Chapter 18 Olive oil as a functional food: nutritional and ...



Chapter 17 Olive oil as a functional food: nutritional and health benefits

17.1 INTRODUCTION

The purpose of the diet has in the past been viewed as being to supply the nutrients needed for an individual to survive and remain healthy. In recent years, however, it has become clear that, in addition to providing basic nutrients, some foods have beneficial effects which improve physical and mental health and reduce the risk of disease, and this has led to the development of the idea of functional foods. A functional food is defined as a food consumed as part of the normal diet which which promotes health and/or reduces disease risk in addition to supplying nutrients (Roberfroid, 2002). The active components of functional foods may be vitamins, minerals, fatty acids, antioxidants etc which are commonly found in traditional foodstuffs such as fruit, vegetables and whole grains.

The concept of the Mediterranean diet is now well known by the general public as well as health professionals. This diet is believed to be associated with numerous health benefits which lead to increased longevity and the lower incidence of chronic diseases, including cardiovascular disease (CVD), cancer and neurodegenerative conditions (Huang and Sumpio, 2008; Lairon, 2007; Perez-Jiminez et al., 2007). Although the components of the diet vary somewhat between different cultures in the various Mediterranean countries, olive oil is an important common factor, with approximately 90% of world production of olive oil originating in this geographical area (Huang and Sumpio, 2008). Investigation of the contribution of olive oil to the health-promoting effects of the Mediterranean diet has demonstrated that it has a beneficial influence on a wide range of processes and risk factors (Table 1) (Huang and Sumpio, 2008; Lairon, 2007; Serra-Majem et al., 2004), and thus it is recognised as a key element in this respect.

About 85% of the fat content of the Mediterranean diet is provided by olive oil, which contains mostly monounsaturated fat (MUFA) in the form of oleic acid (Huang and Sumpio, 2008; Perez-Jimnez et al. 2007). It has been known for many years that replacing saturated fat (SFA) in the diet by MUFA reduces the risk of heart disease, and more recently a range of other health benefits of MUFA consumption have been discovered (Table 1) (Covas, 2007; Covas et al., 2009). Certain seed oils rich in oleic acid developed by modern technology (Perez-Jimenez et al., 2007) can provide an alternative source of dietary MUFA. However, since virgin olive oil, like fruit juice, is extracted only by pressing the fruit, it has the advantage of retaining a wide variety of potentially beneficial micronutrients, including vitamins, carotenoids, squalene and phenolic compounds, which are lost during the refining of seed oils. These minor components, together with the high content of MUFA, make olive oil the quintessential functional food.

17.2 OLIVE OIL AND THE MEDITERRANEAN DIET

The Mediterranean area is a broad geographical region, bordering the Mediterranean Sea, that has been the settlement of some of the oldest civilizations of the world. Ancient Greeks and Romans created a culinary culture that lasted for centuries, determined by the local availability of specific foods. This culture allows the combination and preparation of available foods in ways that best preserve health. Ancient Greeks used olives instead of meat as their main source of fat, as they believed that animal fat was unhealthy. In contrast, the so-called Barbarians ate more meat and dairy products because they were nomadic and had less opportunity to grow olive trees or to prepare olive oil. The Mediterranean diet is based on products derived from wheat, olives and grapes, these constituting the Mediterranean triad of bread, oil and wine, although it has been suggested that legumes should be added to form a tetrad. Although the types of foods available differ substantially among different regions of the Mediterranean area, even when they are in close proximity, olive oil is the common element, and differentiates this diet from other models. It is noteworthy that in the Italian and Spanish traditional diets, the daily dietary intake of olive oil is approximately 15-20 g, but in the Cretan diet it is much higher , reaching 70 g (Zampelas and Kafatos, 2004).

In the 1950s, it was reported that populations throughout the Mediterranean region have a lower risk of heart disease (Keys et al., 1966;1986). The World Health Organization sponsored the Seven Countries Study, regarding the dietary habits of people from Greece, Italy, Yugoslavia, Holland, Finland, the USA and Japan, that lasted for 30 years, and involved approximately 13,000 subjects. The main finding was that people from the Greek island of Crete had exceptionally low death rates from heart disease, despite their moderate to high intake of fat (Keys et al., 1966), and this was attributed to their diet and lifestyle. When these studies were carried out, the Mediterranean region was an economically depressed area, and most people had a relatively restricted diet and did hard physical work, hence rates of obesity were very low.

The Mediterranean culinary culture, regarded as the Mediterranean diet, is not really a diet as this term is understood in Western countries, but it is rather a dietary pattern. In addition to social, political and economic differences among the Mediterranean countries, the concept of the Mediterranean diet is based on dietary habits more like those of the 1960s than the present day. It typically emphasizes fresh fruits, cooked vegetables and legumes, grains and, in moderation, wine, nuts, fish and dairy products, with large amounts of olive oil.

Virgin olive oil is obtained directly from pressed fruits of the olive tree (Olea europaea) and its consumption can provide anti-atherosclerotic, anti-inflammatory, antithrombotic and antihypertensive vasodilatory effects which are beneficial for cardiovascular health (Esposito et al., 2004; Pérez-Jiménez et al., 2007; Covas, 2007). In contrast to some other refined seed oils, olive oil is a natural juice rich in non-fatty microcomponents of biological significance, such as carotenes, tocopherols, phytosterols, phenolic compounds and terpenic compounds. However, benefits cannot be expected from just adding quantities of olive oil to an unhealthy diet. A high intake of fresh fruit and vegetables has been shown to protect against both heart disease and cancer, and this has been attributed to the antioxidant content of these foods. Tomatoes have received particular attention, because they are an important component of the Mediterranean diet. The major benefits of tomato ingestion are related to lycopene, a lipophilic antioxidant pigment that gives the red color to tomatoes (Kavanaugh et al., 2007). Oily fish are a source of very-long chain n-3 polyunsaturated fatty acids (PUFA), which appear to be particularly beneficial to heart health because of the anti-inflammatory and vasodilatory properties of their metabolites. Nuts are rich in MUFA and PUFA, and have been reported to reduce cardiovascular risk, ameliorate lipid profile and triglyceride levels, and decrease inflammatory adhesion molecules in patients with hypercholesterolemia (Kris-Etherton, 1999; Hu and Willett, 2002). Walnuts are particularly rich in 18:3, n-3 (α-linolenic acid), which is a precursor of very-long chain n-3 PUFA.

Although the Mediterranean diet is still the model for southern Mediterranean populations, many individuals of the northern regions have changed their lifestyle and food habits. Published evidence indicates that there are heterogeneous degrees of adherence to the diet, and this prevents a strict delineation of the influence of gender on the association of its consumption with various morbid conditions. The combination of healthy weight, varied natural and fresh products, physical activities, a relaxed, well ordered life, and a small dose of sunlight – all together – may reduce cardiovascular events, the metabolic syndrome, insulin resistance, diabetes, cancer and other chronic diseases.

17.3 ACTIVE COMPONENTS OF OLIVE OIL

Major components

According to EC Regulation no. 1638/98 OJEC 210 of 28/7/98, virgin olive oils are those obtained from the fruit of the olive tree by mechanical processes or other physical processes, in conditions, especially thermal ones, that do not cause alterations in the oil, which must not receive any treatment other than washing, decantation, centrifugation and filtering. This category does not include oils that have been obtained by using solvents or by a re-esterification process or any other mixture with oils of different characteristics. The oil obtained in this way will be a natural, fresh and aromatic juice with different flavours depending on the climatologic circumstances of each year, the ground of origin, the variety and the treatments and technical cares applied. Virgin olive oils are commonly classified regarding to their organoleptic properties.

Different processing methods produce virgin olive oil, pomace olive oil, or ordinary (common) olive oil. Virgin olive oil is produced by direct pressing or centrifugation of the olive and is considered “extra” when the free acidity, expressed as oleic acid, is lower than 1 gram per 100 grams and organoleptic characteristics (flavour and colour) are excellent. Virgin olive oil has a maximum acidity of 2 grams per 100 grams. Oils below that standard are named “lampante” and need to be submitted to refining and blended with virgin olive oil before being marketed. Virgin and refined oils differ little in their fatty acid composition, but have important differences in minor components.

Olive oil components can be divided into two fractions according to their ability to form soaps when it is treated with a strong base. The saponifiable fraction constitutes 98-99 % of the oil and is composed mainly of triacylglycerolstriglycerides. The minor components are found in the unsaponifiable fraction and, although it constitutes only a small proportion of the total, this fraction confers important biological activities on the oil. The minor components of virgin olive oil, classified in increasing order of polarity are: hydrocarbons, tocopherols, fatty alcohols, triterpenic alcohols, 4-methylesterols, sterols, triterpenic dialcohols, polar-coloured pigments (chlorophylls and pheophitins) and polyphenols.

The MUFA, oleic acid (18:1n-9), is the main component of olive oil. The oleic acid content may range from 55% to 83% depending on the maturation stage, the variety of olive tree and the growing conditions (Boskuo et al., 2000). The palmitic acid (16:0) and linoleic acid (18.2, n-6) content range from 7.5 to 20% and from 3.5% to 21%, respectively. These fatty acids are esterified to form triacylglycerols. According to the fatty acid composition of olive oil, more than 70 molecular species of triacylglycerols are possible, but in fact, only a few major ones are found. The most abundant one is triolein (trioleoyl-glycerol), accounting for about 40-60% of total triacylglycerols, followed by dioleoyl-palmitoyl-glycerol (12-20%) and palmitoyl-oleoyl-linoleoyl-glycerol (5.5-7.0%). Usually, unsaturated fatty acids, like oleic and linoleic acids, are preferently found at the sn-2 position of the triacylglycerol molecule, although because of its high oleate content olive oil contains this acid at all three positions. These features are extremely important for all the processes related to the digestion, absorption, transport and accumulation of olive oil triacylglycerols.

The digestion and absorption of the saponifiable fraction of olive oil, as dietary triacylglycerols, is a dynamic, complex and very efficient process that is only partially understood at the molecular level. The hydrophobicity of lipids is a limiting factor for the digestion because of hydrophilic character of lipases (Konturek et al., 1998). Digestion begins with the formation of an initial emulsion (chyme) to solubilize the oil. Lingual and gastric lipases can hydrolyze partially emulsified triacylglycerols and have a preference for short and medium-chain molecules (Ramirez et al., 2001). The hydrolysis products of these lipases, as well as those of pancreatic lipase, are 1,2- and 2-3-diacylglycerols and free fatty acids. Diacylglycerols are then further hydrolyzed to 2-monoacylglycerols and free fatty acids. The positional distribution of fatty acids in dietary oils determines which fatty acids are absorbed as free fatty acids or 2-monoacylglycerols. The fatty acid at the sn-2 is conserved throughout the absorption and remaining metabolic processes (Renaud et al., 1995). Once in the enterocyte, fatty acids are sequentially transferred to 2-monoacylgycerols by monoacylglycerol-acyltransferases (MGAT) and to diacylglycerols by diacylglycerol-acyltransferases (DGAT) to resynthesize triacylglycerols. These enzymes form a complex called triacylglycerol synthetase (Lehner and Kuksis, 1995).

Minor components

The beneficial effects of olive oil on cardiovascular disease has often only been attributed to its high levels of MUFA. Actually, the Federal Drug Administration of the USA permitted a claim on olive oil labels concerning its benefits on health, on the basis of its oleic acid content (US FDA Press Release). However, olive oil is not merely a MUFA fat, but it contains other minor components with important biological properties (Covas et al., 2006).

The unsaponifiable fraction of olive oil contains highly bioactive compounds that are present in minor concentrations, usually in the range of mg/kg (ppm). It is important to note that only virgin olive oil (and not refined olive oil) contains minor compounds, since most of them are removed as a result of the refining processes (Rastrelli et al., 2002). Among the minor components with a higher biological activity, α-tocopherol (with vitamin E activity) and ß-carotene (which functions as vitamin A) and phenolics (antioxidant activity), have received the greatest attention.

One of the main differences between virgin olive oil and other edible oils is the hydrocarbon composition (Lanzon et al., 1994). The most abundant of these in virgin olive oil is squalene (Guinda et al., 1996), a polyunsaturated triterpene constituted by condensation of six isoprene units. Its concentration varies from 1.2-7.5g kg of oil and it is a precursor in the biosynthesis of cholesterol and steroid hormones. Other olive oil components in this group include carotenes such as β-carotene and lycopene, which are found at amounts lower than 1 mg/kg (Su et al., 2002). β-carotene plays an important role as precursor of vitamin A and lycopene is a potent antioxidant. Both compounds contribute to the yellowish color of the oil. α-Tocopherol, with vitamin E activity, is the most abundant tocopherol in olive oil, although it is found in lower concentrations compared to other seed oils (Herrera and Barbas, 2001). Chlorophylls a and b and their oxidation products, pheophytins a and b, are naturally present in olive oil and are responsible for the greenish color. In virgin olive oil from mature olives, chlorophyll levels vary from about 1 to 10 mg/kg, while those of pheophytins are in the range of 0.2–24 mg/kg (Psomiadou and Tsimidou, 2001).

Phytosterols comprise a major proportion of the unsaponifiables in all vegetable oils, including olive oil. Therefore, the analysis of the sterol fraction is of importance because it not only helps the characterization of the varieties from which the oil has been extracted, but also aids the identification of adulterations, particularly with other MUFA-oils, such as hazelnut oil (Zamora et al., 1994). The phytosterol content varies from one olive oil to another, but is always below 2600 mg/kg. The main sterol found in virgin olive oil is β-sitosterol (about 95%), but there are other species present, like Δ5-avenasterol, campesterol, Δ7-stigmastenol, stigmasterol and campestanol. The β-sitosterol content in virgin olive oil ranges from 683-2600 mg/kg (Benitez-Sánchez et al., 2003).

In 1962, Martel and Gracián isolated a compound in the unsaponifiable fraction of second pressing oil, which was identified as homo-olestranol, now known as erythrodiol, with the structure of a triterpenic dialcohol. The presence of erythrodiol, which in some cases is accompanied by another triterpenic-tetracyclic diol, identified as uvaol, was confirmed employing gas chromatography and mass spectrometry (Akasbi et al., 1993). Both compounds are found in the skin of the fruit in amounts fluctuating between 100 and 120 mg/kg of oil, but in virgin olive oils the concentration of erythrodiol is usually as low as 6-10 mg/kg. Maslinic and oleanolic acids are also pentacyclic triterpenes present in the skin of olive fruits with higher concentrations in olive pomace oil than in virign olive oil. In olive fruits maslinic and oleanolic acids were found at concentrations of 681227 mg/kg and 420356 mg/kg, respectively in the Picual variety (Perez-Camino and Cert, 1999).

Phenolic compounds are rarely determined in routine analysis because of their solubility in water, thus they are the ‘polar fraction’ in virgin olive oil, which explains their absence from both unsaponifiable and glyceridic fractions. Four groups of polyphenols are present in virgin olive oil: simple phenolic acids (homovainillinic, gentisic, p-hydrobenzoic and siringic acids), cinnamic acids (p-cumaric, sinapic and caffeic acids), oleuropein derivatives (hydroxytyrosol and tyrosol) and flavonoids (lutein and apigenin). These substances prevent virgin olive oil autooxidation and underlie its exceptional thermal stability (Gutfinger, 1981; Tsimidou et al., 1992), as well as contributing to its characteristic flavour and taste. The concentration of these phenols in olive oil depends on many factors, including the species, location, climate and maturation of the olives (Kiritsakis and Markakis, 1987), being highest in the first pressed extra virgin olive oil. The most abundant phenolic compounds in virgin olive oil are oleuropein- and ligstroside-aglycones and their derivatives, which are formed during ripening of olive fruits by enzymatic removal of glucose from their respective oleuropein and ligstroside glycosides. Further degradation of the aglycones generates the simple phenolic compounds hydroxytyrosol and tyrosol, respectively (Owen et al., 2000a). Tyrosol, hydroxytyrosol, and their secoiridoid derivatives make up around 90% of the total phenolic content of a virgin olive oil.

After olive oil ingestion, tyrosol and hydroxytyrosol, as well as oleuropein, undergo rapid hydrolysis under gastric conditions, resulting in significant increases in the amount of tyrosol and hydroxytyrosol free forms in the small intestine (Corona et al., 2006). Simple phenols can be absorbed in the intestine, but few data on the phenolic derivatives are available. In the process of crossing epithelial cells of the gastrointestinal tract, phenolic compounds from olive oil are subject to a biotransformation phase. The structure of phenolic derivatives and their transformation into glycosylated and esterified compounds have a major impact on the mechanisms of intestinal absorption. In addition, they are degraded by microorganisms in the colon, which results in an overestimation of the absorbed amount when faecal excretion is measured (Scalbert and Williamson, 2000).

17. 4 OLIVE OIL AND INFLAMMATION

Inflammation occurs as the response of the body to harmful conditions, such as infection by pathogens or tissue injury. Acute inflammation is characterised by a local increase in temperature, reddening of the skin, swelling and pain (hence the name), but is of relatively short duration, and its function is to start the healing process, enabling infections to be eliminated and damaged tissue to be repaired. In contrast, chronic inflammation is associated with long term malfunction of the body’s homeostatic mechanisms which triggers prolonged active inflammation and leads to tissue damage (Medzhitov, 2008). This persistent inflammation has been linked to a number of chronic human diseases, including atherosclerosis, rheumatoid arthritis, asthma and multiple sclerosis. Current evidence for a role for olive oil in reducing inflammatory processes is, in the main, related to atherosclerosis (Perona et al. 2006; Covas, 2007; Covas et al., 2009) although there is some evidence that it may reduce the risk of the development of rheumatoid arthritis (Sales et al. 2009), and a few very recent reports suggest that it is possible that it may also help to protect against asthma (Wood et al., 2010) and multiple sclerosis (Materljan et al., 2009).

The understanding that prolonged inflammation plays an important role in atherosclerosis has evolved over the past two decades. It is now clear that inflammatory processes are involved in the initiation, progression and final stages of the disease which result in cardiovascular events (Libby, 2002; Libby et al. 2002). Risk factors such as hypercholesterolemia, hyperlipidemia and hypertension cause activation of the endothelium leading to the release of inflammatory mediators such as prostaglandin E2 (PGE2) and thromboxane which influence vasoreactivity, and cytokines such as tumour necrosis factor-α (TNF-α) and interleukin (IL)-1β which up-regulate the expression of adhesion molecules, including intracellular (ICAM-1) and vascular (VCAM-1) adhesion molecules and P-and E-selectins. In addition, the secretion of chemoattractants such as leukotriene B4 (LTB4) and the monocyte chemoattractant protein-1 (MCP-1) is stimulated (Perona et at., 2006; Libby et al. 2002).

These changes activate leukocytes and promote their adherence to the endothelium and migration into the artery wall, where they differentiate into macrophages which scavenge lipoproteins, particularly oxidized low density lipoprotein (LDL), which have become trapped in the subendothelial space. The cells become engorged with lipid, forming foam cells, aggregates of which cause fatty streaks, the first visible atherosclerotic lesions (Libby, 2002; Albertini et al. 2002). Activated monocytes and macrophages also contribute to the inflammatory response in several ways; they enhance LDL oxidation by producing reactive oxygen species (ROS); they secrete inflammatory chemokines and cytokines including TNF-α, IL-1β and MCP-1; and they produce IL-6 which stimulates the release by the liver and adipose tissue of C-reactive protein (CRP), an established marker of vascular inflammation, although it appears not to have a direct causal role in atherosclerosis (Covas, 2007; Genest, 2010).

Inflammatory processes contribute to the progression of atherosclerosis via the release of fibrogenic factors which promote the formation of the dense extracellular matrix and fibrous cap seen in advanced lesions (Libby et al., 2002). The final stage of atherosclerosis is rupture of the fibrous cap causing thrombosis and acute myocardial infarction, and inflammation also plays a role here. Activated macrophages produce proteolytic enzymes which can weaken the fibrous cap, and also secrete tissue factor, which triggers coagulation and thromobosis (Libby, 2002; Libby et al., 2002).

A number of studies have shown that consumption of olive oil has anti-inflammatory effects. When food consumption was assessed in 772 participants at high cardiovascular risk, Salas-Salvado et al. (2008) found that subjects with the highest consumption of olive oil and nuts had the lowest plasma levels of VCAM-1, ICAM-1, IL-6 and CRP, and these finding have been supported by several intervention studies in similar types of patients. In a cohort of patients with the metabolic syndrome, subjects following a Mediterranean style diet containing olive oil (n=90) as compared to a control diet (n=90) were found to have lower serum concentrations of CRP, IL-6 and other inflammatory cytokines after two years (Esposito et al. 2004), and three shorter-term studies (1-3 months) with high CVD risk patients (about 900 in total) or hypercholesterolemic men also showed decreased blood levels of ICAM-1, VCAM-1, P-selectin, IL-6 and CRP in subjects consuming a Mediterranean style diet supplemented with virgin olive oil in comparison to a low fat diet (Mena et al. 2009; Estruch et al. 2006; Fuentes et al., 2001). Benefits have also been reported in healthy individuals. Human LDL has been shown to be enriched in oleic acid after olive oil consumption (Tsimikas et al. 1999), and to have reduced ability to induce monocyte chemotaxis and monocyte adhesion to the endothelium (Covas, 2007). In addition, the surface expression of ICAM-1 on peripheral blood mononuclear cells (PBMC) has been reported to be reduced in middle aged men after consumption of an olive oil enriched diet for 2 months (Yaqoob et al. 1998).

Other investigations in humans have focused on the postprandial phase, since postprandial lipemia is known to have inflammatory effects, as genes involved in this response are activated by the pro-oxidative state induced (Perez-Jiminez et al. 2007). In these studies, volunteers are typically given a fat meal containing olive oil or a control fat, sometimes following a short period (1-4 weeks) on a diet with a similar fat composition, and measurements are made up to 9 h postprandially. Decreases in serum concentrations of adhesion molecules, including ICAM-1, VCAM-1 and E-selectin, have been found after a meal containing olive oil, either compared to baseline or to an alternative fat (butter, high palmitic sunflower oil or n-3 PUFA) in several studies with healthy, hypercholesterolemic and hypertriglyceridemic subjects (Bellido et al., 2004; Cortes et al. 2006; Fuentes et al., 2008; Pacheco et al. 2008), although Tousoulis et al. (2010) did not detect any effect on blood ICAM-1 levels. In addition, a meal containing extra virgin olive oil, but not refined olive oil or corn oil, has been demonstrated to cause a significant decrease in blood levels of thromboxane B2 and LTB4 (Bogani et al., 2007). Furthermore, Jiminez-Gomez et al. (2009) have reported that induction of the expression of mRNA for TNF-α in PBMCs isolated postprandially was lower in healthy subjects given a breakfast meal containing olive oil or walnuts as compared to butter, although mRNA expression for IL-6 was higher after the olive oil breakfast than after the walnut test meal. Plasma levels of TNF-α and IL-6, however, were unaffected. It has also been shown nuclear factor-κB (NF-κB), a transcription factor which controls the expression of genes for a number of pro-inflammatory factors, including TNF-α, IL-6 and MCP-1 (deWinther et al., 2005), in monocytes is activated after a meal containing butter or walnuts, while a meal containing olive oil does not cause this effect (Bellido et al., 2004).

In addition to human studies, animal and in vitro work have contributed important evidence for the anti-inflammatory effects of olive oil. In rats, a diet containing 20% olive oil has been reported to decrease natural killer cell activity (Covas, 2007); supplementation of the diet with 10% olive oil reduces lipoprotein oxidative susceptibility in hypercholesterolemic animals (El Seweidy et al., 2005); the production of ROS and PGE2 has been shown to be decreased in neutrophils after feeding 15% olive oil rather than a low fat diet for 2 months (de la Puerta et al. 2004). Moreover, the secretion of inflammatory mediators such as TNF-α, IL-1β, IL-6 and PGE2 by LPS-stimulated murine peritoneal macrophages isolated from mice fed 15-20% olive oil for 8 weeks has been found to be reduced (de la Puerta et al., 2009; Yaqoob and Calder, 1995).

In vitro studies have investigated the modulation of inflammatory processes by oleic acid in cultured human endothelial cells, and reduced levels of intracellular ROS, lowered expression of adhesion molecules, and decreased transcriptional activation of NF-κB on addition of oleic acid to the cultures have been demonstrated, in addition to decreased induction of the expression of VCAM-1 and E-selectin by oxidized LDL isolated from subjects consuming a diet supplemented with olive oil as compared to SFA (Covas, 2007, Perez-Jiminez et al. 2007; Perona et al. 2006). Moreover, monocyte chemotaxis and adhesion to endothelial cells was increased on exposure to liposomes containing linoleic acid, but this effect was almost abolished when linoleic acid was replaced with oleic acid. Another recently reported anti-inflammatory effect of oleic acid is the reversal of the inhibitory effect of TNF-α on insulin production in the rat pancreatic B cell line, INS-1 (Vassiliou et al., 2009).

The anti-inflammatory action of oleic acid has been attributed to its low oxidizability in comparison to linoleic acid, which it is likely to replace in lipoproteins in individuals consuming a diet rich in olive oil (Tsimikas et al., 1999). Lee et al. (1998), however, have demonstrated that increasing the liposome content of oleic acid in the presence of a constant level of linoleic acid decreases the susceptibility of the particles to oxidation, suggesting that oleic acid may also have a direct antioxidant effect. Current evidence suggests that this may occur by suppression of intracellular ROS production and/or by quenching of ROS after their formation (Perona et al., 2006). It is clear from many recent studies, however, that in addition to oleic acid, the minor components of olive oil, including phenolic compounds, and triterpenes, tocopherols and plant sterols which are found in the unsaponifiable fraction, make an important contribution to its anti-inflammatory properties (Covas et al., 2009; Covas, 2007; Perez-Jiminez, 2007; Perona et al., 2006).

Intervention studies in humans have shown that a diet enriched in virgin olive oil as compared to refined olive oil is associated with reduced serum thromboxane B2, LTB4, ICAM-1 and VCAM-1 levels in patients with hyperlipidemic and stable heart disease and also in healthy subjects in the fasting state (Covas, 2007; Fito et al., 2008), and with lowered postprandial plasma concentrations of these inflammatory markers in hypertriacylglycerolemic and normal individuals (Bogani et al., 2007; Pacheco et al., 2007). In addition, in post menopausal women consuming a diet containing virgin olive oil as compared to oleic acid-rich sunflower oil, the production of inflammatory prostaglandins was decreased (Bogani et al. 2007; Covas 2007). Many authors have attributed these effects to phenolic compounds, including oleuropein and its metabolites hydroxytyrosol and tyrosol, since they are abundant in virgin olive oil, but absent after refining. Considerable evidence has accumulated from studies with cell types such as leukocytes and endothelial cells to indicate that these compounds have anti-inflammatory properties via inhibition of LTB4 and cytokine and eicosanoid production and metalloproteinase expression, and via a decrease in monocyte adhesion due to down-regulation of VCAM-1, ICAM-1 and E-selectin expression (Dell’Agli et al., 2010; Zhang et al., 2009; Perona et al., 2006), and that some of these effects may be mediated by suppression of the activation of NF-κB (Dell’Agli et al., 2010; Brunelleschi et al. 2007; Perona et al., 2006). Moreover, a minor component of the olive oil phenolic fraction, oleacanthal (the dialdehydic form of (-)deacetoxy-ligstroside aglycone), has been found to have a similar action to the anti-inflammatory drug, ibuprofen, in inhibiting the activity of cyclooxygenase enzymes, which are involved in the biosynthesis of inflammatory prostglandins (Beauchamp et al., 2005). The idea that phenolic compounds contribute to the anti-inflammatory effects of a diet rich in olive oil is also supported by an intervention study in which diabetic patients showed decreased serum TBX2 levels after consuming olive mill waste rich in hydroxytyrosol for four days (Leger et al., 2005) and by a recently published nutrigenomic study in which consumption of virgin olive oil rather than washed virgin olive oil (which differed only in having a lower phenolic compound content) was found to result in a decrease in the profile of expression of inflammatory genes (Konstantinidou et al. 2010).

Compounds present in the unsaponifiable fraction of virgin olive oil may also contribute to its anti-inflammatory properties. Perona et al. (2006) have demonstrated that the induction of endothelial cell production of inflammatory prostaglandins by postprandial TRLs from healthy subjects was reduced when the virgin olive oil in the test meal was enriched with its unsaponifiable fraction. Potential active components of this fraction include tocopherols (vitamin E), plant sterols, long chain fatty alcohols and triterpenoids. α-Tocopherol and the plant sterol β-sitosterol have been reported to have anti-inflammatory effects (Perona et al., 2006) and the triterpenoid, oleanolic acid, which is present in significant amounts in pomace oil, but not virgin olive oil, has also been shown to suppress prostaglandin production via inhibition of COX-2 and to reduce ROS generation in leukocytes (Simon et al, 1992; Ringbom et al. 1998). In addition, a recent report has suggested that long chain fatty alcohols found in pomace oil reduce inflammatory cytokine and prostaglandin secretion by macrophages and neutrophils (Fernandez-Arche et al. 2009).

Evidence suggests that the Mediterranean diet can reduce pain and stiffness in the joints as well as disease activity in patients with rheumatoid arthritis (Sales et al., 2009). Berbet etal. (2005), have reported that the improvements brought about by a dietary supplement of fish oil are enhanced when used in combination with olive oil, and Linos et al. (1999) found that consumption of olive oil is inversely related to the risk of development of the disease. The components of virgin olive oil that are believed to contribute to these beneficial effects include oleic acid, phenolic compounds and oleocanthal (Sales et al. 2009; Iacono et al., 2010). Asthma is an allergic inflammatory condition characterised by raised eosinophil numbers in the blood and lungs and increased secretion of pro-inflammatory cytokines such as IL-4, IL-5 and IL-13 (Wood et al., 2010). It has been reported recently that a dietary supplement containing olive oil in addition to marine oils reduced the influx of eosinophils into bronchoalveolar lavage fluid (Wood et al., 2010) and that increased consumption of olive oil by the mother during pregnancy decreases wheezing due to asthma in the first year of life (Castro-Rodriguez et al., 2010). Finally, from the results of a recent epidemiological study, Materljan et al. (2009) have suggested that olive oil may protect against inflammation in mutiple sclerosis by inhibiting COX enzymes involved in demyelination, possibly due to the effects of oleocanthal.

17.5 OLIVE OIL AND LONGEVITY

It was first noticed in the 1950s that the population of the Greek island of Crete had long life spans, and it was suggested that this was due to their Mediterranean diet, high in olive oil, fruit and vegetables and fish (Perez-Lopez et al., 2009). More recently, mortality statistics collected by the World Health Organisation (WHO) between 1960 and 1990 also indicated that life expectancy was increased in Mediterranean Countries compared to that in more developed Western Countries, despite the fact that the health care available was poorer and smoking was more prevalent during that period (Trichopoulou & Vasilopoulou, 2000). The first direct evidence for a link between reduced mortality and the Mediterranean diet came from a study by Trichopoulou et al. (1995) which used data from 183 elderly Greeks to show that adherence to the diet was inversely related to overall mortality, and similar results were obtained in subsequent studies in Denmark (Osler and Schroll, 1997), Australia (Kouris-Blazos et al., 1999), the US (Mitrou et al., 2007) Finland, Italy and the Netherlands (Knoops et al., 2004), Spain (Lasheras et al., 2000), and in the European Prospective Investigation into Cancer and Nutrition (EPIC) Elderly Study which covered 9 European countries (Trichopoulou et al., 2005; Bamia et al. 2007), although one study covering 7 European countries found no significant correlation (Haveman-Nies et al., 2002). Adherence to the Mediterranean diet has also been shown to be positively related to lifespan in the EPIC study, with good adherence found to be associated with an increase of 1 year in males aged 60, (although in some countries the association was not significant), and in a metanalysis involving more than 1.5 million subjects, Sofi et al. (2008) found that the risk of early death from all causes was reduced by 9% when a Mediterranean diet was followed.

The increased longevity associated with the Mediterranean diet is mainly due to reduced mortality from cardiovascular disease, cancer, Alzheimer’s disease and Parkinson’s disease (Sofi et al., 2008). Since consumption of olive oil has been found to be beneficial for all these conditions (see Section –18.6, below) and is an major feature of all Mediterranean diets, it has been suggested that it is an important contributory factor to this effect, perhaps because of the many micronutrients that it contains (Perez-Jiminez, 2005; Perez-Lopez et al., 2009). This idea is supported by data from the Italian and Greek cohorts of the EPIC study, which showed that high consumption of olive oil as well as fruit, nuts and vegetables was inversely related to overall mortality (Masala et al., 2007; Trichopoulou et al., 2009). Thus, there is strong and consistent evidence to indicate that adherence to the Mediterranean diet is associated with increased lifespan, and it is highly likely that olive oil is at least partly responsible, however, there are other components of the Mediterranean diet (for example, high intake of fruit and vegetables) which could play a part, and further investigation is needed to establish the mechanisms by which olive oil and/or other constituents of the diet help to extend life.

17.6 OLIVE OIL AND DISEASE RISK

Cardiovascular disease

Cardiovascular disease (CVD), the main forms of which are coronary heart disease (CHD) and stroke, is a major cause of mortality in the Western world, accounting for 30-40% of total deaths per annum (Allender et al., 2008; Lloyd-Jones et al. 2009). Moreover, CHD is the single most common individual cause of death, killing 9-16% of the men who die each year and 9-12% of women. A link between Mediterranean diet and mortality from CHD was first uncovered by the Seven Countries Study . The traditional Cretan diet was found to be associated with the lowest rates of deaths from heart disease (Aravanis et al., 1970), and more recently in the Spanish cohort of the EPIC study, Moreno-Iribas and co-workers (Guallar Castillon et al., 2010) have reported that both the traditional diet as consumed in the Mediterranean region in the 1960s, and the modern version (the evolved Mediterraenan diet, which includes more red meat, saturated fats and simple carbohydrates and less whole grain cereals and legumes), lower the risk of CHD. The Mediterranean diet has also been found to be effective in secondary prevention of CHD in the Lyon Diet Heart Study, which compared the effects of a Mediterranean style diet rich in olive oil with a control diet formulated following the recommendations of the American Heart Association in more than 600 patients who had suffered one myocardial infarction over a period of 4 years. The results showed a very substantial reduction of about 65% in CHD mortality in the subjects given the test diet (de Lorgeril et al., 1999).

The cardioprotective effects of the Mediterranean diet have been linked to olive oil consumption in a 15 year follow up study to the Seven Countries study, showing that the mortality rate of men aged 40-59 from CHD was negatively correlated with the MUFA content of the diet (Keys et al., 1986) and in a Spanish case control study, which found that the olive oil content of the diet was negatively correlated with the risk of a first non fatal myocardial infaction. However, a population-based prospective investigation involving more than 22,000 Greek adults found no significant correlation between consumption of olive oil or other individual food group from the Mediterranean diet, although a higher degree of adherence to the diet was associated with a reduction in overall total mortality (Covas, 2007). Despite this, there is a wealth of evidence to indicate that dietary olive oil has a beneficial influence on a number of contributory causes of myocardial infarction, including atherosclerosis development, hypertension and hemostasis (Covas, 2007; Lopez Miranda et al. 2007; Huang and Sumpio 2008; Covas 2009; Bester et al. 2010), and that these benefits are due not only to the high MUFA content, but also to the many micronutrients present in the oil.

Atherosclerosis development

In addition to its anti-inflammatory effects (see olive oil and inflammation), olive oil and its components help to protect against atherosclerosis development by lowering plasma cholesterol levels and by decreasing the oxidation of LDL.

It has been recognised since the 1950s that raised plasma cholesterol levels contribute to the development of atherosclerosis and, by the mid 1960s, it was clear from the work of Keys and co-workers that this risk factor is modulated by the type of fat consumed in the diet. The initial studies indicated that dietary SFA increases blood cholesterol concentrations, while dietary PUFA has a hypocholesterolemic effect (Keys, 1965). It soon became clear, however, that the increased risk of atherogenesis is associated with cholesterol carried in LDL, while increased levels of cholesterol in HDL are beneficial (Miller, 1985), and in 1985, Mattson and Grundy reported that a diet rich in MUFA (oleic acid) as compared to PUFA (linoleic acid) was as effective in reducing LDL cholesterol in patients and also decreased HDL cholesterol less frequently. Similar results were obtained in later studies, and metanalyses have confirmed that dietary MUFA and PUFA have comparable cholesterol lowering effects (Gardner and Kraemer, 1995; Covas, 2007; Perez-Jiminez, 2007). In addition, postprandial lipemia, which is also a risk factor for atherosclerosis, has been found to be decreased by diets supplemented with MUFA as compared to SFA (Bravo and Botham, 2010). Clearly, therefore, diets rich in olive oil are hypocholesterolemic and thus protect against atherosclerosis.

Although LDL is strongly implicated in the early events in atherosclerosis development, its damaging effects are greatly enhanced by oxidative modification of the particles (Albertini et al. 2002). Oxidative stress results in the increased production of ROS, thus leading to increased LDL oxidation. A number of studies in humans and animals have suggested that consumption of olive oil reduces oxidative stress, and this has been partly attributed to its high oleic acid content. As the single double bond of MUFA makes conjugated diene formation less favourable, oleate-rich LDL would be expected to be more resistant to oxidation than PUFA-rich LDL (Fito and de la Torre, 2007), and dietary supplementation studies have generally supported this view (Bester et al., 2010; Fito et al., 2007). For example, in a recent study with 200 healthy subjects, Cicero et al. (2008) found that supplementation of the diet with 25 ml olive oil/day increased the oleic acid content of LDL, and that this was associated with a reduction in lipid oxidative damage. Other work has also shown that an olive oil- as compared to an SFA-rich diet reduces the uptake of oxidized LDL by macrophages, thus reducing foam cell formation, an early event in atherogenesis. (Moreno et al., 2008).

In addition to MUFA, virgin olive oil contains many minor components with antioxidant properties, and considerable attention has been paid to the potential role of olive oil phenolic compounds in protecting against atherosclerosis. Experiments in vitro and with animal models have supported the idea that they protect LDL from oxidation (Bester et al. 2010; Raederstorff, 2010; Covas, 2007). Moreover, human intervention studies have shown that these compounds reduce the concentration of oxidized LDL and markers of oxidative stress in the blood (Raederstorff, 2010), and in the recent EUROLIVE study, levels of phenols in LDL after consumption of virgin olive oil as compared to refined olive oil were found to be increased and inversely correlated to the degree of LDL oxidation in healthy men (de la Torre-Carbot et al., 2010). Among the individual olive oil phenolic compounds, hydroxytyrosol and oleuropein have been reported to work dose-dependently and synergistically to inhibit LDL oxidation (Bester et al., 2010). There is some evidence to suggest that other minor components of olive oil which have antioxidant properties, including squalene (Covas, 2007; Bester et al., 2010), triterpenoids (Covas, 2007) and plant sterols (Chan et al., 2007), may also help to protect against oxidative stress and atherosclerosis development, but further work is needed to establish their effects.

Hypertension

In hypertension (high blood pressure), systemic arterial blood pressure is chronically raised. The condition is diagnosed when the diastolic blood pressure is > 90mm Hg or when the systolic blood pressure is > 140mm Hg consistently after three or more visits to the doctor. Secondary hypertension, due to diseases of the kidney, heart or endocrine system, accounts for only 5-10% cases, leaving 90-95% as primary hypertension for which no medical cause can be found (Carretero and Oparil, 2000). Hypertension is common in Western countries, with the age and sex-adjusted prevalence being reported to be 28% for North America and 44% for European countries in a study published in 2003 (Wolf-Maier et al, 2003), and is an important risk factor for cardiovascular disease and stroke in particular (Carretero and Oparil, 2000; Wolf-Maier et al., 2003).

Consumption of the Mediterranean diet has been found to be associated with reduced blood pressure in a number of studies (Waterman and Lockwood, 2007; Covas, 2007; Perez-Jiminez et al. 2007; Perez-Lopez et al. 2009). In the Greek cohort of the EPIC study, adherence to the Mediterranean diet and olive oil consumption were inversely related to both systolic and diastolic blood pressure (Psaltopoulou et al, 2004), and high intake of olive oil was also inversely associated with diastolic blood pressure in the Italian (Florence) cohort of the same study (Masala et al., 2008). Systolic blood pressure in patients at high risk for cardiovascular disease has also been shown to be reduced by consumption of a Mediterranean diet enriched with virgin olive oil for 3 months in the PREDIMED study (Barcelo et al., 2009).

Evidence suggests that the effects of olive oil in reducing hypertension are related to both its high MUFA content and its minor components. Diets high in MUFA (almost always from olive oil), as compared to SFA, have been shown to lower blood pressure (Covas, 2007), and Ferrara et al. (2000) have reported that patients given sunflower oil (a rich source of PUFA) in the diet needed more medication to control their hypertension than those given an equivalent amount of olive oil. In hypertensive women, however, virgin olive oil was found to be more effective in reducing blood pressure than high-oleic acid sunflower oil, which has similar MUFA content (Ruiz-Gutierrez et al. 1996; Perona et al, 2004), suggesting that the micronutrients in olive oil also play a part in its beneficial effects on hypertension. This is supported by the finding that systolic blood pressure was decreased after consumption of olive oil with a high, as compared to low, content of phenolic compounds in hypertensive patients with stable CHD (Fito et al., 2005).

The mechanisms by which olive oil reduces blood pressure are not yet understood, but they may involve correction of the structural and functional alterations in erythrocyte membranes which occur in hypertension (Barcelo et al., 2009; Perona et al., 2004) and changes in the fatty acid composition of the aorta (Ferrara et al., 2000). The antioxidant properties of both MUFA and the minor components such as phenolic compounds may also decrease ROS production and increase the availability of NO, leading to improved endothelial function (Covas, 2007, Waterman and Lockwood, 2007; Bester et al., 2010). In addition, studies in normotensive rats have suggested that olive oil may act as a calcium channel agonist (Gilani et al., 2005).

Hemostasis

Hemostasis is the process by which bleeding is stopped after damage to a blood vessel, and in a healthy individual a balance is maintained between the formation of the clot, or thrombus, and its breakdown by fibrinolysis after the injury is healed. In pathological conditions, however, the regulatory mechanisms fail and thrombosis may result. Thrombosis is responsible for a considerable proportion of the morbidity and mortality associated with CVD and is also the second most common cause of death in cancer patients (Furie and Furie, 2008).

Thrombus formation is initiated when coagulation Factor VII binds to Tissue Factor, which along with collagen, is exposed to the blood after damage to the endothelium. Platelets become activated and accumulate at the injury site, initially via binding to von Willebrand factor, and this leads to the conversion of fibrinogen to fibrin via the blood clotting cascade and the formation of thrombin is triggered. The breakdown of the clot, or fibrinolysis, requires the activation of the plasma protein plasminogen to the proteolytic enzyme plasmin by plasminogen activator secreted by the vascular endothelium, and the breakdown process is regulated by the balance between plasminogen activator and plasminogen activator inhibitors (PAI), particularly PAI-1 (Furie and Furie, 2008). A possible beneficial effect of an olive oil-rich Mediterranean diet on hemostasis was reported as early as 1986 (Sirtori et al., 1986). Moreover, it is now thought that there is chronic activation of the mechanisms of thrombosis in subjects at high risk of CVD, creating a ‘prothrombotic environment’. Thus, in the past 25 years there has been considerable interest in exploring the potential to modify this by simple dietary changes. As a result, there is now evidence to indicate that olive oil may improve defences against thrombosis in a number of ways, including inhibiting platelet aggregation, decreasing plasma levels of blood coagulation factors and promoting fibrinolysis (Lopez-Miranda et al. 2007).

Consumption of olive oil, as compared to SFA-rich fats, has been found to be associated with reduced platelet aggregation in a number of studies, and this effect has also been found with other MUFA-rich oils such as high-oleic sunflower oil, suggesting that MUFA is at least partly responsible (Lopez-Miranda et al., 2007). In addition, MUFA, as compared to SFA or carbohydrate-rich diets, have been reported to lower serum levels of von Willebrand factor and TBX2, another promoter of platelet aggregation, although the effects on von Willebrand factor have not been found consistently (Lopez-Miranda et al., 2007). Minor components of olive oil may also be important for its beneficial effects on platelet aggregation. There is good evidence from both human and animal studies to indicate that phenolic compounds, including hydroxytyrosol, oleuropein aglycone, quercitin and luteolin, play a significant part via modulation both of the aggregation process and of serum TBX2 levels (Lopez-Miranda et al., 2007; Dell’Agli et al., 2008; Piora et al., 2008; Gonzalez-Correa et al., 2008; Correa et al., 2009; Cicerale et al., 2010). Additionally, compounds present in the unsaponifiable fraction may also have a role (Perona et al., 2004; Lopez-Miranda et al., 2007), although more work is needed to establish the specific effects and components involved.

The effects of olive oil- and SFA- rich diets on coagulation factors have been compared, but still some controversy remains. Lopez-Miranda et al. (2007) found that an olive oil diet reduced plasma levels of activated Factor VII (FVIIa). However, whereas Junker et al., (2001) reported a reduction of FVII coagulant activity (FVIIc) (and also Factor XIIa, XIIc and Xc) in healthy men after diets rich in olive oil, others have found increments (Sanders et al., 2001). Blood concentrations of FVIIa and FVIIc are known to rise after a fat meal as part of a postprandial procoagulant tendency, whatever the type of fat consumed. Recent work by Delgado-Lista et al. (2008), however, has shown that the increase in FVIIc after a test meal was reduced when healthy men were given a test meal containing MUFA rather than SFA or carbohydrate and n-3 PUFA, and this is consistent with a number of other studies which suggest that olive oil may provide some protection against the postprandial procoagulation environment (Lopez-Miranda et al., 2007).

Although a few studies have suggested that diets rich in olive oil as compared to SFA, are associated with lower basal levels of fibrinogen, this effect has not been shown consistently (Lopez-Miranda et al., 2007). Current evidence, however, does support the idea that consumption of MUFA rather than SFA lowers blood concentrations of PAI-1, which would promote fibrinolysis (Delgado-Lista et al., 2008, Lopez-Miranda et al., 2007), although in this case low fat and PUFA-rich diets are likely to have a similar effect.

Obesity, metabolic syndrome and diabetes

The metabolic syndrome is considered a clustering of metabolic alterations that seems to affect around 25% of the population (Alvarez-Leon et al., 2003; Ford et al., 2004; Athyros et al., 2005). Since Reaven (2005) described the metabolic syndrome for the first time in 1988, diagnostic criteria have been systematically updated by expert groups (World Health Organization, 1999; Alberti et al., 2006) but no general consensus regarding the definition of the metabolic syndrome has been reached.

The lack of a universal definition of the metabolic syndrome hinders the determination of the true global prevalence both locally and internationally. While the clustering of the components that define the different versions of the metabolic syndrome is similar, each place a slightly different emphasis on the metabolic phenotype. The World Health Organization (WHO) criteria focus on risk for diabetes centered around impaired glucose tolerance, (Alberti and Zimmet, 1998). The International Diabetes Federation (IDF) definition focuses on central adiposity, whereas the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel (ATP) III, 2001) assigns no priority to any of the criteria. Therefore, estimates of the prevalence of the metabolic syndrome will depend on the definition used. Using the NCEP definition, the prevalence of the metabolic syndrome is estimated to be 25% of the general population with no gender differences (Ford et al., 2002).

Epidemiological studies suggest that Western-style dietary patterns promote the metabolic syndrome, while diets rich in fruits, vegetables, grains, fish and low-fat dairy products, the paradigm of the Mediterranean diet, have a protective role (Esmaillzadeh et al., 2007; Lutsey et al., 2008). Apart from a cross-sectional study by Alvarez-Leon et al. (2003) which did not find a relationship between the adherence to the Mediterranean Diet pattern and prevalence of metabolic syndrome, studies that have analyzed this relationship support a beneficial effect (Williams et al., 2000). Four feeding trials have assessed the effect of dietary patterns on metabolic syndrome status to date (Esposito et al., 2004; Orchard et al.,2005; Azadbakht et al., 2005; Salas-Salvado et al., 2008). In a cross-sectional substudy of the PREDIMED intervention trial, an inverse relationship between the score of adherence to the Mediterranean Diet and the prevalence of metabolic syndrome of a cohort was observed (Babio et al; 2009). Esposito et al.(2004) showed that at the end of 2 years follow-up, only 44% patients on a Mediterranean diet had features of the metabolic syndrome compared to 87% patients in the control group. It was noteworthy that energy intake was reduced, especially in the Mediterranean Diet intervention group, and substantial weight loss was achieved. However, a high-fat Mediterranean Diet, as traditionally followed in the Mediterranean countries, has only been tested within the PREDIMED study, which compared the effects of two high-fat Mediterranean Diets, supplemented with virgin olive oil (VOO) or mixed nuts, to a low-fat diet in volunteers at high risk for CVD. After 1 year, prevalence of metabolic syndrome was reduced by 6.7 %, 13.7 % and 2.0 % in the MedDiet+VOO, MedDiet+Nuts, and Control diet groups, respectively. However, incident metabolic syndrome rates were not significantly different among groups (22.9 %, 17.9 % and 23.4 %, respectively) (Salas-Salvado et al, 2008).

The prevalence of obesity is one of the greatest public health problems in the industrialized world, and is associated with the rapid adaptation to the current lifestyle, the reduction in physical exercise and the increased consumption of fatty, affordable food. The human genotype has remained unchanged for thousands of years and the increase in the prevalence of obesity is considered to be the result of the interaction between this genotype and the changing lifestyle of the industrialized countries (Neel, 1999). The increase in obesity has arisen not only in the USA (Stunkard, 1996), but also in most European countries, especially those around the Mediterranean basin (Papandreou et al., 2008). Since the Seven Countries Study (Keys et al., 1986), the patterns of the Mediterranean diet have changed substantially. Spain, Italy and Greece have undergone very important changes in lifestyle, eating habits and physical activity, with an increase in the dietary consumption of energy, animal proteins and saturated fats. Obesity increases the risk of diabetes, hypertension, coronary disease and non-alcoholic hepatic steatosis, either independently or within the context of the metabolic syndrome (Kopelman, 2000; Friedman, 2004). Central adiposity, specifically visceral obesity, has been thought to be one of the key factors in the physiopathology of insulin resistance and all the other components of the metabolic syndrome. Several components of the Mediterranean diet have been inversely associated with body mass index (BMI) or waist circumference. This is the case for whole grain and fibre (Liese et al., 2004).

Traditionally, nutritional advice for treating obesity has emphasized reducing all kinds of dietary fat, and replacing them with carbohydrate. However, there is increasing evidence showing that in Mediterranean countries, restricted energy diets that were relatively high in fat from olive oil may be effective alternatives to the traditional low-fat diet for initial weight loss in obese persons (Schroder et al., 2004). Additionally, usually the Mediterranean diet shows better palatability and compliance, which helps to maintain the weight loss (Shai et al., 2008). In contrast to fast food and unhealthy dietary patterns, which have been consistently associated with a higher risk of weight gain and obesity (Pereira et al., 2005; Bes-Rastrollo et al., 2006), olive oil consumption was associated with a non-significant lower likelihood of weight gain in a large Mediterranean cohort of 7368 individuals, who were followed for a median period of 28.5 months (Bes-Rastrollo et al., 2006). The EPIC study suggested that adhering to the Mediterranean diet was not associated with becoming overweight. Therefore, promoting eating habits consistent with traditional Mediterranean diet patterns may play a useful part in efforts to combat obesity (Mendez et al., 2006). Moreover, the PREDIMED study showed weight loss with high MUFA diets after a 3-month intervention (Estruch et al., 2006), which was attributed to a satiating effect of olive oil intake. In this regard, recent experimental evidence suggests that mobilization of intestinally-derived oleoylethanolamide, a lipid messenger of satiety, is enabled by uptake of dietary oleic acid (Schwartz et al., 2008).

BMI and waist circumference correlate positively with insulin resistance (Parker et al., 1993; Clausen et al., 1996). Actually, waist circumference has been singled out as the most important risk factor in the new IDF definition of the metabolic syndrome. Insulin resistance is one of the key contributors to the metabolic syndrome and the development of type-2 diabetes.

There is little evidence that low-fat, high-carbohydrate diets can really improve insulin sensitivity (Reaven, 2005). In developed countries, low-fat diets are usually rich in refined carbohydrates, which increase plasma glucose and insulin concentrations. The quality of dietary fat seems to be determinant in the effect of diet on insulin sensitivity. Diets high in saturated fatty acids (SFA) consistently impair both insulin sensitivity and blood lipids, while substituting carbohydrates or MUFA for SFA reverts these abnormalities in both healthy (Salas et al., 1999; Vessby et al., 2001) and diabetic cohorts (Parillo et al., 1992). Postprandial lipemia and glucose homeostasis are also improved after meals containing MUFA from olive oil compared to meals rich in SFA (Paniagua et al., 2007).

Back in 1988, a study in patients with type-2 diabetes mellitus demonstrated that a high fat, MUFA-enriched diet (33% of total energy) resulted in lower insulin requirements and lower plasma glucose concentrations compared to a low-fat (25% total energy), high-carbohydrate diet (60% total energy) (Garg et al., 1988). However, subsequent studies failed to show positive effects of dietary MUFA on fasting insulin in diabetics (Garg, 1998). Olive oil, as a single component of the Mediterranean diet, has been studied in less detail. In a cross-sectional study in the South of Spain, levels of insulin resistance were found to be lower in people who used olive oil than in those who used sunflower oil (Soriguer et al., 2004). The sectional Pizarra study showed that dietary MUFA from olive oil and PUFA contributed to the variability of β-cell function (Rojo-Martinez et al., 2006). Ryan et al. (2000) examined the relationship between changes in membrane fatty acid composition and glucose transport and found a reduction in insulin resistance when a linoleic acid-rich diet was changed to oleic acid-rich diet. This was attributed to a reduction in its fluidity when the membrane was enriched in oleic acid.

After a comprehensive review, Ros (2003) concluded that natural foods and olive oil as the main source of MUFA provided a similar degree of glycemic control. Nevertheless, high-MUFA diets generally had more favorable effects on proatherogenic alterations associated with the diabetic status, such as dyslipidemia, postprandial lipemia, small LDL, lipoprotein oxidation, inflammation, thrombosis, and endothelial dysfunction. Of particular interest was the ability of an olive oil-rich Mediterranean diet to improve mild systemic inflammation in subjects with metabolic syndrome in the study of Esposito et al. (2004) and in the PREDIMED study (Estruch et al., 2006).

The role of minor components has not yet been sufficiently addressed. Phenolic compounds are important in regard to insulin resistance and the metabolic syndrome as they inhibit LDL cholesterol oxidation, platelet aggregation and thromboxane production, they stimulate anti-inflammatory components and increase nitric oxide production (Serra-Majem et al., 2003).

Alzheimer’s disease and Parkinson’s disease

Most age-related diseases have been associated with low-grade inflammation triggered and sustained by oxidative stress. Results from animal studies suggest that MUFA-enriched membranes are more resistant to oxidation, protecting the aged cell, mitochondrial structure and DNA stability (Bello et al., 2006; Quiles et al., 2006). In the last decade, a number of studies have investigated the relationship between adherence to the Mediterranean diet and the development of Alzheimer’s and Parkinson's disease. In a meta-analysis of 12 prospective studies by Sofi et al. (2008), a two-point increase in a score of Mediterranean diet adherence was associated with a significant reduction in the incidence of these conditions.

Alzheimer’s disease, the most common form of dementia, is a neurogenerative disease causing cognitive and memory decline, usually in elderly individuals, which is progressive and ultimately fatal (Sofi et al., 2010). Its incidence is increasing in developed countries, but currently there is no cure and little preventative treatment available. In recent years, however, evidence has begun to emerge which suggest that modifying lifestyle factors such as the diet may be effective in delaying the onset of the disease and retarding its progression (Pasinetti & Eberstein, 2008). Consumption of the Mediterranean diet has been shown to be associated with slower cognitive decline and a reduced risk of mild cognitive impairment and subsequent progression to the full disease (Feart et al. 2010).

There is evidence to suggest that olive oil may contribute to the beneficial effects of the Mediterranean diet on Alzheimer’s disease development. High intake of MUFA, mainly from olive oil, has been identified as being inversely related to cognitive decline in an elderly Italian population, and this effect was particularly marked in people with a low educational level (Lopez Miranda et al., 2010; Del Parigi et al., 2006; Solfrizzi et al., 1999). In addition, a recent study by Berr et al. (2009), which followed the olive oil intake and cognitive ability of nearly 7,000 elderly subjects, found that moderate (used for cooking or as a dressing) or intensive (used for both) consumption as compared to no use of the oil was associated with lower risk of decline in verbal fluency and visual memory. It has been suggested that MUFA may help to maintain neuronal membrane structure and increase the fluidity of synaptosomal membranes, and thus aid neuronal transmission (Lopez Miranda et al., 2010).

The brain has a low level of endogenous antioxidants and is, therefore, particularly susceptible to oxidative damage, and oxidative stress is thought to have an important role in the development of Alzheimer’s disease (Darvesh et al., 2010; Ramesh et al., 2010). For this reason, there is considerable interest in the possible role of dietary antioxidants as a potential therapeutic approach. Plant polyphenols have been the most widely studied, and compounds found in tea, red wine and grape seed extract have been shown to have beneficial effects on neurodegeneration (Ramesh et al., 2010). Moreover, it has been reported in two recent studies that oleocanthal, a minor component of the polyphenol fraction of virgin olive oil, may protect against neurodegeneration (Li et al., 2009; Pitt et al., 2009). No studies to date have specifically addressed the effects of the major olive oil polyphenols on Alzheimer’s disease, but the relatively high content of these compounds and other antioxidants in virgin olive oil may be a factor in its reported effects in reducing cognitive decline (Berr et al., 2009).

Parkinson's disease is one of the most common age-related neurodegenerative disorders and is characterized clinically by resting tremor, rigidity, bradykinesia, and postural instability. Dietary fatty acids have been studied in association with disease risk, but the results have been inconsistent (Logroscino et al., 1996; Anderson et al., 1999; Chen et al., 2003; de Lau et al., 2005). Omega-3 PUFA have been suggested to be neuroprotective in rat models of the disease (Delattre et al. 2010). In addition, the Rotterdam Study evaluated the association between intake of unsaturated fatty acids (by dietary assessment) and its incidence. After a 6-year follow-up, intakes of total fat, MUFA and PUFA were associated with a lower risk (de Lau et al., 2005). However, a case-control study carried out in Japan, involving 249 cases of Parkinson’s disease, no decrease in risk was found with consumption of total fat, SFA, MUFA and alln-6 and n-3 PUFA (Miyake et al., 2010) .

Gao et al., (2007) examined the associations between dietary patterns, including the Mediterranean diet, and risk of Parkinson's disease in the Health Professionals Follow-Up Study and the Nurses' Health Study. Compared to Western diets, a “healthy diet” rich in fruit, vegetables, and fish with a low intake of saturated fat and a moderate intake of alcohol was inversely associated with that risk. In spite of this result and that the effect of olive oil was not specifically addressed in those studies, in these cohorts, the intake of vitamin E and carotenoids was not associated with a reduction in the risk of Parkinson's disease (Zhang et al., 2002). However, a subsequent meta-analysis of observational studies investigating the effect of vitamin C, vitamin E, and beta-carotene intake on the risk of the disease found a neuroprotective effect of vitamin E (Etminan, 2005).

Cancer

A high number of cancers in humans are induced by carcinogenic factors present in our environment, including our food. Actually, it is estimated that about one-third of all cancer deaths are related to dietary factors and reduced physical activity. The incidence of all kinds of cancer in Mediterranean countries is lower than in the rest of Europe and the United States. This is mostly accounted for by the lower incidence of large bowel, breast, endometrial, and prostate cancers, which have been linked to dietary factors, particularly low consumption of vegetables and fruit, and to a certain extent, high consumption of meat. Additionally, epidemiological data suggest an inverse correlation between regular consumption of olive oil and cancer risk (Levi et al., 1999; Calza et al., 2001). This hypothesis has been supported by animal studies that showed a protective effect of olive oil against the UV induced damage of the skin (Budiyanto et al., 2000) and its ability in preventing the colon crypts aberrant foci growth and colon carcinoma in rats (Bartoli et al., 2000).

It has been estimated that up to 25% of colorectal, 15% of breast and 10% of prostate, pancreas and endometrial cancers could be prevented by shifting to a healthy Mediterranean diet (Trichopoulou et al., 2000). Long-term consumption of olive oil, but not n-6 PUFA, has been reported to be associated with decreased risk of breast cancer (Martin-Moreno et al., 1994; Trichopoulou, 1995, Hunter et al., 1996; Holmes, 1999), but there are also contradictory results showing no beneficial effects derived from olive oil intake (Yu et al., 1990; Gaard et al., 1995). All efforts to achieve a relationship between dietary fatty acids and colorectal cancer, however, have failed. A combined analysis of 13 case-control studies indicated that there was essentially no association of intake of total, saturated, monounsaturated or polyunsaturated fats with the risk of colorectal cancer (Howe et al., 1997).

In contrast, a series of epidemiological studies conducted in Italy indicate that there is an inverse relation of breast and ovarian cancer risk with the intake of olive oil, but not of butter or margarine (Lipworth et al., 1997; Bosetti 2002). However, the most consistent evidence for a favorable role of olive oil came for upper digestive and respiratory tract cancers. High intake of olive oil has been associated with significantly lowered risk of pharyngeal, laryngeal and oesophageal cancer compared to seed oils, margarine and butter (Franceschi et al., 1999; Bosetti et al., 2000;2002), but no association with colorectal cancer risk was found in these studies (Galeone et al., 2007). Nevertheless, it is likely that the observed associations with olive oil are not only due to its specific components, but to the fact that higher consumption of olive oil is an indicator of healthier dietary habits, with a more frequent consumption of vegetables, and possibly of other beneficial lifestyle factors.

The beneficial effect of olive oil against cancer has been attributed to its antioxidant properties, due to the presence of oleic acid and minor components with biological activity, such as vitamin E, sterols, and polyphenols (Owen et al., 2000b). Carcinogens present in our diet can damage DNA directly by forming covalent adducts with DNA, or indirectly after being activated from inactive procarcinogens or via their induction of ROS production. Other carcinogens are not genotoxic, but stimulate cell proliferation, thus increasing the probability of spontaneous occurrence of errors during DNA replication. Phenolic compounds can directly scavenge radical species by acting as chain-breaking antioxidants and suppress lipid peroxidation by recycling other antioxidants, such as α-tocopherol, by donating a hydrogen atom to the tocopherol molecule. However, there is little experimental evidence indicating a potential role of virgin olive oil phenolics against cancer (Ragione et al., 2000; Babich and Visioli, 2003). β-sitosterol may be protective against breast cancer cells, as it has been shown to inhibit tumor cell invasion and cell growth by 70% compared with controls (Awad et al., 2001). α-Tocopherol has also been shown to inhibit the growth of human prostate and colon cancer cells by 86% in androgen-independent prostate cancer cell line DU-145, 74% in the androgen-dependent prostate cancer cell line LNCaP and 64% in human colon adenocarcinoma (Caco-2) cells compared to control (Gysin et al., 2000).

In the search for antitumor promoters from natural sources, the anticancer effects of pentacyclic triterpenes from olive oil have drawn attention (Hsu et al., 1997; Ukiya et al., 2002). Triterpenic acids are potent inducers of apoptosis in human colon (Juan et al., 2006; Reyes et al., 2006) and brain cancer cells (Martin et al., 2007). In human HT-29 colon cancer cells, oleanolic acid showed moderate antiproliferative activity, and moderate cytotoxicity at high concentrations (≥250 μmol/l). In contrast to maslinic acid, oleanolic acid, which lacks a hydroxyl group at the carbon 2 position, failed to activate caspase-3 as a prime apoptosis protease. Completion Induction of apoptosis by maslinic acid was confirmed microscopically by the increase in plasma membrane permeability, and detection of DNA fragmentation (Juan et al., 2008). Astrocytomas are among the most common and aggressive type of primary malignant tumors in the neurological system which lack effective treatments. In the human 1321N1 astrocytoma cell line, the triterpenic diols, erythrodiol and uvaol, effectively modulated cell proliferation and the apoptotic response, promoting nuclear condensation and fragmentation. At the molecular level, changes in the expression of surface proteins associated with adhesion or death processes were also observed. Moreover, triterpene exposure correlated with the activation of c-Jun N-terminal kinases (JNK) (Martin et al., 2009).

Most of the aforementioned effects may be associated with reduced ROS production. ROS concentrations are lower when dietary n-6 PUFA are replaced by virgin olive oil and in turn, there is a decrease in the level of exocyclic DNA adducts (Weisburger, 1997; Hong et al., 2000; Owen et al., 2000c).

17.7 SUMMARY AND CONCLUSIONS

The Mediterranean diet is believed to be associated with numerous health benefits, with the consequence of increased longevity and lower incidence of chronic diseases, including cardiovascular disease, cancer and neurodegenerative conditions. Olive oil has a crucial role in these health-promoting effects, but its benefits are due not only to its high MUFA content, but also to the many micronutrients present in the oil, which makes it the quintessential functional food. However, although the traditional Mediterranean diet is still the model for southern Mediterranean populations, in recent years many individuals of the northern regions have changed their lifestyle and food habits.

Consumption of olive oil has anti-inflammatory effects by lowering plasma levels of cytokines and adhesion molecules and by reducing the induction of monocyte adhesion to the endothelium. In addition to its anti-inflammatory properties, it helps to protect against cardiovascular disease by reducing plasma cholesterol levels, protecting against the oxidation of LDL, lowering blood pressure and attenuating platelet aggregation. In addition, there is increasing evidence showing that in Mediterranean countries, diets relatively high in fat from olive oil may be effective alternatives to the traditional low-fat diet for initial weight loss in obese persons, which is attributed to a satiating effect of olive oil intake.

The mechanisms by which olive oil exerts its health promoting effects are not yet fully understood, but it is now clear that the MUFA content alone is not sufficient and that minor components must also be considered. However, the role of these minor constituents has not yet been addressed in detail. Phenolic compounds have been the most widely investigated, and it is now known that they can inhibit LDL cholesterol oxidation, platelet aggregation and thromboxane production, and that they stimulate anti-inflammatory components and increase nitric oxide production. However, there is still a great deal of work to do regarding the components of the unsaponifiable fraction of olive oil. These include compounds such as phytosterols and tocopherols, which apart from their well-known hypocholesterolemic and antioxidant effects, respectively, have also been shown to be active against inflammation. Another group of components that are receiving attention lately are terpenoids, encompassing acids and alcohols, which are found in low concentrations in olive oil. It has been claimed that these components may have not only anti-inflammatory properties, but can be also beneficial against blood pressure and carcinogenesis.

Further investigations of the properties of the multitude of minor compounds found in olive oil, therefore, is likely help to explain not only some of the classic beneficial effects of the Mediterranean diet, but also some of the more recently discovered effects on the pathophysiology of atherosclerosis, metabolic syndrome, diabetes, cancer and neurodegenerative disorders .

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Table 1: Health benefits of olive oil

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|Benefit |Diseases affected |Active components |Recent reviews |

|_____________________ |_____________________ |___________________ |______________________ |

|Lower cardiovascular mortality |Atherosclerosis, CVD |MUFA, phenolic compounds |Covas et al., 2009; Lairon, 2007 |

|Improved blood lipid profile |Atherosclerosis |MUFA |Covas et al., 2009; Huang and Sumpio, |

| | | |2008; Covas, 2007; Perez-Jiminez et al.,|

| | | |2007 |

|Reduced blood pressure |Hypertension, CVD, particularly |MUFA, phenolic compounds |Covas, 2007; Perez-Jiminez et al., 2007 |

| |stroke | | |

|Reduced inflammation |Atherosclerosis, rheumatoid |MUFA, phenolic compounds, |Covas et al., 2009; Sales et al. 2009; |

| |arthritis, asthma |oleuropein, oleocanthal, |Covas, 2007; Perez-Jiminez et al.,2007; |

| | |α-tocopherol, β-sitosterol, |Perona et al., 2006 |

| | |oleanolic acid | |

|Reduced oxidative damage |Atherosclerosis, CVD, NAFLD, NASH, |MUFA, phenolic compounds, |Bester et al., 2010; Raederstorff, 2010;|

| |cancer |α-tocopherol |Assy et al., 2009; Fito & de la Torre, |

| | | |2007 |

|Reduced haemostasis |Thrombosis, CVD |MUFA, phenolic compounds |Huang and Sumpio, 2008; Covas, 2007; |

| | | |Lopez Miranda et al. 2007; Perez-Jiminez|

| | | |et al., 2007 |

|Reduced risk of neurodegenerative |Alzheimer’s disease, Parkinson’s |MUFA, phenolic compounds |Lopez Miranda et al., 2010; Del Parigi |

|diseases |disease | |et al. 2006 |

|Reduced cancer risk |breast, ovarian, colorectal, prostate|MUFA, squalene |Bosetti et al., 2009; Waterman & |

| |and upper aero-digestive tract | |Lockwood, 2007; Escrich et al., |

| |cancers | |2007 |

|Increased life span |CVD, cancer, neurodegenerative | |Perez-Lopez et al., 2009; Perez-Jiminez,|

| |diseases | |2005; Trichopoulou & Vasilopoulou, 2000 |

____________________________________________________________________________________________

Table 2

Anti-inflammatory effects of olive oil

_______________________________________________________________________________________

|Effect |Types of study |Active ingredients |References |

|Reduced levels/ expression of |Epidemiological |Oleic acid |Mena et al. 2009; Fito et al., 2008; Fuentes |

|adhesion molecules |Human intervention, including |Phenolic compounds |et al., 2001, 2008; Pacheco et al., 2008; |

| |postprandial | |Salas-Salvado et al., 2008; Cortes et al., |

| |Cultured human endothelial cells | |2006; Bellido et al., 2004; Esposito et al., |

| | | |2004; Yaqoob et al. 1998 |

|Decreased plasma levels of |Human intervention, including |Oleic acid |Fito et al., 2008; Bogani et al., 2007; Leger |

|inflammatory cytokines, |postprandial |Phenolic compounds |et al., 2005 |

|prostaglandins and leukotrienes | |Hydroxytyrosol | |

|Decreased production of inflammatory |Human intervention, including |Oleic acid |Dell’Agli et al. 2010; Fernandez-Arche etal., |

|cytokines, prostaglandins and |postprandial, coupled with isolated or |Phenolic compounds |2009; Jiminez-Gomez et al., 2009; Zhang et |

|leukotrienes by vascular cells |cultured cells in vitro |Long chain fatty alcohols |al.,2009; Perona et al., 2006; De la Puerta et|

| | | |al., 2004; Yaqoob and Calder, 1995 |

|Decreased plasma C-reactive protein |Epidemiological |Not identified |Mena et al., 2009; Salas-Salvado et al., 2008;|

| |Human intervention | |Estruch et al. 2006; Esposito et al., 2004; |

|Reduced monocyte activation/migration|Human postprandial |Oleic acid, |Covas, 2007; Perona et al., 2006; Bellido et |

| |Cultured cells in vitro |Phenolic compounds |al., 2004 |

|Decreased ROS production |Endothelial cells in vitro |Oleic acid, Oleuropein, |Covas, 2007; De la Puerta et al., 2004; Perona|

| | |hydroxytyrosol |et al., 2006; Simon et al., 1992 |

| | |Oleanolic acid | |

|Inhibition of COX-2 |Cultured cells in vitro |Oleocanthal |Beauchamp et al, 2005; Ringbom et al.,1998 |

|activity/expression | |Oleanolic acid | |

|Decreased NF-κB activation |Human postprandial |Oleic acid |Dell’Agli et al., 2010; Brunelleschi et al., |

| |Cultured human endothelial cells |Phenolic compounds |2007; Covas, 2007; Perona et al., 2006; |

| | | |Bellido et al., 2004 |

Table 3. Diagnostic criteria for the metabolic syndrome

|Marker |WHO |EGIR |NCEP |IDF |AHA |

| | | |(ATP III) | | |

|Insulin Resistance |Positive |Positive | | | |

|Fasting Plasma Glucose |≥6.1 |≥6.1 |≥6.1 |≥5.6 or treatment |≥5.6 or treatment |

|(mmol/L) | | | | | |

|Obesity |WHR>0.9 men |≥94 men |≥102 men |≥94 men |≥120 men |

|(Waist, cm) |WHR>0.85 women |≥80 women |≥88 women |≥80 women |≥88 women |

|Obesity |>30 | | | | |

|(BMI, kg/cm2) | | | | | |

|Blood pressure |≥140/90 |≥140/90 or |≥130/85 |≥130/85or treatment |≥130/85 or treatment |

|SBP/DBP (mmHg) | |treatment | | | |

|Triacylglycerols |≥1.7 |≥2.0 or treatment |≥1.7 |≥1.7 or treatment |≥1.7 or treatment |

|(mmol/L) | | | | | |

|HDL-cholesterol | ................
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