Keywords

1 Introduction

In a number of studies, the Mediterranean diet (MD) has been connected with longevity and a reduced risk of morbidity and mortality. Life-style factors, such as regular physical activity, a healthy diet, and the existing social cohesion in southern European countries have been recognized as candidate protective elements which may explain the Mediterranean paradox. The term MD was coined in the 1960s by Ancel Keys within the framework of the Seven Countries Study. This epidemiological study with more than 12,000 individuals reported that Italian and Greek populations had lower mortality rates, and a reduced incidence of cancer and cardiovascular disease (CVD), compared to those from other European countries, America, and Asia [1]. Such findings led to an exponential increase from 1999 of original articles regarding the MD [2]. High adherence to this diet pattern has been associated with a reduction in the risk of suffering CVD and cerebrovascular diseases, diabetes mellitus, metabolic syndrome, certain cancers, and neurodegenerative diseases [3]. The link between adherence to the MD and a reduction in total mortality has also been confirmed [4, 5].

In general, the MD is characterized by (1) a high intake of cereals, vegetables including leafy greens, legumes, nuts, and fruit; (2) a moderate intake of poultry, fish, eggs, milk and dairy products, as well as a regular but moderate ethanol consumption (generally in the form of wine during meals); and (3) a low intake of red and processed meat and industrial confectionary [4,5,6,7]. Along with some other traits of the Mediterranean diet, the use of olive oil (OO), as the main source of fat (especially dressings), is common in southern European countries. A relatively high fat consumption (up to 40% of total energy intake), mostly from monounsaturated fatty acids (MUFAs) (up to 20% of total energy consumption) is characteristic of this diet [8]. In the Mediterranean area, it is estimated that subjects consume between 25 and 50 mL of OO per day (raw and that used for cooking). Nevertheless, its consumption varies around the Mediterranean countries.

The health benefits of consuming OO have been known since antiquity and were traditionally attributed to its high MUFA content, mainly oleic acid. In this regard, a recent meta-analysis of 32 cohort studies with the aim of studying MUFA (of both plant and animal origin), oleic acid, MUFA/saturated fatty acid (SFA) ratio, and OO intake, indicated that, when comparing the upper to the lower tertile of consumption, OO, but not MUFA, was associated with a reduced risk of all-cause mortality, CVD events, and stroke [9]. Thus, the extra constituents of OO may also have a protective potential [10,11,12].

2 Cancer

Cancer is a multifactorial disease in which several aberrant processes are involved (deregulation of cell cycle, abnormal expression of pro-oncogenes, deregulated angiogenesis, excessive oxidative stress, chronic inflammatory responses, etc.). Several lifestyle factors such as smoking, unhealthy eating, and sedentary habit can increase the predisposition to develop cancer. Thirty to 40% of all cancers could be prevented by appropriate diets, physical activity practice, and maintenance of appropriate body weight [13]. Traditionally, a high consumption of fruit and vegetables has been inversely related to chronic degenerative diseases such as cancer [13, 14]. In the EPIC study, fiber intake from cereals, fruit, and vegetables showed a protective effect on colorectal cancer, and fruit consumption was also associated with lower rates of lung cancer [15]. Among the Mediterranean countries, meta-analyses of ecological and cohort studies found that cancer morbidity and mortality are lower than in other ones [16]. A high adherence to the MD, in which OO is the main source of fat, has been associated with reduced mortality for all type of cancers in prospective studies [5]. Around 25% of colorectal cancer incidence, 15% of breast cancer, and 10% of prostate, pancreas, and endometrial cancer could be prevented by a TMD in the Western countries [17]. Recently, a 4.8-year adherence to a traditional MD (supplemented with virgin olive oil (VOO) or nuts) was found to protect against breast cancer development in an elderly women [18]. In contrast, in Mediterranean cohorts within the framework of the EPIC Study, OO consumption was not linked to lower breast cancer risk in postmenopausal women. Nevertheless, an inverse association between OO intake and the levels of estrogens and progesterone receptor-negative tumors was suggested [19]. Also within the EPIC Study, the adherence to an MD was associated with a decrease in the incidence of gastric adenocarcinoma [20]. In this respect, the antimicrobial activity conferred by OO against Helicobacter pylori (a microorganism related to gastric ulcers and subsequent carcinomas) could play a role in such an observation [21]. Finally, in Caucasian populations in the Mediterranean basin, prostate cancer incidence is lower than that in Caucasian males from other areas. The richness of MUFAs versus SFAs in the MD pattern has been postulated as a possible explanation [22].

With reference to OO, an inverse association between its intake and the appearance of different types of cancers has been described mainly from case-control studies [23]. In this respect, a meta-analysis of case-control studies assessing the effects of OO and MUFA intake was performed (N = 19, 13,800 cancer patients and 23,340 controls). Subjects in the group with the highest OO consumption presented lower odds of suffering any type of cancer (logOR = −0.41; CI: [−0.53, −0.29]). Considering different cancer origins, the meta-analysis showed that high OO intake is linked to a lesser probability of having cancer of the digestive tract (logOR = −0.36; CI: [−0.50, −0.21]) and breast cancer (logOR = −0.45; CI: [−0.78, −0.12]) [24].

In a clinical trial, patients with advanced cancer received a dietary intervention rich in oleic acid and Gc protein-derived macrophage activating factor (GcMAF) which can inhibit cancer cell proliferation. The diet, which was low in carbohydrates, rich in proteins, fermented milk products (which contains naturally-produced GcMAF), Vitamin D3, and omega-3 fatty acids, enhanced the immune system, and a 25% reduction in tumor volume was observed [25].

3 Neurodegenerative Diseases

Chronic inflammatory status, together with oxidative stress, affects neuron functionality. Oxidation and inflammation processes promote the deposition of a number of proteins inside neurons, consequently, the correct function of the mitochondria becomes impaired. When these processes are perpetuated over a long period of time, the development of several neurodegenerative diseases can occur. In particular, Alzheimer’s disease, which is one of the greatest challenges of any national health system, given the population aging. As there is no curative treatment to date, preventive strategies based on a healthy aging are being promoted. A number of epidemiological studies suggests that several nutrients (such as antioxidants, E and B-vitamins, and polyunsaturated fatty acids) [26], and foods (such as fish, vegetables, fruit, and wine) [27] may decline cognitive impairment, including Alzheimer’s disease [28]. As oxidative stress can play a role in the development of neurodegenerative diseases [29], the intake of phenolic compounds (PCs), with a considerable spectra of bioactivities in vitro and in vivo, has been proposed for their management [30].

Given the association between cardiovascular risk factors and neurodegenerative ones, the cardiovascular health benefits of the MD can also confer protection against neurodegenerative disorders [31]. While diets rich in saturated fats and simple carbohydrates are linked to neurodegenerative diseases [32], the MD is able to enhance cognitive function. An association between MD adherence and delay in cognitive decline was observed in elderly subjects in a prospective cohort study in France [6]. Moreover, in elderly individuals at high cardiovascular risk following the MD, better cognitive efficiency [28] and performance were reported [33]. The majority of these studies have been performed in the Mediterranean areas; nevertheless, other projects have been conducted in non-Mediterranean countries which suggest that the healthy benefits of an MD can be transferred to other populations. In this respect, greater adherence to the MD pattern was linked to a reduced risk of Alzheimer’s disease with approximately 2000 subjects in New York [7].

The reduced vascular comorbidities observed with an MD, together with its richness in compounds with antioxidant and anti-inflammatory effects, can play a role in central nervous system benefits [34,35,36]. In this regard, VOO, one of the key foods of the MD pattern, has been linked to improved cognitive function due to its relevant bioactive compounds [28]. Hydroxytyrosol, oleuropein, and especially oleuropein aglycon have been shown to inhibit Tau aggregation in vitro [37].

4 Diabetes Mellitus

4.1 Type-II Diabetes and Impaired Glucose Tolerance

Impaired glucose tolerance is defined as high blood glucose levels after eating, whereas impaired fasting glucose is defined as high blood glucose after a period of fasting. People with impaired glucose tolerance are at high risk of developing DM2. Unsurprisingly, impaired glucose tolerance shares many characteristics with DM2 and is associated with obesity, advancing age, and the inability of the body to use the insulin it produces. Not everyone with impaired glucose tolerance goes on to develop DM2 [38]. DM2 is a chronic disease that occurs either when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. Hyperglycemia is a common effect of uncontrolled diabetes and over time leads to serious damage to many of the body's systems, especially the nerves and blood vessels [39]. Some 382 million people worldwide, or 8.3% of adults, are estimated to have diabetes. According to International Diabetes Federation, the causes are still unclear but people with overweight, poor diet, lack of physical activity, and family story of diabetes are at high risk of DM2 [38].

Several studies have found a link between MD and glucose metabolism. The ATTICA study observed that adherence to MD was related to better homoeostasis factors related to fasting glucose (fasting plasma glucose, insulin levels and the insulin resistance index: HOMA) in normoglycemic people [40]. Moreover, PREDIMED study found that a long-term intervention with a high-quality dietary pattern based on traditional MD and rich in EVOO could reduce the incidence of DM2 in older people at high cardiovascular risk. This beneficial effect was mainly due to the overall composition of the dietary pattern and not to calorie restriction, increased physical activity, or weight loss [41]. A couple of meta-analysis [42, 43] also found a significant association between adherence to dietary patterns and decreased risk of DM2. One of the previous meta-analysis specifically concluded that adherence to a MD is associated with a decreased risk of becoming diabetic at a reasonable magnitude (19%) [43]. Other systematic review of eight meta-analyses and five randomized controlled trials studied the effect of MD on the treatment of DM2 and prediabetic states. This review indicated that in DM2 patients, the adherence to MD was associated with lower glycated hemoglobin (HbA1c) levels and improved cardiovascular risk factors, as compared with control diets, mainly lower fat diets [44]. Thus, it is suggested that the Mediterranean diet is not only suitable for prevention but it is also an appropriate dietary pattern for the management of DM2.

Another meta-analysis of prospective cohort studies to assess the association between different diets and prevention of DM2 found that although the diets associated with prevention of DM2 may vary in their composition, nonetheless they shared several common components, including whole grains, fruit, vegetables, nuts, legumes, protein sources such as white meat and seafood, little or moderate alcohol, and reduced intake of red and processed meats and sugar-sweetened beverages, and noteworthy healthy table oils (i.e., olive oil) [45]. MD covers all of the above being one of its emblematic characteristics is the use of olive oil.

One of olive oil’s characteristics is its high content in monounsaturated fatty acids (MUFA). Evidence suggests that diets enriched in MUFAS from OO have a positive effect in glycemic control. A study examining intakes of MUFA through the increased consumption of olive oil found an association with lower fasting plasma glucose concentration [46, 47]. Another cohort study of women found a similar result after a 22 years follow-up. The published results showed that higher olive oil intake was associated with modestly lower risk of DM2 and that hypothetically substituting other types of fats and salad dressings (stick margarine, butter, and mayonnaise) with olive oil was inversely associated with the onset of DM2 [48]. In another cross-sectional study in Spain (Pizarra study), it was found that insulin resistance was significantly lower in people who consumed OO than in those who consumed sunflower oil or a mixture [167].

Furthermore, a randomized trial with two groups of DM2 patients, following a MD using OO or a control low-fat diet presented that the MD with OO can improve endothelial dysfunction, inflammation, and oxidative in DM2 patients compared to a control diet [49]. The PREDIMED trial also provides strong evidence that long-term adherence to a MD supplemented with EVOO, which is high in MUFAS and bioactive polyphenols, results in a substantial reduction in the risk for DM2 among older people with high cardiovascular risk [41].

Oleic acid (cis C18:1 n-9), the predominant MUFA on OO, has been related to a lower insulin resistance as well. A study addressing [50] the relationship between changes in membrane fatty acid composition and glucose transport as an index of insulin sensitivity found a reduction in insulin resistance when a polyunsaturated (linoleic acid; C18:2 n-6) rich diet was changed to an oleic acid (C18:1 n-9) rich diet. This improvement was related to the change in membrane fluidity, as an oleic acid-rich membrane would be less fluid to its linoleic acid-rich equivalent [46]. Similar results were found in another study [51] where changes in membrane fatty acids and signaling proteins induced by VOO consumption in elderly persons with DM2 compared to a control group were analyzed. The long-term consumption of VOO induced changes in the fatty acid content of erythrocyte membranes from elderly DM2 participants. These changes were due to an increase amount of oleic acid in the membranes and in consequence biochemical changes in the amount of signaling proteins (G proteins and protein kinase C). The above could explain the mechanisms of glycemic homeostasis after consumption of olive oil.

In addition to MUFA, extra virgin olive oil contains also other bioactive components, some of them are called the phenolic compounds such as oleuropein and hydroxytyrosol, flavonoids, specially flavones, and lignans. Apart from PREDIMED, other clinical trials have evaluated the effect of EVOO rich in polyphenols on glycemic biomarkers [52]. Daily consumption of polyphenol-rich EVOO (25 mL/day, 577 mg of phenolic compounds/kg) for 8 weeks significantly reduced fasting plasma glucose and HbA1c, as well as other circulating inflammatory adipokines (visfatin), in overweight patients with DM2 [53], in a crossover randomized trial.

Mediterranean-type dietary patterns are known to improve several parameters of the postprandial state with high atherogenic potential, such as the glycemic load and the secretion and clearance of chylomicrons [54]. The consumption of OOPCs has been able to decrease oxidative stress (as observed in several biomarkers related to oxidative modifications of plasma lipids, proteins, and DNA) in healthy volunteers after meals [10] and in long-term interventions [11]. Concretely, a single dose of 25 mL of OO does not promote postprandial oxidative stress whereas doses equal or superior to 40 mL do [10, 55]. In addition, phenolic compounds from OO have been able to modulate postprandial oxidative stress in healthy volunteers [10]. The glycemic load of a meal can depend on the bioavailability of carbohydrates and food preparation. In this regard, in a study with 12 women with obesity and insulin resistance, food fried in VOO improved both insulin and C peptide responses after a meal [56]. VOO may additionally contribute, within the context of a traditional MD, to the long-term improvement of the glycemic load and the dietary glycemic index [57].

In conclusion, there is already widespread experience of the benefits of olive oil in glucose metabolism, both in a medium- and long-term period and in the postprandial phase, in the context of dietary patterns, of olive oil by itself, and the bioactive compounds of olive oil.

5 Cardiovascular Diseases

The development of an atherosclerotic plaque in the endothelium of blood vessels is common to CVDs. The plaque is formed by the accumulation of cholesterol inside the macrophages and other cells, such as the smooth muscle ones, located in the intima media. This generates an inflammatory chronic response that eventually can trigger acute thrombotic vascular disease, including myocardial infarction, stroke, and sudden cardiac death [58]. Atherosclerotic plaques are linked to the coexistence of several processes related to inflammation, lipid oxidation, dysfunction of the vascular endothelium, exacerbated activation of immune cells, and migration of vascular smooth muscle cells, among others [59].

Since Ancel Keys presented the MD as a health protecting one [1], there have been many studies supporting this link [5, 7, 16, 60]. The most impressive benefits of this diet, however, have been related to reductions in cardiovascular morbidity and mortality [61]. In general, countries from southern Europe present the lowest values of accumulated incidence and mortality rate of coronary heart disease [62, 63]. The paradox of the Mediterranean countries with a low incidence rate of cardiovascular disease [64,65,66], in spite of a marked prevalence of classical cardiovascular risk factors [67, 68], is attributed in part to a high degree of adherence to the MD. Nevertheless, most studies were observational so that any causal inference was hindered by residual confounding among other biases. Thus, large-scale randomized trials using dietary patterns, and assessing clinical end-points, are needed to provide a high level of scientific evidence. In this regard, very few randomized trials have been performed. On one hand, the Lyon Diet Heart Study, a secondary prevention trial, showed a large reduction in rates of coronary heart disease events with a modified MD enriched with alpha-linolenic acid [69]. On the other hand, the PREDIMED study, a multicenter, randomization, intervention trial with the MD, reported the protection of the traditional Mediterranean Diet (TMD) on incident CVD in high cardiovascular risk individuals, in primary prevention [70]. In addition, the PREDIMED Study has also provided evidence of the efficacy of the TMD on primary prevention for stroke [70], atrial fibrillation [71], type-2 diabetes (DM2) [72], and peripheral vascular disease [73].

Nowadays, the relevance of overall high-quality diet patterns, rather than focusing on single nutrients and foods, has highlighted the need to address the complexity of dietary exposures. Nevertheless, it is well-known that OO plays a pivotal role in this diet pattern. Data from EPIC cohorts showed an inverse relationship between OO consumption and coronary heart disease mortality and incidence [74,75,76]. Also, results from the Three-City Study reported an inverse relationship between OO consumption and stroke risk in women [77]. Finally, results of the PREDIMED Study showed that consumption of OO, specifically the extra-virgin variety, within the framework of the Mediterranean diet, reduces the risk of CVD and mortality in elderly high cardiovascular risk individuals [78].

It is increasingly accepted that chronic degenerative diseases, such as CVD, cancer, and neurodegenerative ones, share common risk factors. Besides the classical cardiovascular risk factors (diabetes, hypertension, lipid profile, tobacco, and obesity), perpetuated molecular dysregulation with respect to oxidation, low-grade inflammation, LDL atherogenicity, HDL function, and endothelial dysfunction, among others, may be behind their onset.

5.1 Arterial Hypertension and Endothelial Dysfunction

OO has also been linked to an improvement of endothelial dysfunction and blood pressure state. In a meta-analysis of randomized controlled assays (N = 12, with a duration of 6 months or longer) high- versus low-MUFA intake (low MUFA intake was considered a MUFA consumption below 12% of total daily energy consumption) was compared, and MUFA-rich diets decreased systolic (mean effect: −2.26 mmHg; CI: [−4.28, −0.25]; p = 0.03) and diastolic blood pressure (mean effect: −1.15 mmHg; CI: [−1.96, −0.34]; p = 0.005]. In addition, an improvement of the fat mass −1.94 kg, CI: [−3.72, −0.17], p = 0.03] was additionally reported [79]. MUFA intake also has effects on doses of antihypertensive drugs prescribed to patients. A MUFA-rich diet (17.2% of total daily energy intake by MUFAs, 3.8% by PUFAs) was able to decrease blood pressure relative to a polyunsaturated fatty acid (PUFA)-rich one (10.5% of total daily energy intake, 10.5% by PUFAs) and, moreover, decreased the daily dosage of hypertensive agents [80]. A decrease of diastolic blood pressure in hypertensive women was observed after an MD intervention, enriched with VOO or nuts, within the context of the PREDIMED Study [81]. Nitric oxide and endothelin-1 levels, together with endothelin-1 receptor gene expression, could play a role in blood pressure improvement [82].

Regarding OOPCs, in a meta-analysis with 13 studies concerning the effects of high phenolic OO oil on cardiovascular risk factors, medium effects for lowering systolic blood pressure (n = 69; mean effect: −0.52; CI: [−0.77, −0.27]; p<0.01) were described; however, no effects for improving diastolic blood pressure were reported (mean effect: −0.20; CI: [−1.01, 0.62]; p = 0.64) [83].

Endothelial function improved in hypercholesterolemic patients at postprandial state with phenol-rich OOs and OOPC-enriched functional OO intake [84, 85], after a 4-month intervention of a daily intake of VOO in patients with incipient atherosclerosis [86], and after 2 months in women with high-normal blood pressure or stage-1 essential hypertension [87].

Endothelial homeostasis can be disturbed by oxidative stress and chronic inflammatory processes and finally lead to endothelial dysfunction [58]. An increase in nitric oxide metabolites was observed after a phenol-rich OO postprandial intake versus a low-phenolic OO [84]. Also, a decrease in systolic blood pressure after the intake of VOO was described, with a decrease in lipid oxidation markers, in hypertensive stable patients [88]. Finally, in two randomized crossover studies, a 50 mL intake of phenol-rich OO decreased the postprandial leukotriene B4 (a pro-inflammatory eicosanoid) and thromboxane B2 (a vasoconstrictor eicosanoid) levels in comparison to refined OO in healthy [169] and mildly dyslipidemic subjects [89].

5.2 Haemostasis and Platelet Aggregation

Olive oil has been shown to improve the production of coagulation factors and biomarkers linked to platelet aggregation, thus improving the thrombogenetic profile [90].

With regard to monounsaturated fats, a MUFA-rich diet such as the MD decreases postprandial levels of coagulation factor VIIc [91]. In addition, oleic acid (75% of OO fatty acids) attenuates the prothrombotic state in the postprandial phase [91,92,93].

Regarding OOPCs, the consumption of phenol-rich OOs improved the postprandial prothrombotic state (activated coagulation factor VII, tissue factor, tissue plasminogen activator, plasminogen activator inhibitor type-1, and fibrinogen) in a number of randomized controlled trials in both healthy [94] and hypercholesterolemic subjects [90]. In long-term interventions, a decrease in plasma fibrinogen in women with high baseline fibrinogen concentrations has been reported after OO consumption, in a randomized crossover trial [95].

5.3 Lipid Profile

Improved dietary fat quality, achieved through a replacement of SFA by unsaturated fat, enhances the lipid profile by reducing low density lipoprotein (LDL) cholesterol and increasing high-density lipoprotein (HDL) cholesterol [96]. Olive oil intake assures an increase of MUFA, without a significant rise of SFA, and guarantees an appropriate intake of (PUFA). As a consequence, the MUFA/SFA ratio is much higher in areas where an MD is followed [97]. An updated review suggested a small, but potentially relevant, reduction in cardiovascular risk with low saturated fat intake [98]. The replacement of energy from saturated fat with polyunsaturated fat provides more healthy benefits than with carbohydrate. Regarding the substitution of SFAs for MUFAs, although the benefits are more modest, some positive effects on lipid profile have been observed. The reduction of dietary saturated fat, and partial replacement by unsaturated fats, has been proposed to achieve maximum health benefits although the ideal type of unsaturated fat is still unclear [98].

Schwingshackl et al. published a meta-analysis including 32 studies with overweight and obese patients. On one hand, decreases in total cholesterol (weighted mean difference −0.12 mmol/L, 95% CI: [−0.28 to −0.03]; P = 0.01) and LDL cholesterol (−0.08 mmol/L, 95% CI: [−0.12 to −0.04]; P<0.0001) were more marked after low-fat diets. On the other hand, a rise in HDL cholesterol (0.06 mmol/L, 95% CI: [0.03, 0.09]; P<0.0001) and a reduction in triglyceride (−0.095 mmol/L, 95% CI: [−0.15, −0.04]; P = 0.001) were more pronounced after the high-fat diet groups [99].

Regarding OO, in a recent meta-analysis about the effects of PC-rich OO on cardiovascular risk factors, no significant effects in improving lipid profile were observed (total cholesterol N = 400; mean effect: −0.05; CI: [−0.16, 0.05]; p = 0.33); HDL cholesterol (N = 400; mean effect: −0.03; CI: [−0.14, 0.08]; p = 0.62); LDL cholesterol (N = 400; mean effect: −0.03; CI: [−0.15, 0.09]; p = 0.61); and triglycerides (N = 360; mean effect: 0.02; CI: [−0.22, 0.25]; p = 0.90). Nevertheless, the small number of studies (N = 8) is a limitation [83]. Specifically, the beneficial effects of OO polyphenols on blood HDL cholesterol concentrations were evaluated by the European Food Safety Authority (EFSA) and they concluded that evidence was insufficient to establish a cause-effect relationship [100]. A recent review indicated that the intake of PC-rich OO induced no significant increases in HDL cholesterol levels [83], while several high-quality randomized controlled trials have pointed to a dose-dependent increment in HDL cholesterol after the consumption of OOPCs [11, 12, 101].

5.4 Lipid Oxidation

In November 2004, the USA Federal Drug Administration [102] permitted a claim on OO labels regarding “the benefits on the risk of coronary heart disease of taking 2 tablespoons (23 grams) of OO daily, due to monounsaturated fat.” However, if the effect of OO is only attributed to its MUFA content, any type of MUFA-rich food (such as rapeseed oil, canola oil, or MUFA-enriched fats) would provide the same beneficial effects for health. The minor components of OO (1–2% of the total content) are classified in two groups: (1) the unsaponifiable: squalene and other triterpenes, sterols, tocopherol, carotenoids, and pigments and (2) the soluble fraction which includes the PCs [168]. In this respect, the EFSA released a health claim concerning the protection of OOPC (5 mg/day) against LDL oxidation [103]. Based on well-designed intervention trials, a cause-effect relationship was established by the EFSA between the consumption of VOO and the protection of LDL particles from oxidative damage [103].

Not only changes in LDL cholesterol are involved in cardiovascular risk, oxidation modifications of the LDL particle may play a major role in atherosclerosis [58, 104, 105]. Several OO components contribute to decreasing LDL oxidizability. On the one hand, MUFAs are less prone to becoming oxidized when compared to other unsaturated fats [106]. On the other hand, OO antioxidants (vitamin E, carotenoids, and OOPCs) can bind to the LDL particle and protect it from oxidative modifications.

A recent meta-analysis (N = 13) reported that oxidized LDL levels decrease significantly after the consumption of high-phenolic OO (N = 300; mean effect: −0.25; CI: [−0.50, 0.00]; p = 0.05) [83]. In the EUROLIVE Study, 200 volunteers were given 25 mL/day of raw OO with high (366 mg/kg), medium (164 mg/kg), and low (3 mg/kg) phenolic content in a randomized, crossover, and controlled trial [11]. Covas et al. reported a decrease of the in vivo lipid oxidative damage (concretely in oxidized LDL, uninduced conjugated dienes, and hydroxy fatty acids) in a linear manner with the phenolic content of the OO administered [11]. As potential mechanisms to explain this benefit, we could consider an increase in the content of vitamin E and OOPC in LDL that may counteract locally oxidative modifications [107, 108]. In addition, the reductive effect of the OOPC on oxidized LDL could be due to the generation of antibodies [109]. Vázquez-Velasco et al. observed, in healthy volunteers, a decrease in the concentration of oxidized LDL when hydroxytyrosol-enriched sunflower oil (45–50 mg/d) was administered during 3 weeks [110]. In 40 males suffering from stable coronary heart disease, VOO was able to decrease the oxidized LDL in plasma compared with another olive oil with a smaller amount of PC in a randomized crossover trial [88]. Finally, LDL oxidizability has also been evaluated in vitro, and it decreased after the consumption of MUFAs [111, 112] and phenol-rich OOs [11, 101, 113, 114].

Finally, Fitó et al. reported an improvement of circulating oxidized LDL after a 3-month MD intervention in high cardiovascular risk patients [115].

5.5 HDL Functionality

Although low levels of HDL cholesterol are considered an independent cardiovascular risk factor [116], it has been recently observed that presenting high HDL cholesterol levels does not always lead to a decrease in cardiovascular risk [117,118,119]. An increase in HDL cholesterol is one of the goals of clinical management of cardiovascular diseases [117]. In this regard, recent studies have shown that the functionality of HDL can be of greater relevance than its amount [120]. Decreased values of the most relevant HDL function have been reported to be related to a high incidence of subclinical atherosclerosis [121] and coronary events [122].

The functionality of the HDL particle involves the promotion of cholesterol efflux from macrophages and peripheral cells, which constitutes part of the so-called “reverse cholesterol transport” [123]. Furthermore, HDLs play a crucial role in inhibiting the oxidation of plasma lipids (mainly, the ones in LDLs) and also present anti-inflammatory and vasoprotective capacities [124]. Oxidative modifications of the HDL can additionally affect the lipid and/or protein of the lipoprotein and alter its physiological properties [120, 124,125,126] and, in this regard, antioxidants linked to the particle could be able, direct or indirectly, to counteract such oxidation. An increment in HDL fluidity, enhanced HDL composition, and better HDL size distribution could also mediate improvements in HDL function [127,128,129].

Regarding OO, the consumption of a MUFA-rich diet improved the cholesterol efflux capacity of HDLs in a linear trial [130]. This functional improvement could be due to a lower degree of oxidative modifications of the lipoprotein after increasing its MUFA content [131]. Regarding OOPCs, Hernáez et al. reported for the first time an increase in cholesterol efflux after the daily intake of 25 mL of VOO (366 mg/kg) in healthy volunteers within the framework of the EUROLIVE Study [132]. In parallel, biological metabolites of OOPC bound to the HDLs (hydroxytyrosol sulfate, and homovanillic acid sulfate, and glucuronate) were determined. The improvement of HDL fluidity and a triglyceride-poor core can also result in a more functional HDL particle [132]. In this respect, functional VOO supplemented with olive and thyme phenols versus a VOO intervention produced an increase in the lecithin-cholesterol acyl-transferase concentration which esterifies free cholesterol and mediates its migration into the particle core [133]. The consumption of OOPCs has also been shown to be able to increase the levels of the main HDL antioxidant enzyme, paraoxonase-1, as well as HDL anti-inflammatory ability, in a noncontrolled trial [134]. Besides the direct antioxidant effect of OOPCs on HDL particles, these compounds have also been observed to be able to improve the gene expression related to HDL function [135].

Finally, a TMD, especially when supplemented with real-life doses VOO, was able to improve HDL functionality [136]. Concretely, a 1-year intervention with an MD increased cholesterol efflux capacity and, in particular, the VOO-rich MD enhanced nitric oxide synthesis by endothelial cells promoted by HDLs, decreased cholesteryl ester transfer protein activity, and increased HDL ability to esterify cholesterol and paraoxonase-1 arylesterase activity [136].

5.6 Inflammatory Processes and Systemic Oxidative Status

Oxidation and inflammation are intertwined processes which, when sustained for a long period, may induce the onset of a number of chronic degenerative diseases, such as CVD, diabetes, neurodegenerative diseases, and cancer. The increased circulating concentrations of pro-inflammatory analytes (tumor necrosis factor-α, monocyte chemotactic protein-1, soluble vascular cell adhesion molecule 1, and soluble intercellular adhesion molecule-1) perpetuate the inflammatory response in the subendothelial space and establish endothelial dysfunction.

Traditionally, the health benefits of the MD have been attributed to its richness in antioxidants. Among the approximately 230 chemical compounds of OO, the main antioxidants are carotenes and phenolic compounds, including lipophilic and hydrophilic phenols [137]. Current evidence points to oxidative damage as a promoter of pathophysiological processes in oxidative stress-related diseases such as coronary heart disease, cancer, neurodegenerative pathologies, and, in addition, aging [138,139,140]. Although phenolic compounds are good antioxidants in vitro, their in vivo effects can be indirectly mediated through the activation of several nutrigenomic pathways and not only by their intrinsic antioxidant activity [141, 170]. Benefits of olive oil on lipid oxidation have been extensively explained in the Sect. 5.4 apart.

Several benefits on the levels of pro-inflammatory biomarkers have been proven in human trials with OO or MUFA-rich diets. A daily intake of real-life doses of OO has been shown to produce a decrease of the C-reactive protein (mean effect: −0.64 mg/L; CI: [−0.96, −0.31]; p<0.0001) and IL-6 (mean effect: −0.29; CI: [−0.70, −0.02]; p<0.04) in a recent systematic review [43]. Nevertheless, the heterogeneity of design among studies makes further research necessary. With regard to other MUFA-rich diets, a randomized controlled trial with 28 hypertriglyceridemic and 14 healthy males who followed a diet rich in refined OO (high-oleic acid diet) or a diet rich in high-palmitic sunflower oil, revealed a postprandial decrease of the soluble adhesion molecules (VCAM-1, ICAM-1) after the high-oleic intervention [142]. And in another randomized controlled trial, a 2-month MUFA-rich diet decreased the expression by peripheral blood mononuclear cells of ICAM-1 in healthy males [143]. In contrast, a randomized crossover trial in healthy subjects regarding the effect of three Malaysian diets: palm olein, coconut oil, and OO (the fat source providing approximately 20% of total energy intake in each case), the postprandial and 2-week fasting circulating concentrations of a number of inflammatory biomarkers (tumor necrosis factor-α, IL-1β, IL-6, IL-8, CRP, and interferon-γ) were not affected [144].

The consumption of OO, which provides oleic acid as the main fatty acid, also yields a moderate intake of PUFA (mainly omega-6 linoleic acid and omega-3 alpha-linolenic acid) without a noticeable increase in the intake of SFA. Omega-6 fatty acids, in which PUFAs are predominant (especially in the Western diets), are precursors of pro-inflammatory eicosanoids (2-prostaglandins, tromboxanes, and 4-leukotrienes) [145]. In this regard, omega-3 fatty acids in OO may play a role in the inhibition of the inflammatory process boosted by omega-6 fatty acids [146]. It has been reported that a low incidence of coronary heart disease is related to a diet rich in omega-3 fatty acids [147].

The OOPCs have also shown effects on pro-inflammatory biomarkers. Surprisingly, Beauchamp et al. described oleocanthal anti-inflammatory properties that were similar to those of ibuprofen (cyclooxygenase-2 inhibition and nuclear factor kappa beta counteract) [148]. Moreover, the intake of phenol-enriched OO (50 mL/day) decreased C-reactive protein (CRP) levels at postprandial state relative to refined olive or corn oils in healthy individuals, in a randomized controlled trial. In this regard, a regular intake of OO at long term can contribute to controlling the postprandial inflammatory burden [149]. Also, a combined consumption of white wine (2–3 glasses/daily) and extra VOO (ad libitum) for a 2-week period decreased the levels of CRP and IL-6 in both patients with chronic kidney disease and healthy subjects [150]. Finally, a raw real-life daily dose of 50 mL of VOO for 3 weeks decreased the IL-6 and CRP concentrations (versus refined OO) in a randomized controlled trial with stable coronary heart disease patients [151].

Within the context of a traditional MD, supplementation with VOO or nuts decreased the systemic levels of CRP, IL-6, sVCAM1, and sICAM1 in high cardiovascular risk volunteers within the framework of the PREDIMED Study [81]. In addition, the traditional MD (supplemented with VOO or nuts) was able after 3 months of intervention to decrease the expression of CD49d (an adhesion molecule) and CD40 (a pro-inflammatory ligand) in monocytes isolated from the blood of high cardiovascular risk volunteers [152].

The MD participants had lower plasma concentrations of atherosclerosis-related inflammatory markers (IL-6, IL-8, MCP-1, and MIP-1β) after 3 and 5 years of an MD intervention versus a low-fat diet control group. In addition, IL-1β, IL-5, IL-7, IL-12p70, IL-18, TNF-α, IFN-γ, GCSF, GMCSF, and ENA78 decreased especially after an MD supplemented with VOO [153]. Finally, the reduction in CD49d and CD40 expressions in T lymphocytes and monocytes at 3 years were greater in the MD group than in the low-fat diet control one [154].

5.7 Immune System

Regarding MUFAs, they have been reported to modulate a number of biological pathways of immune competent cells [155]. In this regard, in a randomized controlled trial with healthy males, there was a significant decrease in the expression of intercellular adhesion molecule 1 by peripheral blood mononuclear cells after MUFA-rich 2 month-diet. Nevertheless, natural killer cell activity and the proliferation of mitogen-stimulated leukocytes were not affected [143].

The consumption of a functional VOO showed an increase in the proportion of IgA-coated bacteria, which indicates a local stimulation of the intestinal mucosal immunity [156]. Based on the effects of OO intake on the immune system, it has been suggested that OO consumption may have benefits on rheumatoid arthritis [155]. In contrast, other authors have published that OO-rich diets do not alter host resistance to infection [157, 158]. Given that data are scarce, more studies are required to establish the possible immunostimulation of OO in vivo.

5.8 Microbiome

Gut microbiota, a complex and dynamic ecosystem, is an emergent factor of a number of diseases including obesity and type-II diabetes [159]. PCs can selectively stimulate growth bacteria, such as Lactobacillus [160], which can play a role in lowering cholesterol levels [161]. Intestinal lactobacilli produce bile-salt hydrolase, which deconjugates bile acids, prevents their reabsorption, and therefore promotes their fecal excretion [162]. This can be one of the mechanisms involved in the decrease of systemic cholesterol after PC consumption [163]. PCs may also be related to the growth of other bacterial populations (such as Bifidobacterium) which might be linked to a lesser development of the atherosclerotic plaque [164].

Since most PCs are not fully absorbed into the upper gastrointestinal tract and reach the large intestine, they can be metabolized by gut microflora [165]. A 3-week intake of a phenol-enriched VOO (with OO and thyme PCs) increased populations of Bifidobacteria and the levels of microbial metabolites of antioxidant PCs, such as protocatechuic acid and hydroxytyrosol, in hypercholesterolemic individuals [166].

6 Conclusion

In summary, current evidence indicates the potential benefits of olive oil, within the framework of a healthy diet such as the Mediterranean one, on the prevention of chronic degenerative diseases including cardiovascular and degenerative ones. To date, the majority of these effects have been demonstrated from the perspectives of atherosclerosis and cardiovascular risk research. Nevertheless, there is increasing evidence that such beneficial properties also display a protection towards other diseases including neurodegenerative ones and cancer.

The daily diet represents the consumption of a mixture of foods in which the type of cooking plays an indisputable role in the availability and properties of nutrients. Furthermore, synergism among nutrients and foods, and their cumulative effects, must also be taken into consideration. With respect to the Mediterranean diet, olive oil as the main source of fat is determinant with respect to the properties attributed to this dietary pattern.

Olive oil intake facilitates more vegetable consumption and thus benefits on health can be maximized. Nutrient-specific biases and type of olive oil should be considered in order to disentangle the benefits of MUFA and/or other minor components. Further well-designed, large-scale cohort studies in Mediterranean and non-Mediterranean areas are needed to reaffirm the therapeutic properties of olive oil and establish in which subjects and under which conditions benefits can be more easily achieved.