Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms

May combine two claims.

Consuming a Mediterranean diet rich in minimally processed plant foods has been associated with a reduced risk of developing multiple chronic diseases and increased life expectancy.

“Consuming a Mediterranean diet rich in minimally processed plant foods has been associated with a reduced risk of developing multiple chronic diseases and increased life expectancy.”

Classified as probably not a substantial claim.

The exact mechanism by which increased adherence to the traditional Mediterranean diet exerts its favorable effects is not known.

“The exact mechanism by which an increased adherence to the traditional Mediterranean diet exerts its favorable effects is not known.”

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Data from several randomized clinical trials demonstrate a beneficial effect of the Mediterranean diet in the primary and secondary prevention of cardiovascular disease, type 2 diabetes, atrial fibrillation, and breast cancer.

“Data from several randomized clinic trials have demonstrated a beneficial effect in the primary and secondary prevention of cardiovascular disease, type 2 diabetes, atrial fibrillation, and breast cancer.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In Southern Italy in the 1950s, very little meat was eaten, typically only once every week or two, and milk was never used except in coffee or for infants.

“For example, in Southern Italy in the 1950s, very little meat was eaten, typically only once every week or two, and milk was never used except in coffee (caffé macchiato) or for infants.”

• cites [1] Keys, 1983, From Naples to seven countries–a sentimental journey, Prog Biochem PharmacolNot checked yet

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• cites [2] Keys, 1954, Studies on serum cholesterol and other characteristics of clinically healthy men in Naples, AMA Arch Intern Med sourceNot checked yet

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In the Lyon Diet Heart Study, after a 27-month average follow-up, the trial was stopped early because the Mediterranean diet group had a significant 70% reduction in all-cause mortality due to a 73% reduction in coronary heart disease mortality and analogous major reductions in nonfatal complications.

“After a 27-month average follow-up, the trial was stopped early because the Mediterranean diet group had a significant 70% reduction in all-cause mortality due to a 73% reduction in coronary heart disease mortality and analogous major reductions in nonfatal complications (21).”

• cites [21] de Lorgeril, 1994, Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease, Lancet sourceNot checked yet

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Several randomized controlled clinical trials have confirmed that replacing dietary saturated fat intake with vegetable polyunsaturated fats reduces cardiovascular disease incidence by approximately 30%, similar to the decrease induced by statin therapy.

“Several randomized controlled clinical trials have confirmed that replacing dietary saturated fat intake with vegetable polyunsaturated fats reduce cardiovascular disease incidence by approximately 30%, which is similar to the decrease induced by statin’s therapy (35).”

• cites [35] Cholesterol Treatment Trialists’ (CTT) Collaborators, 2012, The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials, Lancet sourceNot checked yet

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Epidemiological studies are observational rather than experimental, and the observed associations do not imply a cause-effect relationship.

“However, we need the bear in mind that epidemiological studies are by nature observational rather than experimental, and the observed associations do not imply a cause–effect relationship.”

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Substituting calories from mono- or poly-unsaturated fat with trans fatty acids increases LDL cholesterol, apolipoprotein B, triglycerides, and lipoprotein(a), and lowers plasma high-density lipoprotein cholesterol and apolipoprotein A1 levels.

“Substituting calories from mono- or poly-unsaturated fat with trans fatty acids increases LDL cholesterol, apolipoprotein B, triglycerides, and lipoprotein(a), and lowers plasma high-density lipoprotein cholesterol and apolipoprotein A1 levels (44).”

• cites [44] Mozaffarian, 2009, Quantitative effects on cardiovascular risk factors and coronary heart disease risk of replacing partially hydrogenated vegetable oils with other fats and oils, Eur J Clin Nutr sourceNot checked yet

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In a large epidemiological study involving 22,043 men and women, higher adherence to a traditional Mediterranean diet was associated with a significant lower total, cardiac, and cancer mortality, independently of the individual dietary components.

“In a large epidemiological study, involving 22,043 men and women, higher adherence to a traditional Mediterranean diet was associated with a significant lower total, cardiac, and cancer mortality, independently of the individual dietary components (19).”

• cites [19] Trichopoulou, 2003, Adherence to a Mediterranean diet and survival in a Greek population, N Engl J Med sourceNot checked yet

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In PRIDIMED, the absolute risk reduction was about three major cardiovascular events per 1,000 person-years, for a relative risk reduction of approximately 30%.

“The absolute risk reduction was of about three major cardiovascular events per 1,000 person-years, for a relative risk reduction of approximately 30%.”

• cites [24] Estruch, 2013, Primary prevention of cardiovascular disease with a Mediterranean diet, N Engl J Med sourceNot checked yet

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The incidence of coronary heart disease and certain cancers, which was very low in Mediterranean countries, has increased substantially.

“Consistently the incidence of coronary heart disease and certain cancers, which was very low in those countries, has increased substantially (1,2,4).”

• cites [1] Keys, 1983, From Naples to seven countries–a sentimental journey, Prog Biochem PharmacolNot checked yet

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• cites [2] Keys, 1954, Studies on serum cholesterol and other characteristics of clinically healthy men in Naples, AMA Arch Intern Med sourceNot checked yet

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• cites [4] Menotti, 2007, Forty-year coronary mortality trends and changes in major risk factors in the first 10 years of follow-up in the seven countries study, Eur J Epidemiol sourceNot checked yet

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Reduced intake of saturated fat is associated with lower plasma cholesterol levels and reduced incidence of coronary heart disease, especially when saturated fat is substituted with polyunsaturated and monounsaturated fat.

“Population-based and prospective epidemiological studies have shown that reduced intake of saturated fat is associated with lower plasma cholesterol levels and reduced incidence of coronary heart disease, especially when saturated fat is substituted with polyunsaturated and monounsaturated fat (33).”

• cites [33] Sacks, 2017, Dietary fats and cardiovascular disease: a presidential advisory from the American Heart Association, Circulation sourceNot checked yet

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Plasma low-density lipoprotein cholesterol concentration in monkeys and newborn humans are typically lower than 60 mg/dL, and LDL-cholesterol levels higher than 100 mg/dL are common only in people consuming Western diets rich in saturated fat from animal origin.

“Plasma low-density lipoprotein (LDL) cholesterol concentration in monkeys and newborn humans are typically lower than 60 mg/dL, and LDL-cholesterol levels higher than 100 mg/dL are common only in people consuming Western diets rich in saturated fat from animal origin (32).”

• cites [32] Kwiterovich, 1973, Neonatal diagnosis of familial type-II hyperlipoproteinaemia, Lancet sourceNot checked yet

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Since the 1950s, the composition of the Mediterranean diet has changed dramatically, and the quality and quantity of food people eat nowadays in Italy, Greece, and Spain has little to do with the Traditional Mediterranean diet.

“The problem is that since 1950s, the composition of the Mediterranean diet has changed dramatically, and the quality and quantity of food people eat nowadays, for example in Italy, Greece and Spain, has little to do with the Traditional Mediterranean diet (3).”

• cites [3] Turrini, 2001, Food consumption patterns in Italy: the INN-CA Study 1994-1996, Eur J Clin Nutr sourceNot checked yet

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Other intervention trials using the Mediterranean diet have also shown some beneficial effects in the treatment of obesity, the metabolic syndrome, and arthritis.

“Other intervention trials using the Mediterranean diet have also shown some beneficial effects in the treatment of obesity, the metabolic syndrome, and arthritis (28–30).”

• cites [28] Shai, 2008, Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet, N Engl J Med sourceNot checked yet

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• cites [29] Salas-Salvadó, 2008, Effect of a Mediterranean diet supplemented with nuts on metabolic syndrome status: one-year results of the PREDIMED randomized trial, Arch Intern Med sourceNot checked yet

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• cites [30] Sköldstam, 2003, An experimental study of a Mediterranean diet intervention for patients with rheumatoid arthritis, Ann Rheum Dis sourceNot checked yet

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Low-glycemic foods rich in dietary fiber have been shown to lower insulin production and increase the levels of short-chain fatty acids produced by fiber fermentation, which inhibit cholesterol synthesis.

“In addition, low-glycemic foods rich in dietary fiber have been shown to lower insulin production and increase the levels of short-chain fatty acids produced by fiber fermentation, which have both been demonstrated to inhibit cholesterol synthesis (42).”

• cites [42] Theuwissen, 2008, Water-soluble dietary fibers and cardiovascular disease, Physiol Behav sourceNot checked yet

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In substudies using the PRIDIMED database, the incidence of type 2 diabetes, peripheral artery disease, atrial fibrillation, and breast cancer, but not the incidence of heart failure, was significantly reduced in individuals randomized to the Mediterranean diet.

“The incidence of type 2 diabetes, peripheral artery disease, atrial fibrillation, breast cancer, but not the incidence of heart failure, was significantly reduced in individuals randomized to the Mediterranean diet (25–27).”

• cites [25] Salas-Salvadó, 2011, Reduction in the incidence of type 2 diabetes with the Mediterranean diet: results of the PREDIMED-Reus nutrition intervention randomized trial, Diabetes Care sourceNot checked yet

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• cites [26] Toledo, 2015, Mediterranean diet and invasive breast cancer risk among women at high cardiovascular risk in the PREDIMED trial: a randomized clinical trial, JAMA Intern Med sourceNot checked yet

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• cites [27] Papadaki, 2017, Mediterranean diet and risk of heart failure: results from the PREDIMED randomized controlled trial, Eur J Heart Fail sourceNot checked yet

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Substituting 5% of energy intake from saturated fats with an equal amount of energy from polyunsaturated fats, monounsaturated fats, or carbohydrates from whole grains is associated with a 25%, 15%, and 9% lower risk of coronary heart disease, respectively.

“It has been estimated that substituting 5% of energy intake from saturated fats with an equal amount of energy from polyunsaturated fats, monounsaturated fats, or carbohydrates from whole grains is associated with a 25%, 15%, and 9% lower risk of coronary heart disease, respectively.”

• cites [34] Li, 2015, Saturated fats compared with unsaturated fats and sources of carbohydrates in relation to risk of coronary heart disease: a prospective cohort study, J Am Coll Cardiol sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Hypercholesterolemia is one of the key risk factors in promoting atherosclerosis, which is the underlying cause of approximately 90% of cases of myocardial infarction, 60% of strokes, most cases of chronic heart failure, peripheral arterial disease, and vascular dementia.

“Hypercholesterolemia is one of the key risk factors in promoting atherosclerosis, which is the underlying cause of approximately 90% of cases of myocardial infarction, 60% of strokes, most cases of chronic heart failure, peripheral arterial disease, and vascular dementia (31).”

• cites [31] Goldstein, 2015, A century of cholesterol and coronaries: from plaques to genes to statins, Cell sourceNot checked yet

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Individuals heterozygous for mutations that inactivate one copy of the PCSK9 gene have plasma LDL-cholesterol levels approximately 30% lower and experience a 90% reduction in heart attacks, independently of smoking, hypertension, and diabetes.

“Indeed, individuals heterozygous for mutations that inactivate one copy of the PCSK9 gene have plasma LDL-cholesterol levels that are approximately 30% lower (which are similar to those induced by treatment with statins), and experience a 90% reduction in heart attacks, independently of smoking, hypertension, and diabetes (36).”

• cites [36] Kathiresan, 2008, A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction, N Engl J Med sourceNot checked yet

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The intake of saturated fat in the traditional Mediterranean diet is low, approximately 8% of energy, despite a relatively high intake of total fat, 25% to 35% of calories, coming predominantly from extra-virgin olive oil, nuts, seeds, and the germ of whole grains.

“Because of the very low consumption of meat, milk, and butter, the intake of saturated fat in the traditional Mediterranean diet is low (approximately 8% of energy), despite a relative high intake of total fat (25% to 35% of calorie) coming predominantly from extra-virgin olive oil, a wide variety of nuts, seeds, and the germ of whole grains.”

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Compared with patients randomized to a step I National Cholesterol Education Program prudent diet, those following the Indo-Mediterranean diet rich in α-linolenic acid experienced an approximate 50% reduction in the rate of nonfatal myocardial infarction and an approximate 60% reduction in the rate of sudden cardiac death.

“Compared with patients randomized to a step I National Cholesterol Education Program prudent diet, those following the Indo-Mediterranean diet rich in α-linolenic acid experienced an approximate 50% reduction in the rate of nonfatal myocardial infarction and an approximate 60% reduction in the rate of sudden cardiac death (23).”

• cites [23] Singh, 2002, Effect of an Indo-Mediterranean diet on progression of coronary artery disease in high risk patients (Indo-Mediterranean Diet Heart Study): a randomised single-blind trial, Lancet sourceNot checked yet

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In the Lyon Diet Heart Study, there were 16 cardiac deaths in the control group and 3 in the experimental group, 17 nonfatal myocardial infarctions in the control group and 5 in the experimental group, and overall mortality was 20 in the control group and 8 in the intervention group.

“there were 16 cardiac deaths in the control and 3 in the experimental “Mediterranean α-linolenic acid–rich diet” group; 17 nonfatal myocardial infarction in the control and 5 in the experimental groups; overall, mortality was 20 in the control, 8 in the intervention group (21).”

• cites [21] de Lorgeril, 1994, Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease, Lancet sourceNot checked yet

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The PRIDIMED study was a primary prevention randomized trial on the effects of a Mediterranean diet supplemented with approximately 1 liter per week of extra-virgin olive oil or 30 g of mixed nuts per day, conducted in 7,447 men and women at high cardiometabolic risk but with no evident cardiovascular disease at baseline.

“The PRIDIMED study was a primary prevention randomized trial on the effects of a Mediterranean diet, supplemented with approximately 1 liter per week of extra-virgin olive oil or 30 g of mixed nuts per day, conducted in 7,447 men and women at high cardiometabolic risk, but with no evident cardiovascular disease at baseline.”

• cites [24] Estruch, 2013, Primary prevention of cardiovascular disease with a Mediterranean diet, N Engl J Med sourceNot checked yet

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In PRIDIMED, among the components of the combined primary end point, only the comparisons of stroke risk reached statistical significance, but not myocardial infarction alone.

“However, among the components of the combined primary end point, only the comparisons of stroke risk reached statistical significance, but not myocardial infarction alone.”

• cites [24] Estruch, 2013, Primary prevention of cardiovascular disease with a Mediterranean diet, N Engl J Med sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Other lifestyle factors such as a dramatic increase in sedentary lifestyle, excessive calorie intake, psychological stress, and pollution might have contributed to the increased incidence of chronic diseases in Mediterranean countries.

“Probably, other lifestyle factors, such as a dramatic increase in sedentary lifestyle, excessive calorie intake, psychological stress and pollution might have contributed to the increased incidence of these and other chronic diseases in all these Mediterranean countries (5).”

• cites [5] Bertozzi, 2017, Beyond calories: an integrated approach to promote health, longevity, and well-being, Gerontology sourceNot checked yet

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Data from randomized controlled studies indicate that high consumption of water-soluble fibers has a significant cholesterol-lowering effect; each additional gram of water-soluble fiber in the diet lowers plasma LDL cholesterol concentrations by approximately 1.12 mg/L.

“In particular, data from randomized controlled studies indicate that high consumption of water-soluble fibers (which are found in high concentrations in beans and fruits) has a significant cholesterol-lowering effect; each additional gram of water-soluble fiber in the diet lowers plasma LDL cholesterol concentrations by approximately 1.12 mg/L (41,42).”

• cites [41] Salas-Salvadó, 2008, Effect of two doses of a mixture of soluble fibres on body weight and metabolic variables in overweight or obese patients: a randomised trial, Br J Nutr sourceNot checked yet

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• cites [42] Theuwissen, 2008, Water-soluble dietary fibers and cardiovascular disease, Physiol Behav sourceNot checked yet

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Water-soluble fiber reduces the reabsorption of cholesterol and bile acids in the small intestine, resulting in augmented LDL uptake by the liver.

“It has been hypothesized that water-soluble fiber reduces the (re)absorption of cholesterol and bile acids in the small intestine, thus resulting in an augmented LDL uptake by the liver (42).”

• cites [42] Theuwissen, 2008, Water-soluble dietary fibers and cardiovascular disease, Physiol Behav sourceNot checked yet

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Several population-based and prospective epidemiological studies have shown that adherence to the Mediterranean diet might have a protective effect against cardiovascular disease, stroke, obesity, diabetes, hypertension, several types of cancers, allergic diseases, and Alzheimer and Parkinson's disease.

“Several population-based and prospective epidemiological studies have shown that adherence to the Mediterranean diet might have a protective effect against cardiovascular disease, stroke, obesity, diabetes, hypertension, several type of cancers, allergic diseases and, most recently, Alzheimer and Parkinson’s disease (7–18).”

• cites [7] Fung, 2009, Mediterranean diet and incidence of and mortality from coronary heart disease and stroke in women, Circulation sourceNot checked yet

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• cites [8] Lopez-Garcia, 2014, The Mediterranean-style dietary pattern and mortality among men and women with cardiovascular disease, Am J Clin Nutr sourceNot checked yet

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• cites [9] Tektonidis, 2015, A Mediterranean diet and risk of myocardial infarction, heart failure and stroke: a population-based cohort study, Atherosclerosis sourceNot checked yet

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• cites [10] Schröder, 2004, Adherence to the traditional Mediterranean diet is inversely associated with body mass index and obesity in a Spanish population, J Nutr sourceNot checked yet

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• cites [11] Martínez-González, 2008, Adherence to Mediterranean diet and risk of developing diabetes: prospective cohort study, BMJ sourceNot checked yet

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• cites [12] Núñez-Córdoba, 2009, The Mediterranean diet and incidence of hypertension: the Seguimiento Universidad de Navarra (SUN) Study, Am J Epidemiol sourceNot checked yet

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• cites [13] Panagiotakos, 2007, Long-term adoption of a Mediterranean diet is associated with a better health status in elderly people; a cross-sectional survey in Cyprus, Asia Pac J Clin NutrNot checked yet

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• cites [14] La Vecchia, 2009, Association between Mediterranean dietary patterns and cancer risk, Nutr Rev sourceNot checked yet

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• cites [15] Buckland, 2013, Adherence to the Mediterranean diet and risk of breast cancer in the European prospective investigation into cancer and nutrition cohort study, Int J Cancer sourceNot checked yet

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• cites [16] Buckland, 2010, Adherence to a Mediterranean diet and risk of gastric adenocarcinoma within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study, Am J Clin Nutr sourceNot checked yet

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Accumulating data from epidemiological, human clinical trials, animal, and molecular studies indicate that diet remains a key factor in the prevention of cardiovascular disease, obesity, type 2 diabetes, and some of the most common types of cancer.

“However, accumulating data from a combination of epidemiological, human clinical trials, animal and molecular studies indicate that diet remains a key factor in the prevention of cardiovascular disease, obesity, type 2 diabetes and some of the most common types of cancer (6).”

• cites [6] Fontana, 2015, Promoting health and longevity through diet: from model organisms to humans, Cell sourceNot checked yet

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In another randomized clinical trial, feeding customized, isocaloric, moderately protein-restricted diets for 4-6 weeks to middle-aged overweight and mildly obese men resulted in a significant decrease in body weight, fat mass, and fasting blood glucose levels, and a major increase in circulating FGF21 concentration.

“In contrast, in another randomized clinical trial, feeding customized, isocaloric, moderately protein-restricted diets for 4–6 weeks to middle-aged overweight and mildly obese men resulted in a significant decrease in body weight, fat mass, and fasting blood glucose levels, and a major increase in circulating FGF21 concentration (79).”

• cites [79] Fontana, 2016, Decreased consumption of branched-chain amino acids improves metabolic health, Cell Rep sourceNot checked yet

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Total protein intake in the traditional Mediterranean diet is on average 20% lower than in the typical Western diet, with animal protein consumption being 50 to 60% lower.

“Total protein intake in the traditional Mediterranean diet is on average 20% lower than in typical Western diet (e.g., 90 vs 70 g/day), with animal protein consumption being 50 to 60% lower (e.g., 30 vs 70 g/day).”

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In rodents, methionine restriction improves glucose metabolism, protects against obesity and hepatic steatosis, and reduces oxidative stress.

“In rodents, methionine restriction improves glucose metabolism, protects against obesity and hepatic steatosis, and reduces oxidative stress.”

• cites [80] Brown-Borg, 2017, Cutting back on the essentials: can manipulating intake of specific amino acids modulate health and lifespan, Ageing Res Rev sourceNot checked yet

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The intake of ibuprofen and aspirin has been associated with a reduction in the risk of developing cancer, in particular colon cancer, and possibly Alzheimer's disease because of preferentially reduced secretion of the highly amyloidogenic Abeta42 peptide.

“The intake of ibuprofen and aspirin has also been associated with a reduction in the risk of developing cancer, in particular colon cancer, and possibly Alzheimer’s disease because of preferentially reduced secretion of the highly amyloidogenic, Abeta42 peptide (62,63).”

• cites [62] Harris, 2012, Reduction in cancer risk by selective and nonselective cyclooxygenase-2 (COX-2) inhibitors, J Exp Pharmacol sourceNot checked yet

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• cites [63] Zhou, 2003, Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho, Science sourceNot checked yet

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The high-fiber content of the traditional Mediterranean diet can enhance fecal mass and the excretion of estrogens, resulting in reduced plasma concentrations of estrone and estradiol.

“Moreover, it has been shown that the high-fiber content of the traditional Mediterranean diet can enhance fecal mass and the excretion of estrogens, resulting in reduced plasma concentrations of estrone and estradiol (71).”

• cites [71] Goldin, 1982, Estrogen excretion patterns and plasma levels in vegetarian and omnivorous women, N Engl J Med sourceNot checked yet

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Trans fatty acid intake has been associated with elevated inflammatory markers and an increased risk of developing type 2 diabetes.

“For example, trans fatty acid intake has been associated with elevated inflammatory markers and an increased risk of developing type 2 diabetes (51,52).”

• cites [51] Lopez-Garcia, 2005, Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction, J Nutr sourceNot checked yet

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• cites [52] Salmerón, 2001, Dietary fat intake and risk of type 2 diabetes in women, Am J Clin Nutr sourceNot checked yet

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A high-fiber diet may directly protect against colon cancer by accelerating colonic transit and by sequestering and therefore limiting the absorption of carcinogenic substances.

“Additionally, a high-fiber diet may directly protect against colon cancer, the second most frequent tumor in Western countries, by accelerating colonic transit and by sequestering and therefore limiting the absorption of carcinogenic substances.”

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Individuals randomized to an ad libitum modified Mediterranean diet lost a significant amount of body weight and experienced a substantial reduction in fasting glucose and C-peptide, in the area under the curve for insulin, and in total and free testosterone.

“Importantly, the individuals randomized to the ad libitum modified Mediterranean diet not only lost a significant amount of body weight, but experienced a substantial reduction in fasting glucose and C-peptide, in the area under the curve for insulin, and in total and free testosterone (66).”

• cites [66] Kaaks, 2003, Effects of dietary intervention on IGF-I and IGF-binding proteins, and related alterations in sex steroid metabolism: the Diet and Androgens (DIANA) Randomised Trial, Eur J Clin Nutr sourceNot checked yet

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Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

Short-chain fatty acids produced by the gut microbiota metabolism of resistant starch and oligosaccharides present in the Mediterranean diet can induce satiety by inhibiting gastric emptying through increased production of gut hormones such as GLP-1 and PYY.

“It has been hypothesized that the short-chain fatty acids produced by the gut microbiota metabolism of the great bulk of resistant starch and oligosaccharides present in the Mediterranean diet can induce satiety by inhibiting gastric emptying through the increased production of gut hormones, such as glucagon like peptide-1 (GLP-1) and peptide-YY (PYY) (67).”

• cites [67] Cani, 2009, The role of the gut microbiota in energy metabolism and metabolic disease, Curr Pharm Des sourceNot checked yet

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Women on the Mediterranean diet had a significant elevation of the plasma concentration of IGFBP-1, IGFBP-2, and SHBG, resulting in a reduction of the biological activity of IGF-1, testosterone, and estradiol.

“Moreover, the women on the Mediterranean diet had a significant elevation of the plasma concentration of several binding proteins, such as IGFBP-1, IGFBP-2, and SHBG, resulting in a reduction of the biological activity of insulin-like growth factor 1 (IGF-1), testosterone, and estradiol (66).”

• cites [66] Kaaks, 2003, Effects of dietary intervention on IGF-I and IGF-binding proteins, and related alterations in sex steroid metabolism: the Diet and Androgens (DIANA) Randomised Trial, Eur J Clin Nutr sourceNot checked yet

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The dose of olechantal in 50 g of newly pressed extra-virgin olive oil is not sufficient to exert, by itself, a powerful anti-inflammatory effect, but it might be high enough to produce protection against platelet aggregation and coronary thrombosis.

“This dose is not sufficient to exert, by itself, a powerful anti-inflammatory effect, but it might be high enough to produce a protection against platelet aggregation and coronary thrombosis.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The low-glycemic index, the high intake of monounsaturated and n-3 fatty acids, and the lower intake of branch-chain amino acids may exert some additional beneficial effects in reducing insulin resistance and compensatory hyperinsulinemia.

“However, it is possible that the low-glycemic index, the high intake of monounsaturated and n-3 fatty acids, and the lower intake of branch-chain amino acids may exert some additional beneficial effects in reducing insulin resistance and compensatory hyperinsulinemia (69,70).”

• cites [69] Ludwig, 2002, The glycemic index: physiological mechanisms relating to obesity, diabetes, and cardiovascular disease, JAMA sourceNot checked yet

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• cites [70] Lovejoy, 1999, Dietary fatty acids and insulin resistance, Curr Atheroscler Rep sourceNot checked yet

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The aleuron layer of wheat bran contains phytoprotectants that have antioxidative and anti-inflammatory potential, and anticarcinogenic activities in rodent animal models of colon and skin cancer.

“The aleuron layer of wheat bran contains a number of phytoprotectants (i.e., ferulic acid, alkylresorcinols, apigenin, lignans, and phytic acid), which have antioxidative and anti-inflammatory potential, and anticarcinogenic activities in rodent animal models of colon and skin cancer (56–59).”

• cites [56] Ogiwara, 2002, Radical scavenging activity and cytotoxicity of ferulic acid, Anticancer ResNot checked yet

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• cites [57] Ozaki, 1992, Antiinflammatory effect of tetramethylpyrazine and ferulic acid, Chem Pharm Bull (Tokyo) sourceNot checked yet

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• cites [58] Yang, 2001, Inhibition of carcinogenesis by dietary polyphenolic compounds, Annu Rev Nutr sourceNot checked yet

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• cites [59] Reddy, 2000, Preventive potential of wheat bran fractions against experimental colon carcinogenesis: implications for human colon cancer prevention, Cancer ResNot checked yet

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Selectively reducing dietary intake of branched-chain amino acids significantly improves glucose tolerance, β cell metabolic stress, and body composition in a recent rodent study.

“In contrast, data from a recent rodent study show that selectively reducing the dietary intake of branched-chain amino acids significantly improves glucose tolerance, β cell metabolic stress, and body composition (79).”

• cites [79] Fontana, 2016, Decreased consumption of branched-chain amino acids improves metabolic health, Cell Rep sourceNot checked yet

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Data from several epidemiological studies suggest that high protein intake is associated with an increased risk of obesity, cardiovascular disease, and type 2 diabetes.

“Moreover, data from several epidemiological studies suggest that high protein intake is associated with an increased risk of obesity, cardiovascular disease, and type 2 diabetes (76).”

• cites [76] Tinker, 2011, Biomarker-calibrated dietary energy and protein intake associations with diabetes risk among postmenopausal women from the Women’s Health Initiative, Am J Clin Nutr sourceNot checked yet

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The reduction in body fat induced by the low-energy density high-fiber Mediterranean diet explains most of the improvement in insulin sensitivity, because the beneficial effects on insulin were no longer statistically significant after adjustment for changes in weight and/or waist circumference.

“Most likely, the reduction in body fat induced by this low-energy density high-fiber Mediterranean diet explains most of the improvement in insulin sensitivity, because the beneficial effects on insulin were no longer statistically significant after adjustment for changes in weight and/or waist circumference (66).”

• cites [66] Kaaks, 2003, Effects of dietary intervention on IGF-I and IGF-binding proteins, and related alterations in sex steroid metabolism: the Diet and Androgens (DIANA) Randomised Trial, Eur J Clin Nutr sourceNot checked yet

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Plasma levels of oxidized LDL predict acute coronary heart disease in relatively healthy individuals and in patients with coronary heart disease, and is a prognostic marker for subclinical atherosclerosis.

“Plasma levels of oxidized LDL predict acute coronary heart disease in relatively healthy individuals and in patients with coronary heart disease, and is a prognostic marker for subclinical atherosclerosis (47).”

• cites [47] Meisinger, 2005, Plasma oxidized low-density lipoprotein, a strong predictor for acute coronary heart disease events in apparently healthy, middle-aged men from the general population, Circulation sourceNot checked yet

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In multiple model organisms, including rats and mice, dietary methionine restriction has consistently been shown to extend average and maximal life span, and protect against multiple chronic diseases, in particular cancer.

“This is important because in multiple model organisms, including rats and mice, dietary methionine restriction has consistently been shown to extend average and maximal life span, and protect against multiple chronic disease, in particular cancer (80).”

• cites [80] Brown-Borg, 2017, Cutting back on the essentials: can manipulating intake of specific amino acids modulate health and lifespan, Ageing Res Rev sourceNot checked yet

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May combine two claims.

Calorie restriction without malnutrition has been shown to be extremely effective in cancer prevention in rodents and monkeys, and in humans results in major reductions of several metabolic and hormonal factors implicated in the pathogenesis of numerous common cancers and in the biology of aging itself.

“Calorie restriction without malnutrition has been shown to be extremely effective in cancer prevention in rodents and monkeys, and in humans results in major reductions of several metabolic and hormonal factors implicated in the pathogenesis of numerous common cancers and in the biology of aging itself (65).”

• cites [65] Most, 2017, Calorie restriction in humans: an update, Ageing Res Rev sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Methionine restriction induces plasma elevations of adiponectin and FGF21, and reduces serum IGF-1, T4, and leptin concentration, which are all hormonal adaptations induced in long-lived rodents by calorie restriction as well.

“In addition, methionine restriction induces plasma elevations of adiponectin and FGF21, and reduces serum IGF-1, T4, and leptin concentration, which are all hormonal adaptations induced in long-lived rodents by calorie restriction as well (80).”

• cites [80] Brown-Borg, 2017, Cutting back on the essentials: can manipulating intake of specific amino acids modulate health and lifespan, Ageing Res Rev sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Formononetin, biochanin A, coumestans, genistein, and daidzein, which are low-potency estrogenic molecules known as phytoestrogens, can compete with endogenous estrogens in binding to the estrogen receptors, and thus block their mitogenic effects.

“In particular, formononetin, biochanin A, coumestans, genistein, and daidzein (found in beans and in particular fava beans and lupin), which are low-potency estrogenic molecules (i.e., phytoestrogens), can compete with endogenous estrogens in binding to the estrogen receptors, and thus blocking its mitogenic effects (72).”

• cites [72] Surh, 2003, Cancer chemoprevention with dietary phytochemicals, Nat Rev Cancer sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Isocaloric restriction of protein or substitution of plant for animal proteins markedly inhibits prostate and breast cancer growth in human xenograft animal models of cancer, with reduced serum IGF-1 levels and downregulation of mTOR activity in the tumor and normal tissue.

“Moreover, it has been shown that isocaloric restriction of protein or substitution of plant for animal proteins markedly inhibits prostate and breast cancer growth in human xenograft animal models of cancer, with reduced serum IGF-1 levels and downregulation of the mechanistic target of rapamycin (mTOR) activity in the tumor and normal tissue as well (74).”

• cites [74] Lamming, 2015, Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model, Oncotarget sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In an epidemiological study, individuals aged 50-65 years with the highest protein intake, more than 20% of calories from protein, had a 75% increase in total mortality and a fourfold increase in cancer mortality.

“In a recent epidemiological study, individuals aged 50–65 years with the highest protein intake (more than 20% of calories from protein) had a 75% increase in total mortality and a fourfold increase in cancer mortality.”

• cites [75] Levine, 2014, Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population, Cell Metab sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Spermidine inhibits histone acetyltransferases, resulting in higher resistance to oxidative stress, increased autophagy, and markedly reduced subclinical inflammation and rates of cell necrosis during aging.

“Spermidine is known to inhibit histone acetyltransferases, which results in higher resistance to oxidative stress, to increase autophagy as well as to markedly reduce subclinical inflammation and the rates of cell necrosis during aging (60).”

• cites [60] Eisenberg, 2016, Cardioprotection and lifespan extension by the natural polyamine spermidine, Nat Med sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Insulin, estrogens, androgens, and IGF-1 are powerful mitogens for cells, and stimulate the development and growth of several common tumors, including breast, colon, prostate, pancreatic, and endometrial cancer.

“Insulin, estrogens, androgens, and IGF-1 are powerful mitogens for cells, and stimulate the development and growth of several common tumors, including breast, colon, prostate, pancreatic, and endometrial cancer (68).”

• cites [68] Longo, 2010, Calorie restriction and cancer prevention: metabolic and molecular mechanisms, Trends Pharmacol Sci sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Dietary, genetic, and pharmacological (rapamycin) inhibition of mTOR extends life span in multiple model organisms.

“Dietary, genetic, and pharmacological (rapamycin) inhibition of mTOR extends life span in multiple model organisms (83).”

• cites [83] Fontana, 2010, Extending healthy life span–from yeast to humans, Science sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In a recent randomized clinical trial, obese individuals randomized to a Mediterranean diet for 2 years experienced a reshaping of the gut microbiota, with an increase in Bacteroides, Prevotella, and Faecalibacterium genera, and most importantly of the Roseburia and Ruminococcus genera and Parabacteroides distasonis and Faecalibacterium prausnitzii bacterial species.

“Consistently, in a recent randomized clinical trial, obese individuals randomized to a Mediterranean diet for 2 years experienced a reshaping of the gut microbiota, with an increase in Bacteroides, Prevotella, and Faecalibacterium genera, and most importantly of the Roseburia and Ruminococcus genera and Parabacteroides distasonis and Faecalibacterium prausnitzii bacterial species, which are known”

• cites [93] Haro, 2017 ;61(12), Consumption of Two Healthy Dietary Patterns Restored Microbiota Dysbiosis in Obese Patients With Metabolic Dysfunction, Mol Nutr Food Res sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Both the quantity and quality of what we eat is essential to promote metabolic and molecular health.

“Both the quantity and quality of what we eat is essential to promote metabolic and molecular health (6).”

• cites [6] Fontana, 2015, Promoting health and longevity through diet: from model organisms to humans, Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Poor adherence to the Mediterranean diet is associated with increased l-Ruminococcus and Streptococcus bacteria, and higher urinary TMAO concentration.

“In contrast, a poor adherence to the Mediterranean diet was associated with increased l-Ruminococcus and Streptococcus bacteria, and higher urinary TMAO concentration (96).”

• cites [96] De Filippis, 2016, High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome, Gut sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Restriction of individual amino acids upregulates the GCN2 pathway, which stabilizes ATF4, a transcription factor indispensable for the Integrated Stress Response.

“In contrast, the restriction of individual amino acids upregulates the GCN2 pathway, which stabilizes ATF4, a transcription factor indispensable for the Integrated Stress Response (84).”

• cites [84] Hine, 2015, Endogenous hydrogen sulfide production is essential for dietary restriction benefits, Cell sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Elevated levels of TMAO induce vascular inflammation and a direct prothrombotic effect by increasing platelet hyper-responsiveness to multiple agonists in both rodents and humans.

“Elevated level of TMAO induces vascular inflammation and a direct prothrombotic effect by increasing platelet hyper-responsiveness to multiple agonists in both rodents and humans, and might be involved in the pathogenesis of obesity and type 2 diabetes (90,91).”

• cites [90] Zhu, 2016, Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk, Cell sourceNot checked yet

  Not checked in the free run.

• cites [91] Schugar, 2017, The TMAO-producing enzyme flavin-containing monooxygenase 3 regulates obesity and the beiging of white adipose tissue, Cell Rep sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Activation of the pro-aging and pro-cancer mTOR pathways is modulated by energy intake and by a cocktail of essential amino acids, with branched-chain amino acids leucine and isoleucine playing a fundamental role.

“The activation of the pro-aging and pro-cancer mTOR pathways is modulated by energy intake but also by a cocktail of different essential amino acids, with the branched-chain amino acids leucine and isoleucine playing a fundamental role (82).”

• cites [82] Efeyan, 2012, Amino acids and mTORC1: from lysosomes to disease, Trends Mol Med sourceNot checked yet

  Not checked in the free run.