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The Paleo Lifestyle Using Foods to Treat Disease and to Maximise Optimal Wellness By Stephen Eddey M.H.Sc., B.Sc.(Comp.Med.), Dip.App.Sc.(Nat.), Ass.Dip.App.Sc.(Chem.),

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Presentation on theme: "The Paleo Lifestyle Using Foods to Treat Disease and to Maximise Optimal Wellness By Stephen Eddey M.H.Sc., B.Sc.(Comp.Med.), Dip.App.Sc.(Nat.), Ass.Dip.App.Sc.(Chem.),"— Presentation transcript:

1 The Paleo Lifestyle Using Foods to Treat Disease and to Maximise Optimal Wellness By Stephen Eddey M.H.Sc., B.Sc.(Comp.Med.), Dip.App.Sc.(Nat.), Ass.Dip.App.Sc.(Chem.), Cert.IV(Workplace & Training),N.D. 1

2 The Paleo Diet Finding the right nutrition for: Obesity Anti-aging/Wellness Diseases Heart Disease Detoxification Cancer Inflammation Functional foods 1

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4 Who were our ancestors ? What did our ancestors eat ? How do we know? What dietary changes have occurred ? What impact have dietary changes had ? Basic Questions 2

5 Evolution and Diet Evolution in a geological context OligoceneMiocenePliocenePleistocene 25 mya10 mya2 mya 10,000 ya Mammalian insectivores PrimatesApesRamapithecus “Lucy” (hominid) H. habilis H. erectus H. sapiens Or G Ch Oldest stone tools Major climatic change 2

6 Australopithecus aferensis Approximately 4 million years ago

7 Evolution and Diet Dietary changes Miocene apes: Specialised, leaf /fruit eaters >15 mya Ramapithecus: First hominoid, ~ 10 mya leaves /fruit /roots /meat scavenger (5-10% energy) Lucy: First hominid, small, upright stance, ~ 4.5 mya, fruits /roots /nuts /meat (>10% energy), probably hunted ! Homo habilis: First tool maker, hunter, ~ 3 mya, fruits /meat /roots /nuts (meat > 20% energy) Homo erectus: Tall, large brain, big game hunter, ~ 1.5 mya meat /fruits /roots /nuts (meat 20-50% energy) Homo sapiens: Organised big game hunters, ~ 400,000 ya energy intake from meat estimated > 60% roots, fruits, vegetation, nuts, seeds 3

8 Optimal Foraging Theory u Pre-agriculture we were hunter-gatherers u Day-to-day survival depended on daily energy intake being adequate u Body energy use = Basal metabolism + activity u Best choices were foods with the greatest energy return (ie energy content - energy expenditure for collection and preparation) u High energy dense foods became critical (evident in brain gut trade off in our species) 3

9 Human Brain Size Brain size (cc) Age in millions of years    Homo sapiens Homo erectus Homo habilis Australopithecines (Aiello & Wheeler 1995) 4

10 Gut morphology and diet Insectivores Horse Rabbit Chimpanzee Humans Frugivores Gorilla Dog Cat Cow Folivores (mid-gut) Faunivores Folivores (fore-gut) Martin, The life of primates. In: The Cambridge Encylopedia of Human Evolution 4

11 Hunter-Gatherers in Recent Time u Dietary data on 181 HG societies recorded in: “Ethnographic Atlas” (Murdoch 1967) u Animal:Plant subsistence ratio: 65:35 (Cordain, Brand-Miller, Mann, Eaton & Speth, Am J Clin Nutr, 2000) u Broad characteristic dietary macro-nutrient composition Hunter-gatherers USAAustralia Protein % (15.5%)(17.0%) Carbohydrate % (49.0%)(45.1%) Fat % (34.0%)(32.4%) 5

12 The Paleolithic Diet “It has been postulated that foods that were regularly eaten during human evolution, in particular during the Paleolithic (the 'Old Stone Age', 2.5–0.01 million years BP), may be optimal for prevention and treatment of type 2 diabetes, CVD and insulin resistance.” Cardiovasc Diabetol. 2009; 8: 35. Beneficial effects of a Paleolithic diet on cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study Tommy Jönsson

13 The Paleolithic Diet “A Paleolithic diet is a modern dietary regimen based on foods presumably eaten regularly during the Paleolithic, which includes lean meat, fish, shellfish, fruits, vegetables, roots, eggs and nuts, but not grains, dairy products, salt or refined fats and sugar, which became staple foods long after the appearance of fully modern humans.” Cardiovasc Diabetol. 2009; 8: 35. Beneficial effects of a Paleolithic diet on Cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Tommy Jönsson

14 The Paleolithic Diet “In a randomized controlled study in 29 men with ischemic heart disease (IHD) and impaired glucose tolerance or type 2 diabetes (mean HbA1C 4.8% at baseline), we found improved glucose tolerance independent of weight-loss after 12 weeks of Paleolithic diet compared to a Mediterranean-like diet.” Cardiovasc Diabetol. 2009; 8: 35. Beneficial effects of a Paleolithic diet on Cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Tommy Jönsson

15 The Paleolithic Diet “In a non-controlled study on 14 healthy individuals, Österdahl et al found that three weeks on a Paleolithic diet significantly reduced weight, BMI, waist circumference, systolic blood pressure (SBP) and plasminogen activator inhibitor-1 (PAI- 1).” Cardiovasc Diabetol. 2009; 8: 35. Beneficial effects of a Paleolithic diet on Cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Tommy Jönsson

16 The Paleolithic Diet “In another non-controlled study in nine healthy overweight individuals where intervention food was supplied and weight kept steady, Frassetto et al found that ten days of a Paleolithic diet improved diastolic blood pressure (DBP), glucose tolerance, insulin sensitivity and lipid profiles.” Cardiovasc Diabetol. 2009; 8: 35. Beneficial effects of a Paleolithic diet on Cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Tommy Jönsson

17 The Paleolithic Diet “In a randomized controlled feeding trial in domestic swine, we found higher insulin sensitivity, lower C-reactive protein (CRP) and lower DBP after 15 months of a Paleolithic diet, compared with a cereal-based swine feed.” Cardiovasc Diabetol. 2009; 8: 35. Beneficial effects of a Paleolithic diet on Cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Tommy Jönsson

18 The Paleolithic Diet “In a non-controlled study of ten Australian Aborigines with diabetes and a mean BMI of 27 kg/m 2, O'Dea found that reversion to a hunter- gatherer lifestyle during 7 weeks led to 10% weight loss and reductions in fasting and 2 hour glucose and fasting insulin.” Cardiovasc Diabetol. 2009; 8: 35. Beneficial effects of a Paleolithic diet on Cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Tommy Jönsson

19 The Paleolithic Diet “In a similar study on healthy Australian Aborigines by the same authors, the insulin response to 70 g of starch from white bread was reduced, while the glucose response was not, after 10–12 weeks of reversion to a traditional lifestyle.” Cardiovasc Diabetol. 2009; 8: 35. Beneficial effects of a Paleolithic diet on Cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Tommy Jönsson

20 The Paleolithic Diet “In an epidemiologic study, we found that traditional Pacific Islanders of Kitava, Papua New Guinea, had no signs of IHD, stroke or markers of the metabolic syndrome, possibly because of their traditional lifestyle.” Cardiovasc Diabetol. 2009; 8: 35. Beneficial effects of a Paleolithic diet on Cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Tommy Jönsson

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26 Diseases of Lifestyle Treating Acne with the Paleo Diet

27 Dietary Role in Acne: The Evidence “ The influence of diet on the induction and aggravation of acne has been a matter of intense debate over the last few years. The pioneering observation by Cordain et al., who demonstrated that acne is a disease of Western civilization and is absent in populations consuming Palaeolithic diets without refined sugars, grains, milk and dairy products, resulted in a paradigm change.” Diet in acne: further evidence for the role of nutrient signalling in acne pathogenesis. Melnik BC. Acta Derm Venereol May;92(3):

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29 Glycaemic Load and Acne Improvement in acne and insulin sensitivity after a low-glycaemic-load diet suggests that nutrition- related lifestyle factors may play a role in the pathogenesis of acne. American Journal of Clinical Nutrition, Vol. 86, No. 1, , July 2007

30 Glycaemic Load and Acne Low glycaemic load diets may influence sebum production based on the beneficial endocrine effects of these diets. J Dermatol Sci Apr;50(1):41-52

31 Glycaemic Load and Acne “The randomized, controlled Australian study by Smith et al. provided the first clinical evidence for the beneficial therapeutic effects of a low glycaemic load diet on the clinical course and intensity of acne and sebum production. The randomized controlled South Korean trial of Kwon and co-workers in this issue of Acta Dermato-Venereologica confirmed that glycaemic load plays a substantial role in the pathogenesis and treatment of acne.” Diet in acne: further evidence for the role of nutrient signalling in acne pathogenesis. Melnik BC. Acta Derm Venereol May;92(3):

32 Glycaemic Load and Acne “Subjects within the low glycaemic group demonstrated significant clinical improvement in the number of both non-inflammatory and inflammatory acne lesions.” Diet in acne: further evidence for the role of nutrient signalling in acne pathogenesis. Melnik BC. Acta Derm Venereol May;92(3):

33 Glycaemic Load and Acne “Remarkably, Kwon et al. now provide the first histopathological and immunohistochemical evidence that a low glycaemic load diet reduced the size of sebaceous glands, decreased inflammation, and diminished the expression of pro- inflammatory interleukin-8 and sterol regulatory element binding protein-1 (SREBP-1), the key transcription factor of lipid biosynthesis.” Diet in acne: further evidence for the role of nutrient signalling in acne pathogenesis. Melnik BC. Acta Derm Venereol May;92(3):

34 Glycaemic Load and Acne “ Compelling evidence exists that high glycemic load diets exacerbate acne by increasing the levels of IGF1. Smith et al. demonstrated that low glycemic load diet for 12 weeks decreased serum IGF-1 levels and significantly improved acne. Dietary intervention increases the nuclear content of Fox 01, thereby normalizing increased transcription of genes involved in acne.” Indian J Dermatol Venereol Leprol May-Jun;79(3): Role of insulin resistance and diet in acne. Kumari R, Thappa DM.

35 Glycaemic Load and Acne “ Eating high glycemic index foods causes hyperglycemia. The pancreas responds to hyperglycemia by releasing large quantities of insulin to bring down the blood sugar levels. Large quantities of insulin causes blood sugar levels to fall down rapidly. Too low blood sugar levels trigger another stress response in adrenal glands. The adrenal glands release androgens that signal the liver to release some of its glycogen storages to raise the blood sugar to normal. Incidentally, low blood sugar levels also trigger serious craving for food. With these cravings, the tendency is to again eat food with high glycemic index and the cycle continues chronically.” Indian J Dermatol Venereol Leprol May-Jun;79(3): Role of insulin resistance and diet in acne. Kumari R, Thappa DM.

36 Glycaemic Load and Acne “The more the pancreas releases insulin, the less effective it becomes as a result of reduced sensitivity of the cells to insulin. This is called insulin resistance or reduced insulin sensitivity. To counter this effect, the pancreas has to release increased secretion of insulin from pancreas. Chronic and acute hyperinsulinemia initiates the hormone cascade that favours tissue growth by stimulating increased levels of free IGF1 and reducing levels of IGF binding protein3.” Indian J Dermatol Venereol Leprol May-Jun;79(3): Role of insulin resistance and diet in acne. Kumari R, Thappa DM.

37 Glycaemic Load and Acne “Because free IGF1 is a potent mitogen for virtually all body tissues, it promotes acne via hyperkeratinization. Reduction in IGFBP3 levels after hyperinsulinemia or after ingestion of high glycemic food also makes more free IGF1 available and upregulates cell proliferation.” Indian J Dermatol Venereol Leprol May-Jun;79(3): Role of insulin resistance and diet in acne. Kumari R, Thappa DM.

38 Glycaemic Load and Acne Summary Eat a high CHO diet and insulin goes up Insulin goes up and IGF-1 goes up Insulin goes up and SHBG goes down SHBG down means more available Testosterone and DHT Increased IGF-1 means increased sebocyte production (oil) and increased keratinocytes at the hair follicle ostium All of the above means more acne is susceptible individuals

39 Glycaemic Load and Acne “Two randomized controlled studies, one of which is presented in this issue of Acta Dermato- Venereologica, have provided evidence for the beneficial therapeutic effects of low glycaemic load diets in acne. Epidemiological evidence confirms that milk consumption has an acne-promoting or acne- aggravating effect.” Diet in acne: further evidence for the role of nutrient signalling in acne pathogenesis. Melnik BC. Acta Derm Venereol May;92(3):

40 Dietary Role in Acne: The Evidence “RESULTS: At 12 wk, mean (+/-SEM) total lesion counts had decreased more (P=0.03) in the low- glycemic-load group ( /- 3.9) than in the control group ( /- 3.5).” Am J Clin Nutr Jul;86(1): A low-glycemic-load diet improves symptoms in acne vulgaris patients: a randomized controlled trial. Smith RN, Mann NJ, Braue A, Mäkeläinen H, Varigos GA.

41 Carbohydrate Question and Acne “Acute hyperinsulinemia due to consumption of high glycemic load diet would cause an increase in IGF-1/insulin-like growth factor binding protein- 3 (IGFBP-3) ratio, thus enhancing the effects of IGF-1.” BMC Dermatol Aug 16;12:13. High glycemic load diet, milk and ice cream consumption are related to acne vulgaris in Malaysian young adults: a case control study. Ismail NH, Manaf ZA, Azizan NZ.

42 Carbohydrate Question and Acne “Hyperinsulinemia resulting from high glycemic load diet would also increase circulating androgens and decrease sex hormone binding protein, leading to increased sebum synthesis, which was crucial in acne development.” BMC Dermatol Aug 16;12:13. High glycemic load diet, milk and ice cream consumption are related to acne vulgaris in Malaysian young adults: a case control study. Ismail NH, Manaf ZA, Azizan NZ.

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45 Dairy Question and Acne “This study found that frequency of milk and ice cream intake was positively associated with acne vulgaris occurrence.” BMC Dermatol Aug 16;12:13. High glycemic load diet, milk and ice cream consumption are related to acne vulgaris in Malaysian young adults: a case control study. Ismail NH, Manaf ZA, Azizan NZ.

46 Dietary Role in Acne: Dairy Dilemma “ Milk is a rich source of active IGF-1 and IGF-2 even after pasteurization and homogenization. High milk consumption is associated with a 10-20% increase in circulating IGF-1 levels among adults and a % increase among children. Milk and dairy products increase IGF-1 levels more than other dietary sources of protein such as meat.” Indian J Dermatol Venereol Leprol May-Jun;79(3): Role of insulin resistance and diet in acne. Kumari R, Thappa DM.

47 Dietary Role in Acne: Dairy Dilemma “ The major protein fraction of cow's milk is casein (80%), and the remaining 20% are whey proteins. The insulinotropic component of milk resides predominantly within the whey fraction, whereas casein has a stronger IGF-1 stimulating effect than does whey. Inclusion of milk and hyperglycemic foods in diet may have potentiating effects on serum insulin and IGF-1 levels, thereby promoting the development of acne.” Indian J Dermatol Venereol Leprol May-Jun;79(3): Role of insulin resistance and diet in acne. Kumari R, Thappa DM.

48 Insulin “Milk consumption and hyperglycemic diets can induce insulin and IGF-1-mediated PI3K ⁄ Akt-activation inducing sebaceous lipogenesis, sebocyte, and keratinocyte proliferation, which can aggravate acne. Occurence of acne as part of various syndromes also provides evidence in favour of correlation between IGF-1 and acne.” Indian J Dermatol Venereol Leprol May-Jun;79(3): :Role of insulin resistance and diet in acne. Kumari R, Thappa DM.

49 Dietary Role in Acne: Dairy Dilemma “Until recently only a weak association has been accepted for the role of milk and dairy products in acne pathogenesis. There is, however, substantial epidemiological and biochemical evidence supporting the effects of milk and dairy products as enhancers of insulin-/IGF-1 signalling and acne aggravation. In fact, milk signalling potentiates the signalling effects of hyperglycaemic carbohydrates.” Diet in acne: further evidence for the role of nutrient signalling in acne pathogenesis. Melnik BC. Acta Derm Venereol May;92(3):

50 Insulin and Acne “Acne appears to represent a visible indicator disease of over-activated mTORC1 signalling, an unfavour- able metabolic deviation on the road to serious common Western diseases of civilisation associated with increased body mass index and insulin resistance.” Acta Derm Venereol Aug 8. doi: / Acne: Risk Indicator for Increased Body Mass Index and Insulin Resistance. Melnik BC, John SM, Plewig G.

51 Dairy Question and Acne “ Our study found that yoghurt consumption was not correlated with acne vulgaris occurrence and is consistent with the findings by several studies. When added to milk during fermentation process, probiotic bacteria (specifically Lactobacilli) utilize IGF-1 and lowered IGF-1 level in fermented milk by four-fold compared to skim milk.” BMC Dermatol Aug 16;12:13. High glycemic load diet, milk and ice cream consumption are related to acne vulgaris in Malaysian young adults: a case control study. Ismail NH, Manaf ZA, Azizan NZ.

52 Indian J Dermatol Venereol Leprol May- Jun;79(3): Role of insulin resistance and diet in acne. Kumari R, Thappa DM.

53 What do most people in Australia Eat???

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61 Exp Dermatol May;22(5): Potential role of FoxO1 and mTORC1 in the pathogenesis of Western diet-induced acne. Melnik BC, Zouboulis CC.

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63 Paleolithic Diet “A suitable diet attenuating increased mTORC1 activity is a Palaeolithic-like diet with reduced intake of sugar, hyperglycaemic grains, milk and milk products but enriched consumption of vegetables and fish.” Hautarzt Apr;64(4):252, 254-8, Acne and diet. Melnik BC.

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66 Broccoli is Anti-carcinogenic “Although many epidemiological studies have indicated that vegetables reduce the risk of chronic diseases, it remains unclear whether single extracted chemicals or whole vegetables are effective. Cruciferous vegetables are rich in isothiocyanates which protect the human body against carcinogenesis.” Murashima M, Watanabe S, Zhuo XG, Uehara M, Kurashige A. Phase 1 study of multiple biomarkers for metabolism and oxidative stress after one-week intake of broccoli sprouts. Biofactors. 2004;22(1-4):

67 Broccoli is Anti-carcinogenic “In 1992, sulforaphane, an isothiocyanate, was isolated from broccoli and showed phase 2 enzyme inducer activity [3]. Extracts of broccoli sprouts have 10–100 fold inducer activity of phase 2 enzymes compared to mature broccoli [4]. Mature broccoli also contains indole compounds that induce not only phase 2 enzymes but also phase 1 enzymes.” Murashima M, Watanabe S, Zhuo XG, Uehara M, Kurashige A. Phase 1 study of multiple biomarkers for metabolism and oxidative stress after one-week intake of broccoli sprouts. Biofactors. 2004;22(1-4):

68 Broccoli is Anti-carcinogenic “The anticarcinogenic effects of cruciferous vegetables may derive from the glucosinolates they contain; these are degraded into indoles and isothiocyanates. Indoles were studied in relation to breast cancer partly because of their effects on estrogen metabolism, and isothiocyanates (ITCs) are chemopreventive agents in animal models, perhaps due in part to their potent effects on inhibition of phase 1 and induction of phase II enzymes.” Breast cancer risk in premenopausal women is inversely associated with consumption of broccoli, a source of isothiocyanates, but is not modified by GST genotype. J Nutr May;134(5):

69 Broccoli is Anti-carcinogenic “In this case-control study specifically designed to examine associations between diet and breast cancer, we found that consumption of cruciferous vegetables, particularly broccoli intake, was associated with a reduced risk of premenopausal breast cancer. Significant risk reduction was not noted for postmenopausal women.” Breast cancer risk in premenopausal women is inversely associated with consumption of broccoli, a source of isothiocyanates, but is not modified by GST genotype. J Nutr May;134(5):

70 Broccoli is Anti-atherogenic “One week intake of broccoli sprouts significantly reduced total cholesterol and LDL cholesterol. Females had no significant reduction in total cholesterol but showed increased HDL cholesterol. Triacylglycerol levels were abnormal in six subjects at baseline. After treatment, three of them moved into normal range.” Murashima M, Watanabe S, Zhuo XG, Uehara M, Kurashige A. Phase 1 study of multiple biomarkers for metabolism and oxidative stress after one-week intake of broccoli sprouts. Biofactors. 2004;22(1-4):

71 Broccoli: Anticancer King “The consumption of cruciferous vegetables has been associated with a reduced risk of cancer of the lung, stomach, colon and rectum. The health benefits of cruciferous vegetables such as broccoli, Brussels sprouts, cabbage, and bok choy have been attributed to their high concentration of glucosinolates. The chemoprotective effect of indole-3-carbinol, a constituent of these vegetables, has been shown to have chemopreventive effects.” Heber D. Vegetables, fruits and phytoestrogens in the prevention of diseases.J Postgrad Med 2004;50:

72 Broccoli: Anticancer King “Isothiocyanates (found in Broccoli) act as anti- carcinogens by inducing Phase II conjugating enzymes, in particular Glutathione S-tranferases.” Heber D. Vegetables, fruits and phytoestrogens in the prevention of diseases.J Postgrad Med 2004;50:

73 Sulforaphane from Broccoli Causes G2/M Cell Arrest “Previously, we showed that sulforaphane (SFN), a naturally occurring cancer chemopreventive agent, effectively inhibits proliferation of PC-3 human prostate cancer cells by causing caspase- 9- and caspase-8-mediated apoptosis. Here, we demonstrate that SFN treatment causes an irreversible arrest in the G(2)/M phase of the cell cycle.” Singh SV, Herman-Antosiewicz A, Singh AV, Lew KL, Srivastava SK, Kamath R, Brown KD, Zhang L, Baskaran R. Sulforaphane-induced G2/M phase cell cycle arrest involves checkpoint kinase 2-mediated phosphorylation of cell division cycle 25C. J Biol Chem Jun 11;279(24): Epub 2004 Apr

74 Sulforaphane from Broccoli Causes G1 Cell Arrest “We demonstrated that sulforaphane arrested cell- cycle progression in G1 phase by a significant down-modulation of cyclin D3. Moreover, sulforaphane induced apoptosis (and also necrosis), mediated by an increase in the expression of p53, whereas it exerted little effect on bcl-2 and bax levels. These findings indicate that sulforaphane can exert protective effects inhibiting leukemic cell growth.” Fimognari C, Nusse M, Berti F, Iori R, Cantelli-Forti G, Hrelia P. Sulforaphane modulates cell cycle and apoptosis in transformed and non- transformed human T lymphocytes. Ann N Y Acad Sci Dec;1010:

75 Isothiocyanates from Broccoli Promote Detoxification “Plants of the family Brassicaceae contain high levels of glucosinolates. The latter compounds are degraded to isothiocyanates, some of which have been shown to be potent inducers of phase II detoxification enzymes in vitro.” Munday R, Munday CM. Induction of phase II detoxification enzymes in rats by plant- derived isothiocyanates: comparison of allyl isothiocyanate with sulforaphane and related compounds. J Agric Food Chem Apr 7;52(7):

76 Isothiocyanates from Broccoli Cause Decreased Cancer Growth “Taken together, our findings suggest that selected ITCs can rapidly initiate growth inhibition of cancer cells by simultaneously modulating multiple cellular targets, and their antiproliferative activity may be largely unaffected by their metabolism and disposition in vivo.” Zhang Y, Tang L, Gonzalez V. Selected isothiocyanates rapidly induce growth inhibition of cancer cells. Mol Cancer Ther Oct;2(10):

77 Broccoli Eradicates H. pylori “Consumption of oral broccoli sprouts was temporally associated with eradication of H. pylori infection in three of nine patients. Most patients found broccoli sprouts palatable. Further studies are needed to determine the optimal dose of broccoli sprouts and whether concomitant proton pump inhibitors or antibiotics might augment the effectiveness.” Galan MV, Kishan AA, Silverman AL. Dig Dis Sci Aug;49(7-8): Oral broccoli sprouts for the treatment of Helicobacter pylori infection: a preliminary report. 63

78 Evolution and Nutrition “Humans and a few primate species have trichromatic colour vision so that they are able to distinguish red from green. All other mammals have dichromatic vision and cannot distinguish between the two colours. One hypothesis for the evolution of this visual ability was that it conferred an advantage by enabling primates to distinguish red fruits from the green background of forest leaves.” Heber D. Vegetables, fruits and phytoestrogens in the prevention of diseases. J Postgrad Med [serial online] 2004 [cited 2005 Mar 9];50:

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80 Lycopene in Tomatoes “Several studies have linked the consumption of tomatoes and tomato products with a decreased risk of cancer and cardiovascular disease. The health benefits of lycopene have been attributed to its antioxidant properties, although other mechanisms of lycopene action are possible, including the modulation of intercellular communication, hormonal and immune system changes, and enhancement of gap junctional communication.” Heber D. Vegetables, fruits and phytoestrogens in the prevention of diseases. J Postgrad Med 2004;50:

81 Lycopene Reduces Cancers “In breast cancer cells, lycopene can interfere with insulin-like growth factor 1-stimulated tumour cell proliferation. The relationship between lycopene intake and prostate cancer risk has been reported and supported by studies linking low plasma levels of lycopene with an increased risk.” Heber D. Vegetables, fruits and phytoestrogens in the prevention of diseases. J Postgrad Med 2004;50:

82 Lycopene Reduces Cancers “Lycopene administration may reduce proliferation and increase apoptosis in human prostate tissue where lycopene is the predominant carotenoid. The anti-proliferative properties may extend to other types of cancer, including that of the colorectum. Lycopene may also inhibit cholesterol synthesis and enhance LDL degradation.” Heber D. Vegetables, fruits and phytoestrogens in the prevention of diseases. J Postgrad Med 2004;50:

83 Green Tea The Great Anti-cancer Drink 65

84 Green Tea: Anticancer Drink “Tea is one of the most popular beverages in the world and the consumption of tea has been associated with a decreased risk of developing cancer of the ovary, oral cavity, colon, stomach, and prostate. This beneficial health effect has been attributed to the epigallocatechin gallate (EGCG).” Heber D. Vegetables, fruits and phytoestrogens in the prevention of diseases.J Postgrad Med 2004;50:

85 Green Tea inhibits Cancer Growth “In recent years, epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent present in green tea, has shown remarkable effects in inhibiting cancer cell growth both in cell culture system and in in vivo tumour models.” Gupta S, Hussain T, Mukhtar H. Molecular pathway for (-)-epigallocatechin-3-gallate- induced cell cycle arrest and apoptosis of human prostate carcinoma cells. Arch Biochem Biophys Feb 1;410(1):

86 Green Tea Upregulates p21, an anti cancer gene “Earlier studies in our laboratory have shown that treatment of androgen-sensitive and androgen- insensitive human prostate carcinoma cells with EGCG resulted in G0/G1 phase cell cycle arrest and apoptosis, irrespective of the p53 status of these cells. This effect was mediated by upregulation in the protein expression of WAF1/p21.” Gupta S, Hussain T, Mukhtar H. Molecular pathway for (-)-epigallocatechin-3-gallate- induced cell cycle arrest and apoptosis of human prostate carcinoma cells. Arch Biochem Biophys Feb 1;410(1):

87 Green Tea Normalises the Cyclins that Drive Cancer Cells “In the present study, we demonstrate that EGCG, via modulation in the cki–cyclin–cdk machinery, results in a G1 phase arrest of the cell cycle followed by apoptosis of human prostate carcinoma cells.” Gupta S, Hussain T, Mukhtar H. Molecular pathway for (-)-epigallocatechin-3-gallate- induced cell cycle arrest and apoptosis of human prostate carcinoma cells. Arch Biochem Biophys Feb 1;410(1):

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89 Green Tea Inhibits Cancer “Epidermal growth factor receptor (EGFR) activation is absolutely required for cervical cell proliferation. This suggests that EGFR-inhibitory agents may be of therapeutic value. In the present study, we investigated the effects of epigallocatechin-3- gallate (EGCG), a bioactive green tea polyphenol, on EGFR signalling in cervical cells.” Sah JF, Balasubramanian S, Eckert RL, Rorke EA. Epigallocatechin-3-gallate inhibits epidermal growth factor receptor signaling pathway. Evidence for direct inhibition of ERK1/2 and AKT kinases. J Biol Chem Mar 26;279(13): Epub 2003 Dec

90 Green Tea Inhibits Cancer “EGCG inhibits epidermal growth factor-dependent activation of EGFR, and EGFR-dependent activation of the mitogen-activated protein kinases ERK1/2. EGCG also inhibits EGFR-dependent AKT activity.” Sah JF, Balasubramanian S, Eckert RL, Rorke EA. Epigallocatechin-3-gallate inhibits epidermal growth factor receptor signaling pathway. Evidence for direct inhibition of ERK1/2 and AKT kinases. J Biol Chem Mar 26;279(13): Epub 2003 Dec

91 Green Tea Inhibits Cancer: Mechanisms EGCG increased p53, p21(WAF-1), and p27(KIP-1) levels, reduced cyclin E level, and reduced CDK2 kinase activity. EGCG also caused a G(1) arrest. Moreover, sustained EGCG treatment caused apoptotic cell death. “These results suggest that EGCG acts to selectively inhibit multiple EGF-dependent kinases to inhibit cell proliferation.” Sah JF, Balasubramanian S, Eckert RL, Rorke EA. Epigallocatechin-3-gallate inhibits epidermal growth factor receptor signaling pathway. Evidence for direct inhibition of ERK1/2 and AKT kinases. J Biol Chem Mar 26;279(13): Epub 2003 Dec

92 Green Tea Inhibits Cancer: Actives “Many cell culture and animal studies have shown that catechins, the main compounds of the green tea leaves, are potent natural inhibitors of several RTKs.” Gouni-Berthold I, Sachinidis A. Molecular mechanisms explaining the preventive effects of catechins on the development of proliferative diseases. Curr Pharm Des. 2004;10(11):

93 Green Tea Protects Against LDL Oxidation 68

94 Teas Protects Against LDL Oxidation 69

95 Teas Benefit Atherosclerosis 69

96 Garlic The Prevention of Atherosclerosis and Cancer 83

97 Garlic Prevents Diseases “Recent studies have demonstrated that allium vegetables, especially garlic, have very high antioxidant activity among vegetables examined. Garlic is a popular spice added to several edible preparations all over the world and is a remedy for a variety of ailments. It has been reported to possess antifungal, antibacterial, hypoglycaemic, hyperglycemie, hypolipidaemic, antiatherosclerotic properties, and has been claimed to be effective against a number of diseases.” Khanum F, Anilakumar KR, Viswanathan KR. Anticarcinogenic properties of garlic: a review. Crit Rev Food Sci Nutr. 2004;44(6):

98 Garlic Prevents Cancers “Epidemiological studies have shown an inverse correlation between the consumption of garlic (and other allium vegetables) and gastric cancer in certain areas. Several animal experiments have shown that garlic treatment and aged garlic, in particular, counteracts formation and the development of various forms of experimentally induced tumours.” Khanum F, Anilakumar KR, Viswanathan KR. Anticarcinogenic properties of garlic: a review. Crit Rev Food Sci Nutr. 2004;44(6):

99 Garlic Prevents Cancers Khanum F, Anilakumar KR, Viswanathan KR. Anticarcinogenic properties of garlic: a review. Crit Rev Food Sci Nutr. 2004;44(6):

100 Garlic Prevents Cancers “The preventive effects of garlic on human cancer have been reported, for example, in China Gangshan county, where residents consume a large amount of garlic (on average 20 g garlic daily), this county had the lowest gastric cancer death rates (3.45/100000) and, in contrast, Quixia county, where little garlic is eaten, had the highest (40/100000).” Khanum F, Anilakumar KR, Viswanathan KR. Anticarcinogenic properties of garlic: a review. Crit Rev Food Sci Nutr. 2004;44(6):

101 Garlic Prevents Cancers Better than Chemotherapy “A number of researchers have shown the inhibitory effect of garlic on tumour growth using various cancer cell lines. The Chinese researchers using gastric cancer cell lines have shown that fresh garlic extract and diallyl trisulfide were more potent than 5-fluorouracil or mitomycin C in killing these cancer cells.” Khanum F, Anilakumar KR, Viswanathan KR. Anticarcinogenic properties of garlic: a review. Crit Rev Food Sci Nutr. 2004;44(6):

102 Garlic Prevents Cancers: Mechanisms The hypothesis underlying how garlic works is that garlic might raise the activity of enzyme systems that detoxify carcinogens. Several enzyme systems are known to oxidize, reduce, or hydrolyze (phase I reaction) and then conjugate or otherwise effect (phase 2 reaction) drugs, metabolites, carcinogens, and other toxic chemicals, thereby increasing their polarity and excretability. Khanum F, Anilakumar KR, Viswanathan KR. Anticarcinogenic properties of garlic: a review. Crit Rev Food Sci Nutr. 2004;44(6):

103 Garlic Prevents Cancers: Mechanisms “They also have demonstrated an increase in the GSH levels in rats fed alcohol and garlic protein along with a near normal activity of Superoxide dismutase, glutathione peroxidase, glutathioneS- transferase (GST), and catalase.” “Glutathione S-transferase is an important enzyme that conjugates electrophiles and assists in the detoxification of many carcinogens and other xenobiotics.” Khanum F, Anilakumar KR, Viswanathan KR. Anticarcinogenic properties of garlic: a review. Crit Rev Food Sci Nutr. 2004;44(6):

104 Garlic Prevents Cancers: Reducing Phase I Detoxification “Yang and collegues have postulated that diallyl sulphide (DAS) and its metabolites, diallyl sulphoxide and diallyl sulphone (scheme 4), inhibit cytochrome P450 2El.” Khanum F, Anilakumar KR, Viswanathan KR. Anticarcinogenic properties of garlic: a review. Crit Rev Food Sci Nutr. 2004;44(6):

105 Garlic Prevents Cancers: Reducing Phase I Detoxification “Since P450 2El is vital in catalyzing the activation of N-nitrosodimethyl amine (NOMA), 1,2-dimethyl hydrazine (DMH), benzene, alkanes, halogenated hydrocarbons, and many other low molecular weight environmental chemicals, inhibition of this enzyme is expected to block toxicity and carcinogenecity of these compounds.” Khanum F, Anilakumar KR, Viswanathan KR. Anticarcinogenic properties of garlic: a review. Crit Rev Food Sci Nutr. 2004;44(6):

106 Garlic Prevents Cancers: Antioxidant Effects “The effects of garlic on the activities of a number of antioxidant enzymes have been studied. The enzymes include glutathione peroxidase, GST, catalase, Superoxide dismutase. In these studies, it has been shown that garlic can scavenge free radicals and is a successful antioxidant, wherein garlic has the potency to induce activity of the antioxidant enzymes.” Khanum F, Anilakumar KR, Viswanathan KR. Anticarcinogenic properties of garlic: a review. Crit Rev Food Sci Nutr. 2004;44(6):

107 Garlic Prevents Cancers: Summary “Cancer prevention through dietary modification appears to be a practical and cost effective possibility. Our survey of the literature suggests that garlic may be classified as a dietary anticarcinogen on the basis of epidemiological and experimental investigation. Its anticarcinogenic role is particularly appealing in terms of preventing gastrointestinal cancer.” Khanum F, Anilakumar KR, Viswanathan KR. Anticarcinogenic properties of garlic: a review. Crit Rev Food Sci Nutr. 2004;44(6):

108 Detoxification Foods that enhance detoxification 93

109 Phase I Detox Alone Causes Cancers “Most carcinogen share quite unreactive and innocuous procarcinogens, which require conversion by cellular (Phase 1) enzymes to highly reactive, electrophilic, ultimate carcinogens that react directly with nucleophilic centers of macromolecules such as DNA, to produce a series of damaging events that can evolve into cancer.” Paul Talalay Chemoprotection against cancer by induction of Phase2 enzymes. BioFactors 12 (2000) 5–11 94

110 Phase I : 2 Balance is Critical “Consequently the outcome of carcinogen exposure is controlled in large part by the balance between Phase 1 enzymes that can generate ultimate carcinogens and Phase 2 enzymes that detoxify these products.” Paul Talalay Chemoprotection against cancer by induction of Phase2 enzymes. BioFactors 12 (2000) 5–11 94

111 Phase I : 2 Balance is Critical “Although these families of enzymes are under genetic and hormonal control, they are also regulated by inducers, and the shifting of this balance by induction toward the dominance of Phase 2 enzymes has emerged as an important strategy for achieving chemoprotection against toxicity and malignancy.” Paul Talalay Chemoprotection against cancer by induction of Phase 2 enzymes. BioFactors 12 (2000) 5–11 94

112 Brassica Foods Boost Phase 2 “Allyl isothiocyanate (AITC) is formed from sinigrin, a glucosinolate that is present in many Brassica vegetables. In the present study, the effect of various dose levels of AITC on the activities of the phase 2 detoxification enzymes quinone reductase (QR) and glutathione S-transferase (GST) in rat tissues has been examined.” Munday R, Munday CM. Selective induction of phase II enzymes in the urinary bladder of rats by allyl isothiocyanate, a compound derived from Brassica vegetables. Nutr Cancer. 2002;44(1):

113 Brassica Foods Boost Phase 2 “High dose levels of AITC, given daily for 5 days, increased the activity of QR and/or GST in the liver, kidneys, lungs, spleen, urinary bladder, glandular and nonglandular stomach, duodenum, jejunum, ileum, cecum, and colon plus rectum of the animals.” Munday R, Munday CM. Selective induction of phase II enzymes in the urinary bladder of rats by allyl isothiocyanate, a compound derived from Brassica vegetables. Nutr Cancer. 2002;44(1):

114 Brassica Foods Boost Phase 2 “The dose level of AITC found to be effective in rats approaches the level that could be achieved through human consumption of Brassica vegetables, suggesting that induction of phase 2 enzymes by food-derived isothiocyanates could contribute to the lower incidence of bladder cancer observed in individuals who regularly consume such vegetables.” Munday R, Munday CM. Selective induction of phase II enzymes in the urinary bladder of rats by allyl isothiocyanate, a compound derived from Brassica vegetables. Nutr Cancer. 2002;44(1):

115 Herbal Teas and Liver Detoxification “After four weeks of pretreatment, different cytochrome P450 (CYP) isoforms and phase 2 enzyme activities were determined by incubation of liver microsomes or cytosol with appropriate substrates. Activity of CYP1A2 in the liver microsomes of rats receiving dandelion, peppermint or chamomile tea was significantly decreased (P < 0.05) to 15%, 24% and 39% of the control value, respectively.” Maliakal PP, Wanwimolruk S. Effect of herbal teas on hepatic drug metabolizing enzymes in rats. J Pharm Pharmacol Oct;53(10):

116 Herbal Teas and Liver Detoxification “CYP1A2 activity was significantly increased by pretreatment with caffeine solution. No alterations were observed in the activities of CYP2D and CYP3A in any group of the pretreated rats. Activity of CYP2E in rats receiving dandelion or peppermint tea was significantly lower than in the control group, 48% and 60% of the control, respectively.” Maliakal PP, Wanwimolruk S. Effect of herbal teas on hepatic drug metabolizing enzymes in rats. J Pharm Pharmacol Oct;53(10):

117 Herbal Teas and Liver Detoxification “There was a dramatic increase (244% of control) in the activity of phase 2 detoxifying enzyme UDP- glucuronosyl transferase in the dandelion tea- pretreated group. There was no change in the activity of glutathione-S-transferase. The results suggested that, like green and black teas, certain herbal teas can cause modulation of phase 1 and phase 2 drug metabolizing enzymes.” Maliakal PP, Wanwimolruk S. Effect of herbal teas on hepatic drug metabolizing enzymes in rats. J Pharm Pharmacol Oct;53(10):

118 Detoxification: Role of the Liver “The liver plays an important role in protecting the organism from potentially toxic chemical insults through its capacity to convert lipophiles into more water-soluble metabolites which can be efficiently eliminated from the body via the urine.” Grant DM. Detoxification pathways in the liver. J Inherit Metab Dis. 1991;14(4):

119 Detoxification: Role of the Liver “This protective ability of the liver stems from the expression of a wide variety of xenobiotic biotransforming enzymes whose common underlying feature is their ability to catalyse the oxidation, reduction and hydrolysis (Phase 1) and/or conjugation (Phase 2) of functional groups on drug and chemical molecules.” Grant DM. Detoxification pathways in the liver. J Inherit Metab Dis. 1991;14(4):

120 Detoxification: Role of the Liver “The broad substrate specificity, isoenzyme multiplicity and inducibility of many of these enzyme systems make them particularly well adapted to handling the vast array of different chemical structures in the environment to which we are exposed daily. However, some chemicals may also be converted to more toxic metabolites by certain of these enzymes, implying that variations in the latter may be important predisposing factors for toxicity.” Grant DM. Detoxification pathways in the liver. J Inherit Metab Dis. 1991;14(4):

121 Detoxification: Role of the Liver There are 4 major phase II liver detoxification pathways: Methylation Glycination Glucuronidation Glycination 98

122 Detoxification: Role of Garlic Diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) are major components of garlic oil. Among these components, DADS has been well documented as the most potent in anti- tumour action against human tumour cell lines from colon, lung, and skin. We now report that DATS is the most potent inducer of phase 2 enzymes among allyl sulfides in rat liver. Fukao T, Hosono T, Misawa S, Seki T, Ariga T. The effects of allyl sulfides on the induction of phase II detoxification enzymes and liver injury by carbon tetrachloride. Food Chem Toxicol May;42(5):

123 Fukao T, Hosono T, Misawa S, Seki T, Ariga T. The effects of allyl sulfides on the induction of phase II detoxification enzymes and liver injury by carbon tetrachloride. Food Chem Toxicol May;42(5):

124 Turmeric Increases Phase II Liver Enzymes “Curcumin, a yellow pigment from Curcuma longa, is a major component of turmeric and is commonly used as a spice and food colouring material and exhibits antiinflammatory antitumour, and antioxidant properties. In this study we therefore investigated the effect of dietary supplementation of curcumin on the activities of antioxidant and phase II-metabolizing enzymes involved in detoxification.” Iqbal M, Sharma SD, Okazaki Y, Fujisawa M, Okada S. Dietary supplementation of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY male mice: possible role in protection against chemical carcinogenesis and toxicity. Pharmacol Toxicol Jan;92(1):

125 Turmeric Increases Phase 2 Liver Enzymes “Dietary supplementation of curcumin (2%, w/v) to male ddY mice for 30 days significantly increased the activities of glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and catalase to 189%, 179%, 189%, and 181% in liver and 143%, 134%, 167% and 115% in kidney respectively as compared with corresponding normal diet fed control (P< ).” Iqbal M, Sharma SD, Okazaki Y, Fujisawa M, Okada S. Dietary supplementation of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY male mice: possible role in protection against chemical carcinogenesis and toxicity. Pharmacol Toxicol Jan;92(1):

126 Turmeric Increases Phase 2 Liver Enzymes “Parallel to these changes, curcumin feeding to mice also resulted in a considerable enhancement in the activity of phase 2-metabolizing enzymes viz. glutathione S-transferase and quinone reductase to 1.7 and 1.8 times in liver and 1.1 and 1.3 times in kidney respectively as compared with corresponding normal diet fed control (P< ).” Iqbal M, Sharma SD, Okazaki Y, Fujisawa M, Okada S. Dietary supplementation of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY male mice: possible role in protection against chemical carcinogenesis and toxicity. Pharmacol Toxicol Jan;92(1):

127 Turmeric Increases Phase 2 Liver Enzymes “In general, the increase in activities of antioxidant and phase 2-metabolizing enzymes was more pronounced in liver as compared to kidney. The induction of such detoxifying enzymes by curcumin suggest the potential value of this compound as protective agent against chemical carcinogenesis and other forms of electrophilic toxicity.” Iqbal M, Sharma SD, Okazaki Y, Fujisawa M, Okada S. Dietary supplementation of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY male mice: possible role in protection against chemical carcinogenesis and toxicity. Pharmacol Toxicol Jan;92(1):

128 The “Polypill” – The New Preventative Medicine 101

129 The “Polypill” “In 2003 Wald and Law introduced the concept of the Polypill. The advocates of the Polypill selected six pharmacological components that by modifying different risk factors of cardiovascular disease multiplicatively might reduce the levels of cardiovascular disease in the population by more than 80%.” Franco OH, Bonneux L, de Laet C, Peeters A, Steyerberg EW, Mackenbach JP. The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%. BMJ Dec 18;329(7480):

130 The “Polypill” N J Wald, M R Law. A strategy to reduce cardiovascular disease by more than 80%. BMJ June 28; 326(7404):

131 Who Should Take the “Polypill”? “Among people without existing disease, the most discriminatory screening factor is age. As 96% of deaths from ischaemic heart disease or stroke occur in people aged 55 and over, treating everyone in this group would prevent nearly all such deaths.” N J Wald, M R Law. A strategy to reduce cardiovascular disease by more than 80%. BMJ June 28; 326(7404):

132 The “Polypill” N J Wald, M R Law. A strategy to reduce cardiovascular disease by more than 80%. BMJ June 28; 326(7404):

133 The “Polypill” Theoretical Benefits N J Wald, M R Law. A strategy to reduce cardiovascular disease by more than 80%. BMJ June 28; 326(7404):

134 The “Polypill” Conclusion “It is time to discard the view that risk factors need to be measured and treated individually if found to be “abnormal.” Instead it should be recognised that in Western society the risk factors are high in us all, so everyone is at risk; that the diseases they cause are common and often fatal; and that there is much to gain and little to lose by the widespread use of these drugs. No other preventive method would have so great an impact on public health in the Western world.” N J Wald, M R Law. A strategy to reduce cardiovascular disease by more than 80%. BMJ June 28; 326(7404):

135 The “Polymeal” Tastier and Healthier? 103

136 The “Polymeal” Effects “Combining all the ingredients of the Polymeal resulted in cardiovascular disease being reduced by 76% (95% confidence interval 63% to 84%). Whether increasing the amount of each ingredient would increase the effect of the Polymeal is uncertain. On the other hand, decreasing the quantities could be expected to reduce the effects of the Polymeal.” Franco OH, Bonneux L, de Laet C, Peeters A, Steyerberg EW, Mackenbach JP. The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%. BMJ Dec 18;329(7480):

137 The “Polymeal” Franco OH, Bonneux L, de Laet C, Peeters A, Steyerberg EW, Mackenbach JP. The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%. BMJ Dec 18;329(7480):

138 The “Polymeal” Increases Life Expectancy “The effect of the Polymeal represented a large increase in total life expectancy and life expectancy free from cardiovascular disease and a decrease in life expectancy with cardiovascular disease for both men and women. For men, taking the Polymeal would result in increases of 6.6 years in total life expectancy and 9.0 years in life expectancy free from cardiovascular disease.” Franco OH, Bonneux L, de Laet C, Peeters A, Steyerberg EW, Mackenbach JP. The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%. BMJ Dec 18;329(7480):

139 The “Polymeal” Increases Life Franco OH, Bonneux L, de Laet C, Peeters A, Steyerberg EW, Mackenbach JP. The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%. BMJ Dec 18;329(7480):

140 The “Polymeal” Increases Life Expectancy “The Polymeal is an effective, natural, probably safer, and tastier alternative to the Polypill to reduce cardiovascular disease and increase life expectancy in the general population. The effect was consistent in both men and women at age 50.” Franco OH, Bonneux L, de Laet C, Peeters A, Steyerberg EW, Mackenbach JP. The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%. BMJ Dec 18;329(7480):

141 The “Polymeal” Increases Life Expectancy: Side Effects “Adverse effects reported for garlic include malodorous breath and body odour. As garlic is destined for mass treatment, few people will still notice this after a while. No additional adverse effects should be expected from the other ingredients of the Polymeal.” Franco OH, Bonneux L, de Laet C, Peeters A, Steyerberg EW, Mackenbach JP. The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%. BMJ Dec 18;329(7480):

142 The “Polymeal” Increases Life Expectancy: Side Effects “Driving motor vehicles or performing activities that require high levels of attention shortly after the consumption of the Polymeal should be avoided. Moreover, considering the disturbing adverse effects of garlic, we do not recommend taking the Polymeal before a romantic rendezvous, unless the partner also complies with the Polymeal.” Franco OH, Bonneux L, de Laet C, Peeters A, Steyerberg EW, Mackenbach JP. The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%. BMJ Dec 18;329(7480):


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