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The Center for Genetics, Nutrition and Health, Washington, DC
2To whom correspondence should be addressed. E-mail: cgnh{at}bellatlantic.net
| ABSTRACT |
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KEY WORDS: diet of Crete (n-3) fatty acids wild plants antioxidants cancer (n-6) fatty acids
| INTRODUCTION |
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10.6 in 19461948 (19
This paper describes the characteristics of the traditional diet of Greece before 1960 as exemplified by the diet of Crete and its relationship to cancer. The diet of Crete or the traditional diet of Greece resembles the Paleolithic diet in terms of fiber, antioxidants, saturated fat, monounsaturated fat and the ratio of (n-6) to (n-3) fatty acids (Table 1)
(21
). The Lyon Heart Study (22
25
) and subsequently the study of Singh et al. (26
,27
) support the importance of having a diet consistent with human evolution. Western diets today deviate from the Paleolithic diet and are associated with high rates of cardiovascular disease, diabetes, obesity and cancer.
| The diet of Crete and its relation to cardiovascular disease and cancer |
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The results of the Seven Countries Study are interesting because they show that the population of Crete had the lowest rates of cardiovascular disease and cancer, followed by the population of Japan (20
). The investigators concluded that the reason for these low rates must be the high olive oil intake and the low saturated fat intake of the Mediterranean diet. The fact that Crete had a high fat diet (37% of energy from fat) and Japan had a low fat diet (11% of energy from fat) was not discussed extensively nor were any other fatty acids considered despite the fact that the people of Crete ate 30 times more fish than did the U.S. population. Furthermore, the people of Crete ate a large amount of vegetables (including wild plants), fruits, nuts and legumes, all rich sources of folate, calcium, glutathione, antioxidants, vitamins E and C and minerals. In addition, because the meat came from animals that grazed rather than being fed grain, it contained (n-3) polyunsaturated fatty acids (PUFA) as did the milk and milk products, such as cheese (Table 2
). The population of Crete eats snails during Lent and throughout the year. Renaud (Serge Renaud, INSERM, Bordeaux, France, personal communication) has shown that the snails of Crete and Greece contain more (n-3) fatty acids and less (n-6) fatty acids than do the snails of France.
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-linolenic acid [LNA, 18:3(n-3); 400 mg/100 g] as well as in vitamin E (12 mg/100 g), vitamin C (27 mg/100 g) and glutathione (1520 mg/100 g) (37
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Renaud et al. (43
) had been working with LNA and had shown that it decreases platelet aggregation. Everything seemed to fall into place in terms of defining the characteristics of the diet of the population of Crete. Their diet was very similar to the Paleolithic diet in composition (Table 1)
. The diet was low in saturated fat, balanced in the essential fatty acids [EFA; (n-6) and (n-3)], very low in trans fatty acids and high in vitamins E and C. This diet formed the basis of the diet used by de Lorgeril and Renaud in their now famous Lyon Heart Study (22
25
). The Lyon Heart Study was a prospective randomized, single-blind secondary prevention trial that compared the effects of a modified Crete diet enriched with LNA with those of a Step I American Heart Association diet. The study showed a decrease in death rate by 70% in the experimental group and clearly showed that a modified Crete diet low in butter and meats such as deli products but high in fish and fruits and vegetables and enriched with LNA is more efficient than the American Heart Association or similar prudent diets in the secondary prevention of coronary events and total deaths (22
). The same subjects were followed for 5 y. At 4 y of follow-up, de Lorgeril et al. (24
) reported that the reduction of risk in the experimental subjects compared with control subjects was 56% (P = 0.03) for total deaths and 61% (P = 0.05) for cancers, indicating that a modified diet of Crete was associated with lower risk for coronary heart disease and cancer.
| Bioprotective nutrients and mechanisms |
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Olive oil is high in the monounsaturated fatty acid oleic acid [18:1, (n-9)] and low in saturated and (n-6) fatty acids; it does not compete with the desaturation and elongation of LNA nor with the incorporation of (n-3) fatty acids into the red cell membrane phospholipids, providing an additional benefit to the functions of (n-3) fatty acids (5
). Furthermore, the (n-6) to (n-3) ratio in the Greek diet is between 2:1 and 1:1, which is very close to the dietary ratio of the Paleolithic diet (Table 1)
. The beneficial effects of such a ratio and their importance in normal growth and development (51
53
) and in the prevention and management of cardiovascular disease, hypertension, diabetes, arthritis and possibly cancer have been reviewed extensively (5
,28
35
,54
57
).
Because Greeks have a cultural dislike for animal fats, the saturated fat intake of the Greek diet is lower than that for other Mediterranean and Western diets (19
). The Greek diet, then, is characterized by being moderate in fat (
35%), low in saturated fat (78%), high in monounsaturated fat and balanced in the (n-6) and (n-3) EFA. The content of antioxidants, phytoestrogens and other phytochemicals is much higher than in other diets of the people around the Mediterranean basin because Greeks continue to eat wild greens that are rich sources of LNA, vitamin C, vitamin E and glutathione (36
38
). The beneficial effects of the various compounds found in the vegetables and fruits eaten by Greeks have been shown to have hypoglycemic, hypocholesterolemic and antitumor properties in animal experiments (44
). Even today, the mortality from breast cancer is lower in Greece than in the United States, Japan and Europe (58
). Finally, the Lyon Heart Study based on the modified diet of Crete described by de Lorgeril et al. (22
25
) clearly showed cardioprotective and anticancer effects in a French population, indicating that such a diet is not only palatable but can be adapted to other populations. Furthermore, one could consider that the traditional diet of Greece even in its present form is the diet that is closer than the diets of other developed countries to the diet on which humans evolved (Fig. 1)
(18
).
| EFA and cancer |
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There are two families of EFA, the (n-6) and (n-3) families. The principal EFA in the U.S. diet is LA, an (n-6) fatty acid. One of the main functions of EFA in the body is as a precursor for eicosanoids, which are mediators of inflammation and cellular growth. EFA are converted to prostaglandins by cyclooxygenases and to leukotrienes (LT) by lipoxygenases. Arachidonic acid [(AA); 20:4(n-6)] and EPA, an (n-3) fatty acid, compete for cyclooxygenases and lipoxygenases, resulting in the production of eicosanoids with opposing effects. In general, AA-derived eicosanoids, such as the 2-series prostanoids and 4-series LT, have proinflammatory effects, whereas EPA-derived eicosanoids, such as the 3-series prostanoids and 5-series LT, have anti-inflammatory effects. There is competition and opposition of EFA in the body; thus research has been conducted to determine the importance of the (n-6) to (n-3) ratio rather than the absolute level of either class of PUFA in cancer prevention (5
,59
).
Animal studies and cell lines.
In animal studies (rats) LA increases the size and number of tumors, whereas fish oil [containing the (n-3) fatty acids EPA and DHA] decreases both (60
,61
). Studies in rats suggest that inhibitors of prostaglandin synthesis, such as indomethacin and flurbiprofen, can inhibit mammary carcinogenesis. The prostaglandin-inhibitory effect of fish oils has been tested in animal tumor systems by many investigators, and the studies provide evidence that at optimal levels, (n-3) fatty acids may be useful as inhibitory agents in some colon, lung, mammary, pancreatic and prostatic tumors in experimental animals, whereas LA supports tumor growth (62
). Studies in cell lines and animals appear to support the epidemiologic evidence concerning the protective role of a ratio of (n-6) to (n-3) of < 2:1 against the development of mammary cancer and to provide evidence that (n-3) fatty acids could have the potential to be used as an adjuvant therapy to prevent recurrence and metastases of mammary cancer (59
).
Epidemiologic studies.
The effects of (n-6) and (n-3) fatty acids on the growth and progression of tumors are different. Epidemiologic studies in humans during the past two decades have demonstrated that the consumption of fish oil protects against the development of cancers, especially mammary cancer (63
). Klein et al. (64
) showed that low LNA levels in mammary adipose tissue were inversely correlated with increased mammary cancer risk in women. In patients with prostate cancer, fish intake was inversely related to cancer (65
).
Mechanisms.
Recent data demonstrated the effectiveness of n-3 EFA in regulating growth, progression, metastasis and postexcision recurrence of mammary tumors in murine models. Furthermore, there is evidence that EFA influence [(n-6) stimulate whereas (n-3) suppress the pathway] the epidermal growth factor receptor/mitogen-activated protein kinase pathway, targeting many of the same components as drugs under development (59
).
The data suggest that the most important aspect of EFA in the prevention of mammary cancer is the ratio of (n-6) to (n-3) fatty acids rather than the absolute concentration of either (59
). Research data indicate that a ratio of 1:1 or 2:1 protects most against the development and growth of mammary cancer. Western diets have a ratio of 1020:1, or 16.74 (17
). Clearly, these data suggest that further research into the usefulness of dietary manipulation of EFA for the prevention or adjuvant treatment of mammary cancer, as well as continued research into the mechanisms of EFA in mammary tumor development, is warranted. Cyclooxygenase-2 is overexpressed in cancer of the colon (66
). Recently, DeCaterina and Habib (R. DeCaterina, G. dAnnunzio University, Chieti, and CNR Institute of Clinical Physiology, Pisa, Italy, & A. Habib, Hopital Lariboisière, Paris, unpublished observations, 2001) showed that DHA down-regulates the expression of cyclooxygenase-2 and induces apoptosis (67
72
).
Dietary supplementation with (n-3) fatty acids in clinical trials.
Dietary supplementation with (n-3) fatty acids has been tested in several clinical trials. In pancreatic cancer, a malignancy associated with a persistent inflammatory response and increased energy expenditure, 3 mo of dietary supplementation with a median of 12 g/d fish oil (EPA 18% and DHA 12%) led to a significant median weight gain of 0.3 kg/mo, accompanied by a temporary but significant reduction in acute-phase protein production and by stabilization of resting energy expenditure (73
). Gogos et al. (74
) randomly assigned 60 patients with generalized solid tumors to dietary supplementation with either fish oil or placebo daily until death. The (n-3) fatty acids had an impressive immunomodulating effect, as reflected by the ratio of T-helper cells to T-suppressor cells in the subgroup of malnourished patients. There were no significant differences in cytokine production among the various groups. In addition, (n-3) fatty acids prolonged the survival of all patients (74
). These stimulating results warrant further clinical trials to establish the exact benefits and limitations of (n-3) fatty acid supplementation in cancer patients.
Selenium.
A randomized clinical trial in the United States showed that selenium supplementation (200 µg/d) decreased the incidence of prostate, lung and colorectal cancer over a mean follow-up of 4.5 y (75
). An inverse association was reported between advanced prostate cancer and toenail selenium concentrations, a surrogate of long-term selenium intake (76
). The Greek diet, rich in marine products, provides adequate amounts of selenium. Octopus, the Greek national appetizer, contains 90 µg selenium/100 g. In both the Lyon study and the U.S. selenium trials, the benefits in terms of cancer became apparent within 34 y. In animal models, selenium has been shown to interfere with carcinogenesis through several possible mechanisms (77
).
Resveratrol.
Resveratrol (3,4',5-trihydroxystilbene) is a naturally occurring polyphenolic phytoalexin found in wine and medicinal plants of the Polygonum species (Polygonaceae). Resveratrol inhibits lipogenesis from palmitate in the liver and adipose tissue (78
), inhibits the formation of lipoxygenase products (LTB4 and LTC4) and inhibits AA platelet aggregation (79
81
). Resveratrol and its derivatives have been further shown to strongly inhibit the degranulation of polymorphonuclear leukocytes (81
), and resveratrol inhibits tumor growth and causes apoptosis as a cancer chemopreventive agent (82
89
). The antitumor and antimetastatic activities of resveratrol may be due to the inhibition of DNA synthesis in metastatic Lewis lung carcinoma cells, neovascularization induced by these cells and tube formation (angiogenesis) of human umbilical vein endothelial cells by resveratrol (90
).
Glutathione.
The protective role of glutathione as an antioxidant and detoxifying agent has been demonstrated in various clinical studies. It is a ubiquitous compound that is synthesized rapidly in the liver, kidney and other tissues, including the gastrointestinal tract. In animal cells, glutathione acts as a substrate for glutathione peroxidase, which reduces lipid peroxides that are formed from PUFA in the diet, and as a substrate for glutathione S-transferase, which conjugates electrophilic compounds. Recent studies showed that glutathione obtained from the diet is directly absorbed by the gastrointestinal tract and thus dietary glutathione can readily increase the antioxidant status in humans (91
). Dietary glutathione, in addition to that supplied by the bile, may be used by the small intestine to decrease the absorption of peroxides. These results indicate that in intact animals, lumenal glutathione is available for use by the intestinal epithelium to metabolize peroxides and other reactive species and to prevent their transport to other tissues.
Dietary glutathione occurs in highest amounts in fresh meats and in moderate amounts in some fruits and vegetables; it is absent or found only in small amounts in grains and dairy products (92
). Only fresh asparagus (28.3 mg/100 g) and fresh avocado (27.7 mg/100 g) were higher than purslane in glutathione content in a study by the National Cancer Institute that determined the glutathione content of 98 food items that contribute 90% or more of energy, dietary fiber and 18 major nutrients to the U.S. diet (92
94
).
The potential health effects of dietary intake of glutathione in humans are shown in Table 6
(90
,95
103
). In a recent study by Flagg et al. (104
), plasma glutathione concentrations varied widely in humans and were influenced by sex and age (increased with age in men but decreased with age and were lower in women who used estrogen-containing contraceptives).
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| Implementation of the diet of Crete |
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The results of the Seven Countries Studies and the Lyon Heart Study based on a modified diet of Crete indicate that a Paleolithic-type diet such as the traditional Greek diet balanced in (n-6) and (n-3) fatty acids and rich in vitamins C and E (fruits and vegetables) is associated with decreased rates of heart disease and cancer more so than any other diet or drug intervention.
What appears to be so special about the Greek diet relative to the other Mediterranean diets is the content of bioprotective nutrients, specifically the following: 1) a more balanced intake of EFA from vegetable, animal and marine sources; a ratio of (n-6) to (n-3) fatty acids of
2:1 instead of the 15:1 in Western and Northern Europe and 16.74:1 in the United States; and 2) a diet rich in antioxidants, i.e., high amounts of vitamin C, vitamin E, ß-carotene, glutathione, resveratrol, selenium, phytoestrogens, folate, and other phytochemicals from green leafy vegetables; phenolic compounds from wine and olive oil; high intakes of tomatoes, onions, garlic and herbs, especially oregano, mint, rosemary, parsley and dill, which contain lycopene, allyl thiosulfinates, salicylates, carotenoids, indoles, monoterpenes, polyphenols, flavonoids and other phytochemicals used in cooking vegetables, meat and fish.
Such a dietary pattern has been shown to be beneficial to health because it is associated with a reduced risk of cardiovascular disease and cancer. The time has come for the initiation of intervention trials that will test the effect of specific dietary patterns in the prevention and management of patients with cancer.
| FOOTNOTES |
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3 Abbreviations used: AA, arachidonic acid; DHA, docosahexaenoic acid; EFA, essential fatty acids; EPA, eicosapentaenoic acid; LA, linoleic acid; LNA,
-linolenic acid; LT, leukotrienes; PUFA, polyunsaturated fatty acids. ![]()
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