Improve your Health with OLIGENTM
OLIGEN™ is a new product offering and is the first commercially available oleocanthal (OC) produced from extra virgin olive oil (EVOO). OLIGEN™ will dramatically alter how consumers think about inflammation relief, cosmetics, skin disorders, dietary supplements, longevity and neuroprotection.
OC, which is found only in EVOO, is a potent antioxidant, and a non-steroidal anti-inflammatory natural product, with activity similar to FDA approved NSAID (ibuprofen, aspirin etc). OC is a highly effective compound that can promote beneficial effects inside and outside the human body. The following sections will summarize the current state of knowledge concerning the many uses of EVOO and OC, one of the main health-promoting ingredients of EVOO.
History of EVOO
Olive-based products were common in ancient Greece and Rome. According to legend, the city of Athens was named after the Greek goddess Athena, who presented the city with an olive tree. EVOO, a liquid fat at room temperature, is produced from olives, the fruit of Olea europaea trees which are abundantly grown in the Mediterranean Basin. EVOO is prepared by a cold pressing method, and use of the fruit’s extracted oil began between 650 and 450BC and compared to processed oil, EVOO has higher concentrations of health promotimg compounds. EVOO is a staple of the Mediterranean diet and consumption per capita is highest in Greece, although Spain is the largest producer of EVOO. In fact, Greeks use an average of 24 liters of olive oil per capita per year (1). The US is the largest importer of EVOO in the world, but on average just 1 liter is consumed per year per person, which highlights the large growth potential for EVOO in the US, which accounts for over $1B per year in sales (2, 3). Figure 1 illustrates the significant growth in consumption of EVOO in the US over the past 15 years. The US also produces EVOO for export, with California being the largest producer of all the states. The worldwide market for EVOO currently is valued at over $10B.
Figure 1. EVOO consumption in the US
EVOO has gained a positive reputation primarily for the health benefits associated with consumption; however, there are other uses for this oil. EVOO has a rich history in cosmetics dating back to the 7th century.
Today, EVOO continues to be purchased for a variety of cosmetic purposes, including for use as a: 1) pre-shampoo; 2) skin scrub with sugar; 3) eye makeup remover; 4) ear wax remedy; 5) hair shine; 6) shaving crème; 7) cuticle softener and other applications. Also, EVOO is recommended as a carrier for many essential oil based products sold by doTerra and other companies in this rapidly expanding sector.
Health Benefits of EVOO Consumption
Besides supplying a taste many enjoy, EVOO is consciously consumed for its health-promoting benefits. Specifically, EVOO is thought to be a healthier alternative to certain fats due to the unsaturated fats that are the primary fat source of EVOO. Scientific and clinical research suggests mono- and polyunsaturated fats may help lower cholesterol and risk of heart disease, whereas saturated and trans fats, such as those found in butter, are more likely to contribute to disease development and progression. Data supporting the health and disease claims around different types of fats are sometimes conflicting, but one claim commonly supported is that all fats should be consumed in moderation.
An extensive number of claims in scientific journals and public press have been made about EVOO and associated olive leaf products as a preventive or treatment for a range of human indications, including heart problems, high cholesterol, inflammation, aging, gallstones, cancer, hypertension and neurodegenerative problems. However, the gold standard of clinical trials (double blind placebo controlled) is still lacking, thus preventing the FDA from approving EVOO-isolated products as drugs to treat human diseases. The strongest statement so far by the FDA was issued when EVOO was approved for a qualified health claim: “Limited and not conclusive scientific evidence suggests that eating about 2 tablespoons (23 grams) of EVOO daily may reduce the risk of coronary heart disease due to the monounsaturated fat in EVOO. To achieve this possible benefit, EVOO is to replace a similar amount of saturated fat and not increase the total number of calories you eat in a day.” The evidence supporting this conclusion was supplied by more than 70 studies in countries around the world.
Additionally, in 2012, the International Olive Council released a white paper entitled “Health Benefits of Olives and EVOO” which listed a range of other health benefits that EVOO provides. In fact, those who adhere to a Mediterranean diet rich in EVOO have a longer life expectancy and lower risk of heart disease, hypertension and stroke. In further support of the increased interest in the health-promoting properties of EVOO, PubMed lists over 10,000 publications citing olive oil in the title or abstract since the 1890’s, with more than one half of these papers being published in the last 9 years. Interestingly, the first paper, published in 1892, by physician James Goodhart in the British Journal of Medicine, provided case studies suggesting that EVOO was an effective treatment for gallstones (4). Even more striking is the fact that the first modern paper published on EVOO occurred in 1988 and over one half of the subsequent 968 papers occurred in the last 4 years (Figure 2).
Figure 2. PubMed Publications by Year – “Extra Virgin Olive Oil”
EVOO is a rich source of monounsaturated fatty acids and phenolic compounds including: phenolic acids, phenolic alcohols, secoiridoids, lignans and flavones, all of which have been demonstrated in scientific studies to impact processes contributing to human disease (5). This topic will be explored in greater detail in the following sections.
The Health-Promoting Compounds of EVOO
A recent review by Parkinson and Cicerale (5) covers the potential health benefits attributed to more than 30 phenolic compounds found in EVOO; with the class of compounds named secoiridoids representing the highest percentage in EVOO, although the range in concentration is quite extreme depending on a variety of plant and environmental differences. One of the most recently discovered secoiridoids, oleocanthal (OC), has garnered a great deal of interest as a compound demonstrating a wide range of potent effects on human pathologies. One of the chemical names for OC is deacetoxy ligstroside aglycone and the chemical structure is shown in Figure 3. The name oleocanthal derives from oleo (olive), canth (sting) and al (aldehydes).
Figure 3. Chemical Structure of OC
Discovery of OC
As first described by Beauchamp (6), OC is now known to be the compound that causes localized irritation in the back of the throat (oropharyngeal region of the mouth), and shares a similar anti-inflammatory action with ibuprofen, thus, it is now considered a naturally occurring NSAID-like natural product. Much remains to be learned about this compound first described in the literature in 1993 (7), and as of December 2017, just 79 published scientific papers are retrieved by a PubMed search with “oleocanthal” in the article title or abstract. Nevertheless, as described in the next section, this compound has triggered intense research activity to determine how it works and for which medical indications it could be used.
Cosmetic Uses for OC
The skin is the largest organ in the body and protects the internal body against environmental insults, including solar radiation, chemical and physical agents. Over time the skin becomes damaged and with age the repair mechanisms become less efficient leading to wrinkles, collagen loss and sagging skin. Exposure to solar UV light is the major source of damage to human skin, which includes erythema (redness), edema, hyperplasia, wrinkling, dryness premature aging and skin cancer, such as melanoma. It is commonly recognized that UV light causes damage by impairing antioxidant-dependent pathways, leading to an increase in free radicals, which in turn induce production of cytokines. In turn, cytokines together with free radicals damage cells leading to cell death, cancer and aging.
Many cosmetic skin care products contain antioxidants and moisturizers that reduce these damaging insults to varying degrees. Current research has suggested that EVOO may be effective at preventing free radical build up, death of skin cells, cytokine production and promoting skin repair. In addition, these compounds are very effective anti-inflammatory agents and thus may reduce the effects of excess sun leading to sunburn. Thus, OLIGENTM enriched cosmetic products are predicted to be superior in maintaining healthy skin in all kinds of weather, especially when combined with other antioxidants such as polyphenols, vitamin E and selenium combined with anti-aging agents such as vitamin A.
Medical Uses for OC
The potential medical uses for OC are only now being discovered, but the majority of research with this compound covers three areas of medical importance: inflammation, Alzheimer’s disease and cancer which will be covered in the next three sections. The potential for OC to have an impact on additional human indications is great, but the lack of a reliable source for this compound has slowed research.
In 2016, the European Food Safety Authority, the equivalent of the FDA in the US, supported a health claim for polyphenols (which includes OC) found in EVOO. The claim is “olive oil polyphenols contribute to the protection of blood lipids from oxidative stress.” It is well established that oxidative stress induced by a variety of reactive oxygen and nitrogen species is implicated in development and progression of a variety of human diseases. Serum lipid peroxidation products are useful biomarkers to assess the relative level of oxidative stress to which a person is exposed. Thus, the health claim supports the hypothesis that consumption of EVOO minor components, such as OC, will prevent the harmful effects of oxidative stress.
OC as an Anti-Inflammatory Agent
Inflammation is a complex biological response that evolved in animals to protect against harmful agents, such as pathogens and poisons, and involves immune cells and a tightly-regulated large family of molecular mediators. The purpose of inflammation is to remove the initial cause of cell injury, eliminate necrotic tissue and to begin the tissue repair process. Unfortunately, chronic inflammation can lead to a range of medical conditions that include atherosclerosis, cancer (often described as wounds that do not heal), rheumatoid arthritis and many other diseases.
A recent review summarizes the current state of knowledge concerning OC as an anti-inflammatory agent (8). Inflammation plays a major role in diseases of the skin (psoriasis) and joints (osteoarthritis, OA). Joint degenerative diseases are driven by the production of pro-inflammatory cytokines which stimulate nitric oxide (NO) production, up-regulating the synthesis of enzymes degrading cartilage. In OA pathogenesis, cells called chondrocytes, part of the diseased cartilage, synthesize NO from an enzyme called inducible nitric oxide synthase (iNOS). It was reported that OC reduced expression of iNOS in mouse chondrocytes challenged with an inflammation-inducing agent (9). In addition, as reported by Beauchamp (6), OC inhibits production of COX enzymes that produce inflammatory mediators called prostaglandins (10).
Other inflammatory mediators, including cytokines such as interleukin 6 (IL-6) and MIP-1α, are associated with both rheumatoid arthritis (RA) and OA, and NSAIDS are often prescribed with sometimes serious side effects, such as GI mucosal damage. These cytokines can be produced by both macrophages and chondrocytes. OC has been demonstrated to reduce NO production in macrophages, and to inhibit IL-6 and MIP-1α in both chondrocytes and macrophages (11). This report also showed that OC decreased expression of other important pro-inflammatory mediators including IL-1, tumor necrosis factor and granulocyte-macrophages colony stimulating factor. Thus, OC may prevent the synovial fluid inflammatory cascade that contributes to RA and OA.
Thus, OC-containing products may be effective in the treatment of joint disease, including forms of arthritis. In addition, inflammatory skin conditions, which include contact dermatitis, eczema, psoriasis and a host of other conditions, impact 35M people each year in the US who spend $2B for treatments, many of which are not effective and have significant side effects (e.g. corticosteroids). Development of OLIGENTM in a topical formulation for treatment of skin disorders is being pursued by Oleolive LLC.
OC to Treat Alzheimer’s Disease and other Neurodegenerative Disorders
Alzheimer’s disease (AD) is considered one of the major neurodegenerative disorders affecting the elderly, and the number of affected patients is predicted to increase over the next few decades. In the US, 5M people suffer from this disease and this number will rise to 16M by 2050. There are no truly effective drugs on the market, and this sector is predicted to rise in value to $6.4B by 2025 from the 2017 value of $3.6B (Market Insider 2017 report). Global treatment costs for Alzheimer’s and other dementia related diseases will equal $1T annually in 2018 (Olive Oil Times July 27, 2017).
A published clinical study from Australia (12) concluded that a significantly smaller number of subjects suffered neurodegenerative disease when they followed the Mediterranean diet. Other research has demonstrated that there is an observed 40% lower incidence of AD in subjects consuming EVOO (13).
Is it possible OC found in EVOO plays a role in reducing the impact of AD? The current answer is a resounding YES. Over the last few years, at least six publications have confirmed that OC alone or OC-containing EVOO can prevent and/or slow progression of Alzheimer’s disease, with five of these studies being completed in the laboratory of Oleolive’s Chief Scientist - Neuroscience and Biopharmaceutics, Dr. Amal Kaddoumi who is on the faculty at Auburn University.
A peptide called amyloid-beta (Aβ) is considered one of the hallmarks of AD, and Aβ is processed from a membrane associated protein called amyloid precursor protein (APP). A cleaved form named Aβ1-42 is considered to contribute to the pathology of AD, since it has a tendency to form oligomers (Aβo), aggregates and fibrils, which can interfere with the connections between nerves and can form typical AD plaques, a diagnostic marker for AD. Studies from the Kaddoumi laboratory have demonstrated a number of key findings. First, OC attenuates Aβo induced inflammation and prevents down regulation of important transporters in astrocytes which support neuron function (14). Next, two published papers demonstrated that OC increases the clearance of Aβ from brains of normal mice and mice genetically modified to develop AD, as summarized in Figure 4 by activating two clearance pathways (15, 16).
Figure 4. Buildup of Aβ contributes to Alzheimer’s disease progression, and OC facilitates clearance of this peptide from the brain via activation of two pathways. Adopted from reference 15.
Other published studies also support the claim that OC can inhibit the pathology contributing to AD by altering the assembly state of Aβ1-42. Using a variety of biophysical and biochemical approaches, investigators determined that OC physically altered the oligomeric state of Aβ1-42 and reduced binding to synapses, thus reducing loss of function (17). Finally, it has been published that OC abrogated the fibril formation of a protein called tau which can aggregate in neurons of AD patients disrupting neuron signaling. OC appears to directly bind to the tau protein, which locks it in a physical state preventing fibril formation (18).
These compelling scientific publications suggest that OC could be formulated for the prevention and treatment of AD. Although data exists suggesting EVOO also has anti-Alzheimer’s properties, recommendations are for the consumption of 30 ml which contains 300 calories primarily of fat; it seems unlikely the US population would reduce other portions of their diet by this number of calories. Obesity and the associated health risks remain a huge concern in the developed world.
OC to Treat Cancer
The largest number of publications for new medical uses of oleocanthal can be found in the area of cancer therapeutics. More than 15 papers have appeared since 2011, and half of these are from the laboratory of Dr. Khalid El Sayed at the University of Louisiana in Monroe, Chief Scientist – Medicinal Chemistry for Oleolive LLC. The mechanism of action proposed for OC as a drug for cancer is most likely through multiple targets. In 2017, the El Sayed laboratory published (25) that OC reduced growth of HER2(+) breast cancer tumors in mice by over 95% (therapeutic model used). In a recent unpublished study submitted to Nutrients for publication, this laboratory also demonstrated the remarkable effectiveness of OC in a breast cancer prevention mouse model. Triple negative breast cancer (TNBC) cells were implanted in mice, and one group was left untreated, while the other group received oral OC beginning 14 days prior to tumor cell implantation (prevention model). Figure 5 demonstrates that the treatment group developed tumors at a very slow rate. Oleolive scientists have now demonstrated that OC can act as a preventive and therapeutic compound for TNBC. And are now determining if OC can also prevent recurrence.. Demonstration that OC could prevent recurrence would be important since 50% of women diagnosed with TNBC experience cancer recurrence following tumor resection and only 60% survive the next five years (19).
Figure 5. OC is active in a prevention TNBC model. Treatment numbers are days.
Dr. El Sayed’s laboratory has also demonstrated that OC targets the c-Met receptor (20, 21) which has been strongly implicated in tumor cell invasion, survival and metastasis (spread throughout the body) and resistance to targeted therapies. In fact, his laboratory is developing very specific c-Met inhibitors (patents pending) using OC as the base chemical (22, 23). OC has also been demonstrated to inhibit a protein called mTOR as well as the estrogen receptor (24-26); both proteins are known to play a role in metastatic breast cancer.
Others have found that OC may inhibit the growth and metastasis of melanomas, a form of skin cancer with an often-deadly outcome (27, 28). The papers revealed a number of different cancer-promoting pathways that were impacted by OC. Finally, another group found that OC binds directly to two proteins called HSP70 and HSP90; proteins that contribute to progression of a range of cancers (29). Much remains to be learned yet about the the key targets engaged by OC as an anticancer agent.
The range of indications for use of OC extends beyond the examples described herein. A great deal of research is still needed on this compound, including clinical trials, to determine how extensive its medical impact will be.
Market Size and Growth Potential for OC
Estimates for the growth of the global market for EVOO are very strong through 2023, and sales are predicted to be in excess of $10B annually. This market will be driven by the increase in chronic diseases among aging populations in developed and developing countries. In return, the growing EVOO market will coincide with increased public awareness regarding the health benefits of EVOO-derived OC and other compounds in the prevention of cardiovascular disease, stroke, depression, cancer, arthritis and many other indications waiting to be discovered. Already consumers are shifting towards healthier lifestyles by exercising more and making better choices when it comes to food. As the data on EVOO benefits grows, other markets, such as hair and skin products, will also incorporate more EVOO and EVOO-derived compounds to meet consumer demands for superior products.
Accordingly, the US and other countries will increase production and export of EVOO to meet the rising market demand. Currently the US exports 4% of the total EVOO produced (95% from California), and exports are predicted to rise as olive groves develop in Texas, Florida, Alabama and elsewhere. Significantly, the market introduction of OLIGENTM in a variety of formulations for oral and topical use will open new markets and research areas, and will help to change the consumer preferences for medical-based foods that are preventive in nature.
Where Can You Get OC?
Figure 6. NMR Spectrum of 99% Pure OC
The preceding sections have summarized the tremendous potential health benefits of OC in reducing or preventing a range of human diseases, and yet a relatively small number of studies have been published since the compound’s discovery in 1993. Furthermore, the extent of effectiveness for OC in other human indications remains to be discovered. Why is this? The reason is quite simple: before now there was no known commercial source that supplied pure OC for research and medical applications. To date, OC research has relied on chemical synthesis of OC or isolation methods that are costly in terms of time and materials, resulting in an inability to produce large quantities of OC. This has changed with the patent-pending approach used by Oleolive LLC to purify OC from EVOO with a good yield and high purity. Oleolive uses the highest quality of EVOO as starting material and a purification process that takes less than a day with yields that can be scaled to meet any market need.
The approach used by Oleolive to purify OC is efficient and cost effective, and recoveries are high yielding purities up to 99%. Figure 6 indicates the NMR spectrum for a preparation of 99% pure OC. The process yielding 80% pure OC also includes other minor components that also have been demonstrated to have health benefits (not shown).
Access to purified OC will have many benefits. As mentioned previously, consuming EVOO to gain the health benefits of OC comes with an increased intake of calories. Accordingly, Oleolive LLC is developing an OLIGENTM supplement that will enable reduced-calorie natural OC consumption on a daily basis. OLIGENTM is available for sale to consumers, scientists, medical food companies, pharmaceutical companies and cosmetic and skin care companies. OLIGENTM is available at a purity of 80% or 99%.
Scientists at Oleolive LLC are now working on new applications and formulations for OLIGENTM for the study and treatment of chronic diseases in humans such as psoriasis, cancer and Alzheimer’s. The company management is also aware of the rapidly growing market for treatments for family pets, and research will begin to determine the effectiveness of OLIGENTM in the treatment of diseases common to cats, dogs and other pets.
Recently, a faculty member at the Università degli Studi di Salerno wrote “the state of the art knowledge confirms the benefits of the consumption of EVOO, also suggesting that oleocanthal has the potential to be considered a lead molecule for the improvement of a new class of therapeutic or chemopreventive agents”
(https://aristoleo.com/oleocanthal-secret-olive-oil-no-secret/). Time (and much research) will tell if this prophesy is grounded in reality, but the current literature strongly suggests OLIGENTM will have a solid entry into the world of natural products, nutraceuticals and cosmetics to enhance human health.
Oleolive LLC believes in the potential health benefits of OC and aims to enable further scientific and clinical research validating its effectiveness. As such, Oleolive LLC is also looking to partner with companies and scientists to actively pursue the study and commercialization of OLIGENTM.
CEO, Oleolive LLC
James Cardelli PhD
Alana Gray PhD
Khalid El Sayed PhD
Amal Kaddoumi PhD