Health benefits and metabolic effects of the Mediterranean diet: how did it become the world's best diet?

The Mediterranean diet is the general name for the traditional dietary patterns of people living in the Mediterranean region.

Historically, in many, though not all, of the 22 countries surrounding the Mediterranean, a great abundance and variety of vegetables, minimally processed whole-grain cereals, legumes, hazelnuts and other oilseeds were staple foods for both men and women. Unlike in North America and Europe, meat, fish, milk, cheese and eggs were luxury foods. For example, in southern Italy in the 1950s, very small amounts of meat were typically eaten once or twice a week, and milk was not used except in coffee or for infants. Sugar and white potatoes were consumed only in very small quantities, and neither butter nor cream was used. Cold-pressed extra-virgin olive oil was the main source of fat. Fruit and very small amounts of local cheese were consumed regularly, along with moderate amounts of red wine during meals. You can examine the general features of the Mediterranean diet in the table below.

What are the nutritional characteristics of the traditional Mediterranean diet?

1. Minimally processed whole grains and legumes as staple foods
2. A wide variety of fresh vegetables consumed daily
3. Fresh fruit as the daily dessert; desserts based on hazelnuts, olive oil and honey consumed only on celebratory occasions
4. Cold-pressed extra-virgin olive oil, nuts and seeds used as the main sources of fat
5. Moderate fish consumption
6. Dairy products consumed in small quantities, particularly local cheese and yogurt; apart from milk in coffee or for infants, butter and cream were never used
7. Red and processed meat consumed very infrequently, once or twice a week
8. Wine consumed in low to moderate quantities only with meals

The problem is that the composition of the Mediterranean diet has changed considerably since the 1950s. Today, for example, the quality and quantity of the foods people eat in Italy, Greece and Spain have little to do with the "traditional Mediterranean diet."

Coronary heart disease and certain cancers have increased substantially in these countries, where their incidence used to be very low. Other lifestyle factors, such as sedentary living, excessive calorie intake, psychological stress and pollution, may have contributed to the increasing incidence of these and other chronic diseases in Mediterranean countries. Nevertheless, data gathered from a combination of population-based observational studies, human clinical trials, animal studies and molecular studies show that diet is an important factor in preventing cardiovascular disease, obesity, type-2 diabetes and some of the most common types of cancer.

The purpose of this article is to briefly review current knowledge about the effects of Mediterranean dietary patterns on disease risk and to discuss what is known about their metabolic and molecular adaptations.

What are the mechanisms of the Mediterranean diet's beneficial effects?

The exact mechanism through which a traditional Mediterranean diet reduces the risk of cardiovascular disease, certain cancers and other metabolic conditions is unknown. Many interrelated, overlapping factors are thought to play a role.

The five most important mechanisms that may mediate the health effects of a traditional Mediterranean diet are:

1. Lipid-lowering effects
2. Protection against oxidative stress, inflammation and platelet aggregation
3. Modification
4. Inhibition of nutrient-sensing pathways through restriction of certain amino acids
5. Inhibition of gut microbiota-mediated production of metabolites that affect metabolic health

Lipid-reducing (fat-burning) effects

Cardiovascular disease is a leading cause of death in both men and women. Hypercholesterolemia is one of the key risk factors in many diseases. Hypercholesterolemia promotes atherosclerosis, which accounts for approximately 90% of myocardial infarctions and 60% of strokes and underlies most cases of chronic heart failure, peripheral artery disease and vascular dementia. In monkeys and newborns, plasma low-density lipoprotein (LDL) cholesterol concentrations are typically below 60 mg / dL, and LDL-cholesterol levels above 100 mg / dL are commonly seen only in people consuming Western diets rich in animal-derived saturated fats. Replacing 5% of energy from saturated fats with polyunsaturated fats, monounsaturated fats or carbohydrates from whole grains is estimated to be associated with a 25%, 15% and 9% lower risk of coronary heart disease, respectively. In contrast, replacing saturated fats with carbohydrates from refined grains is associated with an increased risk of coronary heart disease. Several randomized controlled clinical trials have confirmed that replacing dietary saturated fat with plant-derived polyunsaturated fats, such as sunflower oil and corn oil, reduces cardiovascular disease incidence by approximately 30%, similar to the reduction produced by statin treatment. However, the cardiovascular benefits may be much greater if plasma cholesterol remains lower throughout life, preventing atherosclerotic plaques from developing in the first place. Indeed, individuals heterozygous for mutations that inactivate one copy of the PCSK9 gene have approximately 30% lower plasma LDL-cholesterol levels, similar to those induced by statin treatment. A 90% reduction in heart attacks independent of smoking, hypertension and diabetes was observed. Similarly, a lifelong reduction of just 11% in plasma LDL-cholesterol levels due to loss-of-function mutations in NPC1L1, an intestinal cholesterol transporter, produces a striking reduction of 53% in myocardial infarction. These data show that lifelong lower plasma LDL-cholesterol levels are much more effective than the later LDL reduction induced by statins in preventing coronary heart disease. Moreover, the extremely low incidence of coronary heart disease observed in southern Italy, Crete, Japan and Okinawa in the 1950s was probably due to lifelong low plasma LDL-cholesterol levels in these populations. Saturated fat intake is low in the traditional Mediterranean diet because consumption of meat, milk and butter is very low, despite a high overall fat intake. Most fat comes from extra-virgin olive oil, a variety of nuts and germ cells in whole grains. Hazelnuts, almonds, walnuts, peanuts and pine nuts are very good sources of omega-6 and omega-3 fatty acids, which may help reduce LDL-cholesterol and coronary heart disease risk. Prospective studies have shown that eating 5 portions of nuts per week is associated with a 40% to 60% reduction in coronary heart disease events. Additional mechanisms may explain lower plasma cholesterol levels in people following a Mediterranean diet. A typical traditional Mediterranean diet rich in whole grains, legumes and dried fruit provides at least 14 g of plant fiber per 1000 kcal each day, more than twice the amount consumed daily in many industrialized countries. In particular, randomized controlled trial data show that water-soluble fibers, present at high concentrations in beans and fruit, have a substantial cholesterol-lowering effect. Each gram of soluble dietary fiber reduces plasma LDL-cholesterol concentrations by approximately 1.12 mg/L. Foods rich in dietary fiber with a low glycemic index have been shown to reduce insulin production, inhibit cholesterol synthesis and increase levels of short-chain fatty acids produced by fiber fermentation. A high intake of phytosterols from nuts, seeds, whole grains, vegetables and fruit may also play an important role in lowering plasma cholesterol by competing with intestinal cholesterol absorption. Finally, the traditional Mediterranean diet in the past was extremely low in partially hydrogenated trans fatty acids, important factors in the pathogenesis of coronary heart disease. Replacing calories from mono- or polyunsaturated fats with trans fatty acids increases LDL cholesterol, apolipoprotein B, triglycerides and lipoprotein (a). It lowers plasma high-density lipoprotein cholesterol and apolipoprotein A1 levels. Accumulated data show that naturally occurring trans fatty acids in the milk and meat of ruminants have similar adverse effects on blood lipids.

Protection against oxidative stress, inflammation and platelet accumulation (thrombosis and clotting problems)

The traditional Mediterranean diet, with high vegetable consumption, whole grains, legumes, fruit, nuts, seeds, extra-virgin olive oil and moderate red wine intake, contains antioxidant vitamins (β-carotene, vitamin C and vitamin E), natural folate, phytochemicals such as flavonoids, and minerals such as selenium. For example, the total average dietary intake of beta-carotene, derived from provitamin A carotenoids, vitamin E (total a-tocopherol), natural folate, flavonoids and selenium in a traditional Mediterranean diet is approximately 6,000 ug/day, 17 mg/day, 400 ug/day, 300 mg/day and 120 ug/day, respectively. Increased oxidative stress has been implicated in the pathogenesis of many chronic conditions, including cardiovascular disease, cancer and dementia. Data from a large case-control study, the INTERHEART study, show a beneficial effect of dietary antioxidants against coronary heart disease. Inadequate dietary antioxidant intake may increase the risk of atherosclerotic plaque development through changes in lipoprotein oxidation. In a recent randomized clinical trial, individuals randomized to a Mediterranean diet supplemented with extra-virgin olive oil had substantial reductions in circulating oxidized LDL and inflammatory markers. Oxidative and inflammatory damage are closely related, and both represent an important early step in atherosclerosis pathogenesis. The anti-inflammatory effect of the Mediterranean diet suggests that multiple nutrients from a variety of foods, rather than just a few specific foods, have synergistic and interactive roles in reducing inflammation. Some foods and nutrients have been shown to independently increase inflammation. For example, trans fatty acid intake has been associated with increased inflammatory markers and a risk of developing type 2 diabetes. Conversely, omega-3 fatty acid intake is inversely related to circulating inflammatory markers and triglyceride levels. The anti-inflammatory effects of omega-3 fatty acids appear to be mediated by binding to a G-protein-coupled receptor and inhibiting NLRP3 inflammasome activity. Phytochemicals in whole grains and extra-virgin olive oil may be responsible for some anti-inflammatory and antioxidant effects. The aleurone layer of wheat bran contains a range of phytoprotectants, namely ferulic acid, alkylresorcinols, apigenin, lignans and phytic acid, with antioxidative and anti-inflammatory potential and anticarcinogenic activity against colon and skin cancer in rodent models. Whole grains also contain a polyamine called spermidine, which has been shown to extend chronological lifespan in nematodes, rodents and human cells. Spermidine is known to inhibit histoacetyltransferases, increase autophagy and consequently resistance to oxidative stress, while substantially reducing subclinical inflammation and the rate of cell necrosis during aging. One hundred grams of extra-virgin olive oil, approximately seven tablespoons, contains 25 mg of a-tocopherol and 1-2 mg of carotenoids, both powerful antioxidants, as well as 20-500 mg of oleuropein and 98-185 mg of phytosterols. In addition, 50 g of freshly pressed extra-virgin olive oil has been shown to contain up to 9 mg of olechantal, a phytochemical with ibuprofen-like COX-inhibitory activity. This dose is not sufficient on its own to exert a strong anti-inflammatory effect, but it may be high enough to provide protection against platelet aggregation and coronary thrombosis. Ibuprofen and aspirin intake has been associated with a reduced risk of cancer, particularly colon cancer, and possibly Alzheimer's disease, especially through preferentially reduced secretion of the amyloidogenic Abeta42 peptide. However, we must remember that one tablespoon of olive oil contains approximately 120 kcal. If we consume excessive amounts of olive oil without balancing it with an appropriate amount of physical exercise, we gain weight. The effects of excess weight and excessive abdominal fat accumulation on chronic inflammation, oxidative stress, insulin sensitivity and overall metabolic health will outweigh the beneficial effects of the polyphenols in olive oil.

Effects on cancer

Calorie restriction without malnutrition (extreme thinness) has been shown to be highly effective in preventing cancer in rodents and monkeys. In humans, calorie restriction substantially reduces various metabolic and hormonal factors involved in the pathogenesis of many common cancers and the biology of aging. Although the Mediterranean diet does not intentionally require calorie counting, randomized clinical trials show that removing refined and processed foods from the diet results in weight loss. Resistant starch and oligosaccharides in the Mediterranean diet enable gut microbiota to produce short-chain fatty acids (SCFAs). These fatty acids are thought to lead to the production of gut hormones such as glucagon peptide-1 (GLP-1) and peptide-YY (PYY), which may induce satiety by inhibiting gastric emptying. Individuals randomized to a Mediterranean diet not only lost substantial body weight but also experienced reductions in fasting glucose and C-peptide. They also had substantial reductions in the area under the insulin curve and in total and free testosterone. Insulin, estrogens, androgens and IGF-1 are powerful cellular mitogens and stimulate the development and growth of several common tumors, including breast, colon, prostate, pancreatic and endometrial cancer. It is not yet clear whether these endocrine changes result from changes in diet quality, weight loss or both. Most likely, this high-fiber Mediterranean diet with low energy density explains much of the reduction in body fat and improvement in insulin sensitivity. However, the low glycemic index, high intake of monounsaturated (n-9) and polyunsaturated omega-3 (n-3) fatty acids, and lower intake of branched-chain amino acids may have additional beneficial effects in reducing insulin resistance and compensatory hyperinsulinemia. The high fiber content of the traditional Mediterranean diet has also been shown to increase stool mass and estrogen excretion, thereby reducing plasma estrone and estradiol concentrations. A high-fiber diet may also directly protect against colon cancer, the second most common tumor in Western countries, by speeding up colonic transit and sequestering carcinogens, thus limiting their absorption. Finally, some plant foods typically consumed in a Mediterranean diet contain rich chemical compounds with other potential health benefits against cancer. These include lycopene in tomatoes; capsaicin in hot peppers; organosulfur compounds in onions and garlic; isothiocyanates, indole-3-carbinol and sulforoptan in cruciferous vegetables; polyacetylenes in squash and carrots; monoterpenes in oranges and lemons; ginkgetin in capers; and ferulic acid and spermidine in whole grains.

Inhibition of nutrient-sensing pathways through amino acid restriction

Total protein intake in a traditional Mediterranean diet is on average 20% lower than in a typical Western diet (for example, 90 to 70 g / day), while animal protein consumption is 50-60% lower (for example, 30 to 70 g / day). Most protein comes from legumes and whole grains; the average daily plant protein content of a traditional Mediterranean diet is approximately 40 grams. This matters because accumulated data show that moderate protein restriction extends lifespan independently of calorie intake in many model organisms, including rodents. Isocaloric restriction of protein or replacing plant protein with animal proteins has also been shown to substantially inhibit prostate and breast cancer growth in human cancer xenograft animal models through reductions in human IGF-1 levels and levels of the mechanical serum target of rapamycin (mTOR) in tumors and normal tissues. In a recent epidemiological study, individuals aged 50-65 with the highest protein intake had a 75% increase in total mortality and a fourfold increase in cancer mortality. These associations disappeared or diminished when people consumed plant-based proteins. Data from various epidemiological studies also show that high protein intake is associated with an increased risk of obesity, cardiovascular disease and type 2 diabetes. For example, the risk of developing type 2 diabetes increases by 20-40% for every 10 g of protein consumed above 64 g / day. Accordingly, in a clinical trial, adding protein to a calorie-reduced weight-loss diet prevented the improvement in insulin-mediated glucose disposal induced by a 10% weight loss in women with obesity. On the other hand, protein quality is likely to matter more than protein quantity in the beneficial effects of the Mediterranean diet. Because the ratio of animal to plant protein differs, the content of some essential amino acids is very different in Western and Mediterranean diets. Dietary methionine intake is on average 40% lower in a traditional Mediterranean diet. Why is this important? Dietary methionine restriction has been observed to extend average and maximum lifespan in multiple model organisms. It has also been shown to protect against multiple chronic diseases, including cancer. In rodents, methionine restriction improves glucose metabolism, protects against obesity and fatty liver, and reduces oxidative stress. It also reduces leptin concentrations.

Methionine content of some foods /per 100 grams):

• Kavurma meat: 996
• Döner meat: 920
• Chicken wings: 422
• Afyon pastırma: 898
• Cağ kebab: 884
• Milk powder: 872
• Mersin çökelek cheese: 732
• Yogurt: 137
• Milk: 86
• Chickpeas: 80

Intake not only of methionine but also of other essential amino acids, such as leucine, isoleucine, valine and tryptophan, is 20 to 30% lower in a traditional Mediterranean diet than in a Western diet rich in meat, eggs and milk. Circulating concentrations of branched-chain amino acids are elevated in humans and rodents with insulin resistance. High consumption of leucine, valine and isoleucine is associated with an 11-13% increased risk of type 2 diabetes in three large prospective cohort studies. Data from a recent rodent study show that selectively reducing dietary branched-chain amino acids substantially improves glucose tolerance, β-cell metabolic stress and body composition. Activation of the anti-aging and cancer-preventive mTOR pathways is modulated not only by energy intake but also by a cocktail of different essential amino acids, with leucine and isoleucine playing key roles. Dietary, genetic and pharmacological inhibition of mTOR with rapamycin extends lifespan in multiple model organisms.

Effects of the Mediterranean diet on gut microbiota (beneficial intestinal bacteria)

Diet has a major influence on the biology of the gut microbiome. Accumulating data show that specific nutrients, especially protein and insoluble fiber, have profound effects on the function and secretions of the gut microbiota structure. For example, the choline and L-carnitine content of a traditional Mediterranean diet is more than 50% lower than in a typical Western diet abundant in red meat, eggs and cheese. In recent human and animal studies, intestinal trimethylamine N-oxide (TMAO) associated with dietary choline and L-carnitine increased cardiovascular disease risk. High TMAO levels induce vascular inflammation and a direct prothrombotic effect by greatly increasing platelet responsiveness to multiple agonists in both rodents and humans. They may thus play a role in the pathogenesis of obesity and type 2 diabetes. Another important feature of the Mediterranean diet is its very high fiber content. In particular, it contains 2 times as much insoluble fiber as a normal Western diet (30 versus 14 g / day).

High dietary fiber intake increases Bacteroidetes bacteria, particularly Bakteroides Acidifecies, which increase the production of short-chain fatty acids, acetate, butyrate and propionate, and reduces Firmicutes bacteria in studies in both mice and humans.

Short-chain fatty acids produced by gut microbiota in response to dietary fiber intake have been shown to suppress the development of various inflammatory, autoimmune and allergic diseases. Some beneficial effects of these microbiome metabolites are thought to be mediated by specific G-protein-coupled receptors expressed on enteroendocrine and immune cells. In a recent randomized clinical trial, individuals with obesity who followed a Mediterranean diet for 2 years experienced gut microbiota remodeling, with increases in certain bacterial genera: Bacteroides, Prevotella, Faecalibacterium, Ruminococcus and Parabacteroides. These bacteria are known for their ability to metabolize carbohydrates into short-chain fatty acids. Bacteroides fragilis and F. Prausnitzii have recently been shown to effectively stimulate CD4 + T cells that secrete anti-inflammatory interleukin-10. In another study, high fiber intake from vegetables, fruit and legumes in a Mediterranean diet was associated with increased short-chain fatty acids in stool. In contrast, poor adherence to a Mediterranean diet was associated with increased L-Ruminoccus and Stretococcus bacteria and higher urinary TMAO concentrations. Long-term adherence to a particular dietary pattern, such as a Mediterranean diet rich in minimally processed plant foods, may have a more profound effect on the composition and diversity of taxa retained in the gut microbiota than a short-term diet.

Indeed, long-term consumption of plant-rich diets with restricted calorie intake has been associated with a richer and more phylogenetically diverse fecal microbiota. In contrast, multigenerational exposure to a Western diet poor in "microbiota-accessible carbohydrates" may adversely affect immune system maturation and function. It may cause the extinction of specific bacterial lineages, which can increase the risk of developing a range of metabolic diseases, including inflammatory, allergic and autoimmune diseases. This matters because accumulating evidence suggests that reprogramming the gut microbiota through long-term adherence to healthy plant-rich diets may effectively promote health.

Conclusion

All these data strongly suggest that nutrition is a key factor in promoting health and preventing the most common age-related chronic diseases. The quantity and quality of what we eat are essential for metabolic and molecular health. Calorie restriction extends healthspan and lifespan only with adequate intake of all necessary macro- and micronutrients. Unlike typical Northern European and American diets, the traditional Mediterranean diet is full of vitamins, minerals and phytochemicals and contains minimally processed, fiber-rich plant foods. Consumption of small quantities of meat, fish, eggs and cheese provides nutrients such as vitamin B12 that are absent from vegetarian diets. In the past, additional energy needed to sustain high levels of physical activity, approximately 70-80 hours of work per week, came from energy-dense foods such as extra-virgin olive oil, wine and dried fruit.

Recent findings from animal and human studies are beginning to shed light on the biological mechanisms that mediate the beneficial effects of the traditional Mediterranean diet and other healthy dietary patterns, such as the traditional Okinawan diet. High consumption of fiber-rich, low-energy plant foods and specific restriction of sulfur-containing and branched-chain amino acids, such as valine, leucine and isoleucine, and saturated fatty acids appear to play important roles in health and lifespan extension.