Fatty acids

The quality of fatty acids is an important nutritional factor in disease prevention, and it was Keys et al. ⁽Reference Keys, Menotti and Aravanis³⁾ who first proposed that the ratio of MUFA:SFA was the key component for the health benefits of the MD. Then, after the Lyon Diet Heart Study, α-linolenic acid appeared as important for the prevention of post-myocardial infarct death⁽Reference de Lorgeril, Salen and Martin⁵⁾. This was explained by the observation that α-linolenic acid, when present in sufficient amounts, is an efficient precursor of EPA, and it is EPA that is responsible for the observed benefits⁽Reference Mozaffarian, Ascherio and Hu⁶⁾. Thus, long-chain n-3 fatty acids, together with their metabolites (anti-inflammatory leukotrienes), were reported as essential for the prevention of CVD.

More recently, the importance of the SFA carbon chain length was evoked. Whereas C12 to C16 SFA are known to be atherogenic, SFA with a medium carbon chain length (caproic C6, caprylic C8 and capric C10) are directly β-oxidised in the liver and so are less atherogenic. Caprylic acid is also an inhibitor of the apoB⁽Reference Rioux and Legrand⁷⁾. This is relevant to the health benefits of the traditional MD, as these fatty acids are in higher concentrations in goats and sheep – the main sources of meat and milk in the MD – than in cows⁽Reference Hoffman and Gerber⁸⁾.

Phenolics

Due to the rich diversity of plant foods in the MD, there is a high and varied intake of phenolic compounds, including flavonoids and various non-flavonoids such as phenolic acids, stilbenes and lignans. Total polyphenol intake by the Prevención con Dieta Mediterránea (PREDIMED) cohort was recently estimated at 820 (sd 323) mg/d, with coffee, fruits, olive oil and wine being the major sources⁽Reference Tresserra-Rimbau, Medina-Remon and Perez-Jimenez⁹⁾. The importance of phenolics for the cardiovascular benefits of extra virgin olive oil (EVOO) has been shown by comparing olive oils that are high and low in phenolics. For example, olive oil increased HDL-cholesterol level and lowered oxidised LDL-cholesterol level in proportion to the phenolic content of the oil⁽Reference Covas, Nyyssonen and Poulsen¹⁰⁾, and the European Food Safety Authority has now recognised the importance of olive oil polyphenols for protecting LDL particles from oxidative damage. Phenolics in wine may also help protect individuals against CVD by contributing to the overall antioxidant effects of the MD, especially when the body is under conditions of oxidative stress that occurs after a meal⁽Reference Covas, Gambert and Fito¹¹⁾.

Although in vitro studies identified phenolics as direct antioxidants, other more likely in vivo targets are now being identified. These include increasing phase II enzymes in order to eliminate xenobiotics such as carcinogens, by repressing molecules involved in proliferation (such as protein kinase C (PKC), c-Jun and c-Fos), and by inducing apoptosis (caspases). Inhibition by phenolics of the pro-inflammatory transcription factor nuclear factor-κB (NF-κB), the pro-oxidant transcription factor activator protein 1 (AP-1), and activation of the antioxidant transcription factor NFE2-related factor 2 (Nrf2) may be involved in reducing oxidative stress and low-grade chronic inflammation and may contribute to the wide ranging benefits of phenolics against chronic diseases⁽Reference Ma^12, Reference Leonarduzzi, Sottero and Poli¹³⁾. Consumption of polyphenol-rich olive oil as part of a MD has also been shown to decrease the expression of a number of genes associated with oxidative stress and inflammation⁽Reference Konstantinidou, Covas and Munoz-Aguayo¹⁴⁾. Phenolics generally have low bioavailability and low concentrations in the systemic circulation, and this tends to confirm that direct antioxidant activity is not their main mechanism of action in vivo ⁽Reference Hollman, Cassidy and Comte¹⁵⁾.

A group of phenolics known as secoiridoids (such as oleuropein) and their breakdown products (such as hydroxytyrosol) are found almost exclusively in olives and olive oil and so are of particular interest in relation to observations that EVOO may confer specific benefits as part of a MD (discussed below). One recently reported target for EVOO secoiridoids (and also resveratrol in red wine) is activation of the energy-sensing enzyme AMP-activated protein kinase⁽Reference Menendez, Joven and Aragones¹⁶⁾. AMP-activated protein kinase is currently attracting a good deal of attention as it switches on catabolic pathways, such as increased uptake and oxidation of glucose and fatty acids, and this is implicated in decreasing the risk for obesity, type 2 diabetes and some cancers.

More disease-specific mechanisms for phenolics have also been reported including reduced plaque formation by oleuropein aglycone in a mouse model for Alzheimer's disease⁽Reference Grossi, Rigacci and Ambrosini¹⁷⁾ and anti-diabetic and anti-cancer effects by flavonoids⁽Reference Babu, Liu and Gilbert^18, Reference Romagnolo and Selmin¹⁹⁾. Polyphenols in EVOO promote the proteasomal degradation of human epidermal growth factor receptor 2 (HER2)⁽Reference Menendez, Vazquez-Martin and Garcia-Villalba²⁰⁾, although it has not been established if this is associated with beneficial effects in HER2+ breast cancer. Olive oil (both virgin and non-virgin) was also identified as the major dietary source of lignans in the PREDIMED cohort⁽Reference Tresserra-Rimbau, Medina-Remon and Perez-Jimenez⁹⁾. Lignans act as phyto-oestrogens in the body and were reported to be associated with a reduced risk of breast cancer in post-menopausal women, although it is unclear if additional anti-cancer mechanisms may also be involved⁽Reference Buck, Zaineddin and Vrieling²¹⁾.

There is now an increased understanding of how crosstalk between phenolics and other nutrients may contribute to disease prevention⁽Reference Nadtochiy and Redman²²⁾, and this is helping to provide a mechanistic basis for explaining the epidemiological evidence which suggests that it is the overall MD that is most important for its benefits. This is discussed in the next section.

Science: the holistic approach

After the historical studies described above, the Harvard group listed the beneficial foods of the MD and those which were either absent or consumed in moderation⁽Reference Kushi, Lenart and Willett^23, Reference Kushi, Lenart and Willett²⁴⁾. But the health benefits of individual nutrients or foods were never completely convincing; it is the holistic approach that best captures the evidence⁽Reference Gerber²⁵⁾.

Different epidemiological designs can be used in this holistic perspective: DP and intervention studies using a nutritional approach. Two techniques are commonly implemented to study the relationship between DP and diseases. A posteriori analysis is a principal component analysis that defines DP in a population. These analyses are transformed into summary scores that can be analysed by regression analysis in order to examine the risk of a disease related to the identified patterns. This technique gives information on the effects of a MD only if a sample of the population follows this model. In the a priori model, a predefined score is applied to the nutritional data of a population. With regard to the MD, the Mediterranean diet score (MDS) of Trichopoulou first described in 1995⁽Reference Trichopoulou, Kouris-Blazos and Wahlqvist²⁶⁾, and completed and finalised in 2003 by the introduction of fish intake⁽Reference Trichopoulou, Costacou and Bamia²⁷⁾, has been used most often. However, it is apparent that the Trichopoulou score, including the quantitatively and qualitatively typical MD of the elderly Greeks, was until recently only appropriate for Mediterranean populations, because (1) in the Greek situation, the MUFA:SFA ratio reflects mainly the consumption of olive oil, which is not the case for North European countries or the USA; (2) the median defining fruit and vegetable consumption in the elderly Greek population (vegetables ≥ 500 g/d, fruits ≥ 350 g/d) is not commonly attained in North European countries or in the USA and therefore the MDS based on the median consumption of these North European countries or the USA may not show a benefit of MD as it did not reflect the typical quantitative characteristics of the MD. Thus, several modifications have been published that adapt the MDS to diverse populations, and in these cases, the health benefits are generally lower than those observed in Mediterranean countries (for a complete evaluation of DP and MD, see Hoffman & Gerber⁽Reference Hoffman and Gerber²⁸⁾).

A few intervention studies⁽Reference Bos, de Vries and Feskens^29–Reference Vincent-Baudry, Defoort and Gerber³²⁾ have implemented a nutritional approach to study the effects of a MD on markers of risk for CVD, with advice for a MD in the experimental group, and either a high intake of SFA, or a prudent diet or an American Heart Association diet as a control group. However, only PREDIMED⁽Reference Estruch, Ros and Salas-Salvado³¹⁾ had a sample large enough and a follow-up that allowed CVD incidence and mortality to be recorded.

The results of these recent approaches constitute a body of studies with convincing levels of evidence with regard to some health effects, namely all-cause mortality and cardiovascular mortality. They also highlight areas requiring further investigation, such as the specific effects of olive oil.

Health: assessing the evidence

The inference of causality has been a long search for epidemiologists and was initiated by Hill⁽Reference Hill³³⁾. The World Cancer Research Fund⁽³⁴⁾ has established criteria for levels of evidence very close to Hill's proposal, with the improvement of introducing a hierarchy for assessing the validity of the designs of the studies, with intervention studies and prospective studies placed at the top. Meta-analyses are also of value as long as they include evaluation of heterogeneity, sensitivity and linear response analysis. An intervention study conducted on a representative population brings results that are the closest to demonstrating a causal relationship between an exposure and health. Consistent results of several prospective studies conducted in different populations in different countries also provide a strong level of evidence. Thus, the only studies presented here are those for which there is enough data to support a conclusion with a convincing or probable level of evidence for a relationship with the MD.

Mediterranean diet

Results are convincing with regard to the effect of a MD on all-cause mortality as illustrated by the meta-analysis of Sofi et al. ⁽Reference Sofi, Abbate and Gensini³⁵⁾ and further supported by the latest results from the Women's Health Initiative (WHI) study⁽Reference Bertoia, Triche and Michaud³⁶⁾ and the Seguimiento Universidad de Navarra (SUN) study⁽Reference Zazpe, Sanchez-Tainta and Toledo³⁷⁾. Further evidence comes from the Nurses’ Health Study and Health Professionals Follow-Up Study⁽Reference Sofi, Abbate and Gensini³⁵⁾, although these cohorts had CVD at the beginning of the study⁽Reference Lopez-Garcia, Rodriguez-Artalejo and Li³⁸⁾. The risk reduction is always greater in Mediterranean countries (by 20–30 %) and always greater for cardiovascular mortality than for cancers, as shown in Table 2 for studies that have evaluated both all-cause and cause-specific mortalities⁽Reference Trichopoulou, Costacou and Bamia^27, Reference Buckland, Agudo and Travier^39, Reference Knoops, de Groot and Kromhout⁴⁰⁾. Table 2 also shows the remarkable consistency between different studies and populations for the hazard ratio for all-cause mortality and cardiovascular mortality.

Table 2 Association (fully adjusted Cox hazard ratio (HR)) between Mediterranean diet scores and all-cause mortality and cause-specific mortality (Hazard ratios and 95 % confidence intervals)

EPIC, European Prospective Investigation into Cancer and Nutrition; HALE, Healthy Ageing: a Longitudinal study in Europe; MDS, Mediterranean diet score; rMDS, relative Mediterranean diet score.

* CVD.

† Restricted to digestive, breast and prostate.

The PREDIMED intervention study best supports a risk reduction effect of the MD on CVD incidence. It has an interesting peculiarity in that there were two experimental groups: one enriched in nuts and the other enriched in EVOO. The control group consumed a low-fat American Heart Association type diet. Compared with the control group, there was a 28 % (95 % CI 0·54, 0·96) risk reduction in the nut-enriched group and a 30 % (95 % CI 0·54, 0·92) risk reduction in the EVOO-enriched group after 5 years of follow-up⁽Reference Estruch, Ros and Salas-Salvado³¹⁾. Total mortality over 5 years (Kaplan–Meier) gave a hazard ratio of 0·81 (95 % CI 0·63, 1·05; P _trend= 0·11) for the EVOO group and 0·95 (95 % CI 0·73, 1·23; P _trend= 0·68) for the nut group, suggesting an advantage for olive oil consumption⁽Reference Estruch, Ros and Salas-Salvado³¹⁾.

Thus, there is a convincing causal relationship between a DP similar to the traditional MD and overall mortality, and cardiovascular mortality and incidence.

The relationship between type 2 diabetes and the MD has progressed since two early Spanish publications⁽Reference Martinez-Gonzalez, de la Fuente-Arrillaga and Nunez-Cordoba^41, Reference Salas-Salvado, Bullo and Babio⁴²⁾ and is now supported by the latest results of the PREDIMED study⁽Reference Salas-Salvado, Bullo and Estruch⁴³⁾, and by two meta-analyses⁽Reference Koloverou, Esposito and Giugliano^44, Reference Schwingshackl, Missbach and Konig⁴⁵⁾. Both meta-analyses concluded that there was a benefit provided by MD in reducing the development of type 2 diabetes (0·81, 95 % CI 0·73, 0·90 and 0·77, 95 % CI 0·66, 0·89, respectively). Both analyses had significant heterogeneity, which was explained by either differences in the lengths of follow-up: the longer the length, the larger the risk reduction⁽Reference Schwingshackl, Missbach and Konig⁴⁵⁾; or in the health status of the cohort⁽Reference Koloverou, Esposito and Giugliano⁴⁴⁾: studies conducted on a cohort at CVD or diabetes risk showed the highest risk reduction. Both analyses observed that the risk reduction was non-significant in the US studies and significant in European countries, further suggesting greater benefits in Mediterranean countries, and the authors evoked the possible effects of other beneficial factors present in the Mediterranean lifestyle not revealed by the MDS⁽Reference Hoffman and Gerber²⁸⁾.

Thus, the level of evidence for a risk reduction of type 2 diabetes development is probable.

An interesting question remains to be elucidated: Which factors present in Mediterranean countries, in addition to the diet, are responsible for this beneficial effect?

Effects on cancer incidence are more difficult to elucidate since the best data come from observational prospective studies because of practical and ethical difficulties with intervention studies. Moreover, not only is each cancer type related to different etiological factors but even within a class of cancer there are different characteristics with regard to the risk factors, e.g. breast cancers with or without oestrogen receptors (ER). Several studies have found inverse associations between increasing MDS and cancer risk. These include studies that did not include olive oil in the score such as head and neck cancers⁽Reference Li, Park and Wu⁴⁶⁾, hepatocellular carcinoma⁽Reference Turati, Trichopoulos and Polesel⁴⁷⁾ and gastric cancer⁽Reference Praud, Bertuccio and Bosetti⁴⁸⁾ and other studies such as for gastric cancer and bladder cancer in smokers, which were analysed with the relative MDS in which olive oil consumption was assessed⁽Reference Buckland, Agudo and Lujan^49, Reference Buckland, Ros and Roswall⁵⁰⁾. For breast cancer, a risk reduction was observed only when olive oil was present as a single food⁽Reference Bessaoud, Daures and Gerber⁵¹⁾, or using an a posteriori DP including olive oil⁽Reference Cottet, Touvier and Fournier⁵²⁾ or when using a MDS applied to a Mediterranean population⁽Reference Trichopoulou, Bamia and Lagiou⁵³⁾, but not when applied to a non-Mediterranean population⁽Reference Couto, Sandin and Lof⁵⁴⁾.

Thus, it is probable that a MD is inversely associated with some cancers.

As for diabetes, the heterogeneity observed between Mediterranean and non-Mediterranean countries may possibly be explained by factors of the global Mediterranean lifestyle, such as physical activity, high vitamin D synthesis and quality of life, that correlate with the diet in Mediterranean countries.

Olive oil

Although studies are sparse and further studies are required, it is interesting to note that EVOO might have specific effects on some diseases. This is suggested in the PREDIMED intervention study, especially with regard to cardiovascular mortality⁽Reference Estruch, Ros and Salas-Salvado³¹⁾. In a study conducted in Spain, there was a reduction of CVD incidence of 7 % for each increase of 10 g of olive oil intake per 8368 kJ (2000 kcal) ingested, especially with EVOO (risk reduction 14 %)⁽Reference Buckland, Travier and Barricarte⁵⁵⁾. In another study on the same population, an intake ≥ 29·4 g of olive oil/8368 kJ per d compared with < 14·9 g of olive oil/8368 kJ per d decreased the risk of overall mortality by 26 % (P _trend< 0·001) and of CVD deaths by 44 % (P _trend< 001)⁽Reference Buckland, Mayen and Agudo⁵⁶⁾. In the European Prospective Investigation into Cancer and Nutrition (EPIC) Greek cohort, olive oil was associated with a risk reduction of cerebrovascular disease incidence⁽Reference Misirli, Benetou and Lagiou⁵⁷⁾. In the latest report on diabetes and the PREDIMED subcohort⁽Reference Salas-Salvado, Bullo and Estruch⁴³⁾, the group treated with a MD enriched with EVOO had the lowest incidence of diabetes, and a significantly decreased RR compared with the group on the control diet (0·60; 95 % CI 0·43, 0·85). Investigating the effects of olive oil on breast cancer incidence in the Mediterranean cohorts of EPIC, a risk reduction was observed for ER − breast cancers, although the small number of these cancers did not allow for statistical significance⁽Reference Buckland, Travier and Agudo⁵⁸⁾. In the Three Cities Study, olive oil was associated with a decrease in cognitive impairment⁽Reference Berr, Portet and Carriere⁵⁹⁾.

Thus, there is some suggestion for a specific role of olive oil in the MD, but further studies towards understanding the precise effects of olive oil and of its specific phenolics are required.

Public health

For a long time, the high lipid content of the MD has created opposition. Lipids represent 37–38 % of the total energy intake in published studies on the MD, which is slightly above the upper limit of 35 % proposed by the Food and Agriculture Organisation (FAO)⁽⁶⁰⁾, and almost at the limit of 35–40 % proposed by the French Food Safety Agency⁽⁶¹⁾. Indeed, a MD might be a way to reduce the public health problem of obesity as (1) the glycaemic indices of most of foods (whole grain cereals, vegetables and fruits) in the MD are low, and the glycaemic load of the MD is decreased by the structure of the Mediterranean meal; (2) a high MDS reduces the risk of weight gain with increasing age as shown in the longitudinal SUN study⁽Reference Beunza, Toledo and Hu⁶²⁾; (3) a traditional MD is the best diet for maintaining a healthy weight after a regimen of weight loss⁽Reference Schwarzfuchs, Golan and Shai⁶³⁾.

Health economics

Stroke is a frequent event in people at cardiovascular risk and, in addition to the human suffering it causes, it is an increasing burden on health budgets due to the increasing longevity of European populations. In France, the mean cost of treating a stroke is €17 000, and the total cost to France is €5·3 billion. In 2006, annual direct health care costs associated with CHD were estimated at £3·2 billion in the UK, and the overall cost to the UK economy was nearly £9 billion⁽Reference Harland⁶⁴⁾. Increased longevity is also accompanied by an increased risk of other degenerative diseases (such as Parkinson's and Alzheimer's diseases), and some studies have shown a risk reduction for these diseases in people adhering to a MD⁽Reference Samieri, Sun and Townsend^65, Reference Scarmeas, Luchsinger and Schupf⁶⁶⁾. Thus, prevention using a MD will save public money.

Environment

The moderate amounts of meat consumed as part of a MD means less animal-derived greenhouse gas production. Moreover, there is a preference for small ruminants, raised non-intensively, or mono-gastric animals, which produce less methane than beef⁽Reference Gerber, Steinfeld and Henderson⁶⁷⁾. The large variety of fruits and vegetables maintains biodiversity and promotes polyvalent agriculture as part of sustainable and organic agriculture and reduces contaminants. The recommendation for seasonal local consumption is also a factor that favours energy economy by reducing the need to heat greenhouses and the need to transport produce from southern hemisphere countries. Hence, adherence to a MD might help to develop sustainable agriculture.

Concluding remarks

It is important to promote the MD in its entirety to include the benefits of olive oil and to respect variety, diversity and other aspects of the MD such as the structure of the meals and their organisation through the day, and without snacking⁽Reference Tessier and Gerber⁶⁸⁾. And to remember that it is more than just a diet, there is also a Mediterranean lifestyle with physical activity – which is mainly outdoors and good for vitamin D synthesis, and also wine drunk in moderation with meals for gastronomy and conviviality. Because a MD is good for individuals, for public health, for health economics and for the environment, Mediterranean countries should treasure it and should work to promote it through information to the public and professionals, and by spreading knowledge of food quality and cooking practices. And, on a larger scale, this needs initiatives from public health and agricultural policies.