016). Neuroprotective effect of geranylgeraniol against neuronal cell death induced by simvastatin. European Journal of Pharmacology, 789, 381-388.
https://pubmed.ncbi.nlm.nih.gov/26978350/
In neuronal cell models, GG co-administration reduces inflammatory markers and prevents mitochondrial damage, maintaining cellular shape and components while reducing programmed cell death.
GG protects neurons from statin-induced mitochondrial damage and cell death.
Hooff, G. P., et al. (2010). Modulation of cholesterol, farnesyl-pyrophosphate, and geranylgeranyl-pyrophosphate in neuroblastoma SH-SY5Y-cells by statins. Biochemical Pharmacology, 79(12), 1729–1738. https://europepmc.org/article/med/20405344
Explores statin effects on cholesterol/isoprenoid metabolism in neuronal models, with implications for neuroprotection.
Alzheimer's Disease mechanisms
Eckert, G. P., Hooff, G. P., et al. (2009). Regulation of the brain isoprenoids farnesyl- and geranylgeranylpyrophosphate is altered in male Alzheimer patients. Neurobiology of Disease, 35(2), 251–257. https://doi.org/10.1016/j.nbd.2009.05.005
Reveals significantly increased FPP and GGPP in Alzheimer’s brain tissue, suggesting abnormal mevalonate pathway activity.
Jeong, A., Suazo, K. F., et al. (2018). Isoprenoids and protein prenylation: implications in the pathogenesis and therapeutic intervention of Alzheimer's disease. Critical Reviews in Biochemistry and Molecular Biology, 53(3), 279–310.
https://pubmed.ncbi.nlm.nih.gov/29718780/
This comprehensive review examines the roles of isoprenoids (including geranylgeranyl pyrophosphate) and protein prenylation in Alzheimer's disease pathogenesis, highlighting how dysregulation of the mevalonate pathway and prenylation processes contribute to AD mechanisms and exploring therapeutic intervention strategies targeting these pathways.
Zhou, Y., Suram, A., et al. (2008). Geranylgeranyl pyrophosphate stimulates γ-secretase to increase the generation of Aβ and APP-CTFγ. FASEB Journal, 22(1), 47–54.
https://pmc.ncbi.nlm.nih.gov/articles/PMC2859886/
This study demonstrates that geranylgeranyl pyrophosphate (GGPP) stimulates γ-secretase activity, increasing the generation of amyloid-β (Aβ) peptides and APP C-terminal fragment γ (APP-CTFγ), providing important mechanistic insights into the role of protein prenylation and isoprenoid metabolism in Alzheimer's disease pathogenesis.
Rare Autoinflammatory Disease
Hyper-IgD Syndrome (HIDS) / Mevalonate Kinase Deficiency
Clinical pilot study
University Hospital Motol, Prague. (2024). Geranylgeraniol Supplementation in Patients With Mevalonate Kinase Deficiency. ClinicalTrials.gov Identifier: NCT06525168.
https://www.clinicaltrials.gov/study/NCT06497829
Ongoing pilot clinical trial in patients with genetically confirmed mevalonate kinase deficiency (HIDS) evaluating safety and efficacy of 150mg daily GG supplementation for 3 months. Study monitors inflammatory parameters (CRP, SAA), clinical status (fever, fatigue, skin manifestations, abdominal pain), and changes in plasma proteomics. Preliminary findings from 3 HIDS patients demonstrated safety with no liver toxicity, though plasma GGPP levels were not significantly increased.
Preprint - Proteomic improvements
Malíčková, K., Šedivá, A., et al. (2024). Geranylgeraniol supplementation in patients with mevalonate kinase deficiency: a pilot study. medRxiv preprint.
https://www.medrxiv.org/content/10.1101/2024.07.17.24309492v1
Note: This is a preprint (not yet peer-reviewed). The study reports that GG supplementation reversed some features of HIDS-specific plasma protein signatures, highlighting potential to modulate inflammation and protein prenylation pathways. Mass spectrometry-based proteomic analysis showed changes in inflammatory markers and prenylation-related proteins after 3 months of supplementation.
Mechanistic basis for HIDS pathogenesis
Politiek, F. A., Waterham, H. R., Firczuk, M., et al. (2024). Mevalonate kinase-deficient THP-1 cells show a disease phenotype and are used to identify novel therapeutic compounds for mevalonate kinase deficiency. Frontiers in Immunology, 15, 1356317.
https://pubmed.ncbi.nlm.nih.gov/38550596/#:~:text=MK%2Ddeficient%20THP%2D1%20cells%20show%20the%20biochemical%20and,a%20good%20model%20to%20study%20underlying%20disease
CRISPR-generated MKD cell models demonstrate that geranylgeranyl-PP shortage impairs protein prenylation of Rho and Rab GTPases, driving IL-1β hypersecretion. This provides mechanistic rationale for GG supplementation to restore prenylation capacity and reduce autoinflammatory symptoms in HIDS.
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