Nutraceutical Properties of Extra-Virgin Olive Oil: A Natural Remedy for Age-Related Disease?

Introduction

In recent years, researchers have been focused on the identification of functional food or nutraceuticals, which have been suggested to have an important effect in extending life span and, in general, improving health. The term “nutraceutical,” coined by Stephen DeFelice in 1989, specifies a new generation of bioactive compounds of natural origin with effects on health. In particular, “nutraceuticals must not only supplement the diet but should also aid in the prevention and/or treatment of disease and/or disorder” and “are represented for use as a conventional food or as the sole item of meal or diet.” ¹

Many studies show a higher life expectancy in Mediterranean populations in comparision with others countries of northern Europe. Meta-analysises of prospective cohort studies demonstrate that the adherence to a Mediterranean diet can significantly decrease the risk of mortality from cardiovascular diseases (CVD), incidence of Parkinson and Alzheimer diseases, and the incidence of mortality from cancer. ² In particular, epidemiologic evidence shows that the Mediterranean diet mainly reduces the incidence of coronary heart disease. ³

The Mediterranean diet is an eating pattern characterizing a lifestyle and culture that has been reported to contribute to better health and quality of life in the Mediterranean countries. It is traditionally characterized by plant foods (fruit, vegetables, legumes, wholemeal bread, and other forms of cereals, nuts, and seeds), fresh fruit, olive oil, dairy products (principally cheese and yogurt), and poultry consumed in low to moderate amounts (fish only by coast inhabitants), zero to four eggs consumed weekly, red meat consumed in very low amounts, and wine consumed in low to moderate amounts, normally with meals. Given that within Mediterranean countries cultural and religious differences exist that bring about diversity in food patterns, today the concept of “Mediterranean diets” is more commonly applied than that of a specific one. However, these diets prevail in the olive tree–growing areas in the countries of the Mediterranean basin, hence they are characterized by the use of olive oil as the principal source of fat. ⁴

In particular, extra-virgin olive oil (EVOO) is thought to promote good health and longevity. ⁵ Extracted from olive fruits of Olea europea, EVOO is described as having a free acidity, expressed as oleic acid, of not more than 0.8 grams/100 grams and a peroxide value of less than 20 milliequivalents of oxygen. It must be produced entirely by mechanical means without the use of any solvents and under temperatures that will not degrade the oil (less than 30°C). ⁶ It is composed of monounsaturated fatty acids, mainly oleic acid, that reduce low-density lipoprotein cholesterol (LDL-C) levels in comparison with saturated fats. Olive oil also contains carotenoids, sterols, lycopene, and hydrophilic phenolics (oleuropein, oleocanthal, hydroxytyrosol, and tyrosol), which represent the most abundant family of bioactive EVOO compounds. ⁷ The mechanical process for the olive oil production, cold-press, preserves both the chemical nature of the oil and the natural anti-oxidants that the olive tree produces in response to environmental stress. ⁸ These substances have been suggested to have the ability to modulate aging-related processes. Indeed, it is well established that the pathophisiology of common age-related disease such as cancer, CVD, arthritis, and neurodegenerative disease are associated with chronic inflammation and oxidative stress. ⁹ In experimental models, it has been shown that EVOO with high concentration of polyphenols has anti-inflammatory and anti-oxidant properties. ¹⁰

Olive Oil phenolic Compounds: Anti-Oxidant and Anti-Inflammatory Properties

To date, more of 36 phenolic compounds have been identified in EVOO in different concentrations and compositions (0.02–600 mg/kg), depending on the variety, the growing region, the agricultural techniques, the maturity at harvest, and the processing of the olive fruit. ¹¹ These compounds are bioavailable and are thus absorbed, metabolized, distributed, and eliminated. In the case of poor absorption, it has been suggested that these compounds may exert local anti-oxidant activity in the gastrointestinal tract for their free-radical scavenging capacity. ¹²

It is well known that an excess of free radicals can cause oxidative damage to biomolecules (lipids and DNA), increasing the risk of developing numerous chronic diseases. ¹³ For example, LDL oxidation is considered a major risk factor for the development of atherosclerosis and cardiovascular disesase because it induces plaque formation within the arterial wall.

In vivo, three mechanistic studies have further shown that EVOO phenolic compounds are able to bind to LDL and this may increase resistance to oxidation; oleuropein is a radical scavenger that blocks the LDL oxidation. ^{14 –16} Other studies have shown beneficial effects of olive oil phenolic compounds on other markers of oxidative stress. In human subjects, the intake of a phenols-enriched (400 mg/kg) olive oil significantly lowered F₂-isoprostane levels, compared to an olive oil poor in phenolic compounds (80 mg/kg). F₂-isoprostanes are producted consequently by a peroxidation of arachidonic acid, a common membrane constituent. Phenol-rich EVOO modulates the balance between gluthathione and gluthathione reductase and increases the amount of gluthathione peroxidase in erythrocytes with a beneficial effects. ^17,18

In vivo and in vitro research has suggested that the dietary intake of EVOO with high polyphenols content may attenuate inflammatory response and therefore reduce the risk of chronic inflammatory diseases. ^{19 –21} In vitro, oleocanthal as well as hydroxytyrosol, have been shown to have ibuprofen-like activity. Indeed, they inhibit the cyclooxygenases 1 and 2 (COX-1 and 2), responsible for prostaglandin production, in a dose-dependent manner. ^22,23

This compound has potent pharmacological actions in attenuating inflammatory mediators such as inducible nitric oxide synthase (iNOS), which plays a role in the pathogenesis of degenerative diseases. ²⁴ Oleocanthal seems also to possess anti-proliferatory effects in human breast and prostate cancer cell lines ²⁵ ; moreover, it promotes cell apoptosis by activating caspase-3 and induces fragmentation of DNA in HT-29 cells derived from human colon adenocarcinoma. ²⁶

Furthermore, the inhibition of the nuclear factor-κB (NF-κB) pathway activation by polyphenols could explain part of anti-inflammatory properties of EVOO. NF-κB induces the expression of a wide variety of genes active in inflammation that include pro-inflammatory cytokines, enzymes (iNOS), adhesion molecules, and acute-phase proteins. Thus, NF-κB is a suitable target to prevent or reduce an inflammatory response. A group of research has studied the effects of some polyphenols on NF-κB activation using human intestinal Caco-2 cells. Data indicate that some of the tested polyphenols were able to modulate this pathway by reducing the levels of the inhibitor-kB phosphorylated; by inhibiting the NF-κB induction initiated by the cytokines and lipopolysaccharide; and by reducing the secretion of the pro-inflammatory cytokine interleukin-8. ²⁷

Nutrigenomic Effects of Virgin Olive Oil Polyphenols

Nutrigenomics is a new field in the “omics” sciences and for this reason represents a specialized branch of post-genomics personalized medicine focusing on the interaction between food and the genome with an implication for both promoting health and preventing disease. Together with proteomics, nutrigenomics offers an advantage for understanding the interactions between the nutrients and protein translation, expression, and modification on the scale of the human proteome, as well as the role of hereditary factors in relation to food effects. ²⁸

At present, few data exist regarding the in vivo effect of the Mediterranean diet on human gene expression. Some of the gene expression-mediated mechanisms underlying the beneficial health effects of particular components of olive oil in humans have been already examined in vitro and in animal models. It has been shown that olive oil polyphenols inhibit the transcription factor cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) phosphorylation, resulting in downstream reduction in COX-2 expression. ²⁹ These findings, obtained in cell culture or in animal models, are relevant for the knowledge of the relation between dietary components and gene expression, but are limited by the use of doses higher than those ingested in the human diet. The identification of peripheral blood mononuclear cells genes responding to EVOO consumption offers insight into the biological molecular mechanisms underlying the benefits of EVOO on human health, particularly in prevention against age-related diseases. Accordingly, an altered expression of genes related to atherosclerosis development and progression has been demonstrated after 3 weeks of nutritional intervention with EVOO supplementation. ²¹

Conclusions

Due to the relevance of olive oil in the economy of Sicily, our group has been funded to assess the nutraceutical properties of different kinds of EVOO. Indeed, the aim of the study is to evaluate effects of EVOOs, with low (L-EVOO) and high (H-EVOO) polyphenols content, on the immuno-inflammatory and oxidative stress responses in young and old people. Moreover, we will evaluate the expression of genes encoding proteins that take part in insulin/insulin-like growth factor-1 (IGF-1) signaling pathway, i.e., IGF-1, IGF-1 receptor, forkhead box O (FOXO) 3A, and sirtuin 1. Indeed, many gene mutations, in particular single-nucleotide polymorphisms, associated with longevity or with increased life span were identified in gene-encoded proteins that take part in this metabolic pathway, as clearly demonstrated by our recent meta-analysis. ³⁰ Due to a key role of FOXO3A in attaining healthy longevity, because it acts as transcription factor activating the expression of many homeostatic genes, we want to investigate the putative action, in vivo and in vitro, of EVOO on expression of this gene. The results of the study will be useful for producing olive oil enriched in nutraceutical properties that will likely be helpful in the prevention of age-related diseases.