Hazards Inherent in Meat Itself
If you are a sometime reader of this blog you will be familiar with some of the perils of eating meat. Scientific evidence shows that meat consumption increases risks for diabetes, cardiovascular disease and some cancers as well as shortens the lifespan. The question is, what is lurking in meat that can be so harmful to the human beings that eat it? That is exactly what these two blog articles are all about.
There is no doubt about the link between early death and meat consumption. Many studies have examined the meat-eating habits of large populations of people in reference to their risk of early death. For example, the Nurses’ Health study followed 83,644 women from 1980 to 2008 and the Health Professionals Follow-up Study followed 37,698 men from 1986 to 2008. All the participants in both studies were free of cardiovascular disease and cancer at the start of the studies. Results showed that consumption of both processed and unprocessed red meat was associated with a shorter lifespan and increased risk of dying from cancer and heart disease. These results held true even after controlling for age, weight, family history, exercise, smoking, alcohol consumption and intake of whole plant foods, thus strengthening the link between meat consumption itself and early death (1). Another large study under the NIH (National Institutes of Health) and the AARP (American Association of Retired Persons) followed over 500,000 men and women for ten years. Once again, meat consumption was associated with increased risk of early death from any cause as well as increased risk of dying from cancer and heart disease. This study also controlled for other diet and lifestyle factors such as smoking, exercising, alcohol use and actual diet content. The link between meat consumption and early death remained strong (2).
No one attribute of meat can be blamed for these unfortunate associations with disease and early death. In fact, meat contains many problematic substances, some a natural part of the meat and some that are acquired during the life of the meat animal or through the processing of its flesh. These next two blogs will attempt to summarize current knowledge about what makes eating meat a danger to human beings.
LET’S START WITH SOME GENERAL EFFECTS
CHOLESTEROL, SATURATED FAT AND ANIMAL PROTEIN
Eating foods that are derived from animals means being exposed to three elements that are potential threats to human health – cholesterol, saturated fat and animal protein. Studies have shown that dietary cholesterol and saturated fat are linked to an increase in the risk for heart disease including atherosclerosis (the build-up of plaques in the lining of blood vessels that can result in devastating cardiovascular events such as strokes and heart attacks) (3,4). There is also evidence that dietary protein rather than fat may have an even greater effect on the promotion of cardiovascular disease (5,6,7). The difficulty is that all animal-sourced foods contain these three substances and it is challenging to ascertain which of them might be the main culprit.
The question that follows is this. Is it really necessary to identify the actual offender before we make modifications in our diet? It may be that all three are partial contributors to the damaging effect of meat on health. The bottom line is that a large amount of scientific evidence accumulated over many decades shows that eating a diet that drastically minimizes or completely avoids animal products dramatically reduces the risk of developing heart disease, the second leading cause of death in Canada (14), and can even reverse atherosclerosis (8,9,10,11). The same diet also reduces the incidence of many cancers, the leading cause of death in Canada (12,13,14). It doesn’t really matter what specific component is inflicting harm on the human body when they are all delivered in the same food “package”.
LACK OF FIBER AND PHYTOCHEMICALS
Fiber is an integral part of plants. Plants are also the only source of phytochemicals, substances produced by plants in order to protect themselves against environmental threats like insects, disease and pollution. Animal-sourced food comes with neither fiber nor phytochemicals. One of the problems of eating more animal-sourced foods is that they displace the plants that can supply these important nutrients.
Higher fiber intake is associated with decreased risk of cancers, especially those of the colon and the breast, and lower risk of stroke, high cholesterol, heart disease, Crohn’s disease, ulcerative colitis and diverticulitis (15,16). Research points to phytochemicals as being a large part of the reason that diets rich in fruits, vegetables and whole grains offer protection against cancer, cardiovascular disease, type-2 diabetes and cognitive degeneration (17,18,19,20,21,22). Studies looking specifically at phytochemicals show links between them and decreased risks of cancer. (23,24,25). Phytochemicals also have a preventative influence on obesity (26) and have been shown to be protective of cognitive ability (27,28,29,30).
Most North Americans consume less than half of the daily amount of fiber that is recommended for good health (31,32). This translates into low consumption of plant-based foods and inevitably means an accompanying low intake of phytochemicals.
Inflammation is a normal body process that helps our bodies fight dangers such as infections or injuries. Such acute inflammation disappears once the immediate threat is gone. However, when inflammation becomes chronic it can lead to illnesses such as asthma, arthritis, acne, chronic infections such as hepatitis C and the development and progression of chronic diseases including cardiovascular, diabetes and cancer (33). Multiple studies point to the consumption of meat as a cause of chronic inflammation. Meat consumption elevates hs-CRP, a measurement of inflammation (34). A 2017 study found that meat intake is associated with high levels of arachidonic acid, an element that promotes inflammation (35). Even a single high-fat animal-sourced meal causes a spike in inflammation soon after eating that takes five to seven hours to calm down. Sadly that is just about time for the next meal which in our culture likely consists of another load of high-fat, inflammation-producing food (36,37).
AND NOW SOME MORE SPECIFIC EFFECTS
Iron is important for carrying oxygen to body tissues. Human beings ingest two types of iron – non-heme iron and heme iron. Non-heme iron is found in plant-based foods; heme iron is derived only from animal sources. We now know that heme iron is associated with cancer (38), particularly gastrointestinal cancers (39). It causes the production of free radicals such as unstable N-nitroso compounds (NOCs) that induce oxidation and inflammation, which contribute to damage to cell membranes, proteins and DNA thereby promoting cancer formation (39,40). Research has substantiated that eating animal-based foods increases NOC levels in the body while eating plant-based foods does not (41,42,43). Higher heme iron intake and increased body iron stores are also significantly associated with greater risk of Type-2 diabetes (44).
For many decades heme iron was thought of as being the superior iron type because it is absorbed more efficiently than non-heme iron. Lack of iron can cause exhaustion, affecting many parts of the body from brain function to the immune system’s ability to fight off infections. But iron is a double-edge sword. Too little iron means we cannot efficiently transport oxygen to our tissues; too much can cause inflammation and increase the risk of heart disease, diabetes and cancer. Unfortunately, humans have more of a problem with excess iron than with too little. The human body has no specific mechanism to get rid of excess iron, although it is interesting to note that removing blood from the body through regular blood donations has been shown to cut the risk of gastrointestinal cancers in half (45). Humans do however have a means to prevent excess iron absorption, though it only works effectively on non-heme iron, the type found predominantly in plant foods. Through this mechanism, once enough iron has accumulated in the body, further absorption of non-heme iron is blocked (46,47).
IGF-1 (INSULIN-LIKE GROWTH FACTOR-1)
IGF-1 is a growth hormone that controls the rate at which our cells increase and decrease in numbers and in size. When we are children IGF-1 levels are high to promote growth; levels go down as we become adults. Since the goal of IGF-1 is to keep cells alive, dividing and growing, high IGF-1 in an adult can lead to the development of cancer. IGF-1 seems to play a major role in transforming normal cells into cancer cells and then helping them to survive, proliferate and even to migrate through the body to grow new tumours (metastasize) (48,49,50,51). Indeed, the more IGF-1 travelling in our bloodstreams, the higher our risk for cancer (50,52).
Excess IGF-1 comes from eating animal proteins such as those found in all types of meat, eggs and dairy products. The more animal protein consumed, the higher the circulating IGF-1 in the bloodstream. Conversely, studies show that eating plant protein lowers IGF-1 levels (53,54) however only completely plant-based diets (no animal protein at all) show significantly lower blood IGF-1 levels. Plant-based diets also result in higher levels of a protein called IGF-Binding-Protein (IGFBP), a protein that binds IGF-1 and limits its availability to the body (55,56,57). In one study, after only eleven days of eating no animal protein, IGF-1 levels dropped by 11% and levels of IGFBP increased by 50%. Tellingly, adding IGF-1 back into the diet of study subjects completely erased the beneficial lowering of IGF-1 (53). A 2014 study followed 6000 American adults for eighteen years and found that those who ate the most animal protein had a 75% increased risk of death from all causes and a four-fold increase in cancer-related death compared to those eating mostly plant-based protein (58).
Animal sourced foods contain two nutrients that are broken down by the microscopic inhabitants of the human gut (the gut microbiome) into a waste product called trimethylamine (TMA).
The first of these is carnitine, a derivative of the amino acid lysine, which is used in transporting fatty acids into the cell mitochondria where they are oxidized to produce energy. It is not necessary to consume carnitine for health because the human body can produce all that it requires. Carnitine is found in animal products such as meat (including fish and poultry) and milk. Some vegetables such as asparagus contain carnitine but in amounts that are only a fraction of those contained in animal-sourced foods (59).
The second nutrient is choline, necessary for the structure of cell membranes and the production of acetylcholine, an important neurotransmitter for memory, mood and other brain functions. The human body can produce some choline but not enough to meet its needs so choline-containing foods are an important part of the diet. Choline is found mainly in eggs but also in meat (including poultry and fish), dairy products and in lecithin supplements. Vegetable sources provide much smaller amounts of choline and include cruciferous vegetables, beans, nuts, seeds and whole grains. Nonetheless a healthy plant-based diet can provide sufficient choline for body health (60).
The problem with TMA is that the human liver oxidizes it to TMAO (trimethylamine N-oxide) within an hour of eating the carnitine- or choline-containing food. TMAO injures the lining of our arteries, creates inflammation, increases blood clotting and increases the build-up of cholesterol and other substances within atherosclerotic plaques in the blood vessels (61). Studies have found that people with the most TMAO circulating in their bloodstream increase their risk of stroke, myocardial infarction and death by two and a half times. This increase in cardiovascular events remains even after adjustment for traditional risk factors (62,63,64). A 2017 meta-analysis of eleven prospective cohort studies found that higher circulating TMAO was associated with 23% higher risk of cardiovascular events and a 55% higher risk of mortality (65).
Diet plays an integral role in the type of bacteria that live in our guts. Eating animal products encourages the type of gut flora that can digest carnitine and choline and release TMA. Conversely, people who do not eat animal products do not harbour these bacteria. In one study, long-term vegans ate an 8-ounce steak, and their TMAO levels remained very low. Vegans simply do not have the bacteria that turn carnitine or choline into TMA and no TMA means no TMAO. Another arm of the same study found that after a week of taking a broad-spectrum antibiotic by a meat-eating subject, eating an 8-ounce steak resulted in no increase in TMAO. Three weeks later, after the gut bacteria had time to recover from the effects of the antibiotic, re-challenge with the meat resulted in a spike in TMAO, illustrating the critical role that gut microbes play in TMAO production (62).
More recently, a strong link between TMAO and the development of colorectal cancer has been discovered (66). In the Women’s Health Initiative Study, women with the highest TMAO levels in their blood had about 3.5 times greater risk of rectal cancer (67). Another study looked at TMAO and prostate cancer and also found a higher risk of prostate cancer with higher TMAO blood levels (68).
Neu5Gc is a member of the sialic acid family, a diverse group of sugars that has been identified in the meat of some mammals, especially that of carnivores. Neu5Gc is produced naturally by many mammals but not by humans due to a gene mutation that occurred about 2 or 3 million years ago during the evolution of human beings. Our closest relatives, the great apes including chimpanzees, gorillas, orangutans and bonobos, still produce Neu5Gc (69). Yet in spite of our inability to form Neu5Gc it can be found incorporated onto the surface of human cells.
Where does it come from? It appears that our source is the meat, animal organs and dairy products that we consume (70). A problem arises when humans eat a source of Neu5Gc. Though our bodies do not recognize this molecule, we begin to incorporate it into our own tissues where it triggers the creation of antibodies. This inflammatory immune response can become chronic inflammation and encourage the formation of cancers and the onset of cardiovascular disease (71,72,73,74).
This is a new finding and more study is needed. However if further investigation corroborates these early findings, we may be able to look to our diet choices as potential non-toxic antidotes for Neu5Gc-caused inflammation.
LEUCINE AND M-TOR
The benefits of calorie restriction on lifespan are clear (75,76) but reducing calories over the long term is difficult. New research is suggesting that it is actually the restriction of protein intake specifically that is important for extending life (77,78). Protein restriction suppresses IGF-1 (see discussion of IGF-1 above) as well as a cell signalling process known as the m-TOR pathway of aging (79). Overstimulation of the m-TOR pathway is implicated in the development of both diabetes and cancers.
One particular amino acid, leucine, appears to have the greatest effect on the m-Tor pathway (80). Simply cutting down on leucine seems to have almost as much benefit for long life as decreasing all protein (81). The amino acid leucine is found predominantly in animal-sourced foods such as meat (including chicken and fish), dairy and eggs. Plant-based foods contain dramatically less of this amino acid. The only way to lower leucine intake is to restrict ingestion of animal protein and increase plant and fruit consumption (82).
Phosphorus is a mineral that is required for bodily functions such as energy metabolism, maintaining cell membranes, translating genetic information and regulating calcium. In the past phosphorus was not a mineral to worry about except in chronic kidney disease where phosphate intake needs to be curtailed. But times have changed. The North American diet with its high amounts of animal protein and processed foods has become very high in phosphorus content.
Many studies have linked high phosphorus intake in human beings to greater risk of early death from all causes (83). High level of phosphorus in the blood is an independent predictor of heart attacks and early death in general (84). In addition high phosphorus levels increase the risk of kidney failure, heart failure, coronary death and are associated with shorter lifespan (84,85,86,87,88). Phosphorus may also be contributing to poor bone health, causing increased bone loss and greater bone fracture risk (89, 85).
Phosphorus is found in its natural organic form in meat, poultry, seafood, dairy foods, nuts, seeds, beans and whole grains. There is also an inorganic form of phosphorus that is absorbed into the body much more easily than the organic form. Inorganic phosphates are food additives used as preservatives, flavour enhancers, moisture binders, emulsifiers, leavening agents and anti-caking agents. They make food taste better, last longer on the shelf and look better. Phosphate additives can be found in packaged meats, processed cheeses, dry cereals and many beverages including colas (90). A recent study found that 44% of top-selling grocery items in north-east Ohio contained phosphate additives. Especially affected foods included frozen foods, dry food mixes and processed meats (91). Food manufacturers are under no obligation to list phosphorus content on labels. Some phosphorus-containing additives to look for are phosphoric acid, pyrophosphate, dipotassium phosphate, hexametaphosphate or diammonium phosphate.
The bioavailability of the natural phosphorus in most animal products is around 75%. Inorganic phosphate additives are almost 100% absorbable. Though nutrient tables list the amount of phosphorus in plants as fairly high, its bioavailability is only around 30 to 50%. This is because the phosphorus in plant foods is in the form of phytic acid which is not easily digestible by humans (92,90). (Bioavailability is the amount of a substance that is actually absorbed into the body and so able to have an active effect.)
The type of protein you eat can have a very significant effect on human hormones. Here are some examples.
Testosterone concentrations of men were found to be consistently higher after ten days on a high carbohydrate diet (93). Conversely body builders who eat higher protein levels before a competition can end up cutting their testosterone level in half (94).
A single meal high in animal protein nearly doubles the blood level of the stress hormone cortisol within a half an hour (95) while a meal containing a lower level of plant protein decreases stress hormone levels (96). Studies show that a high carbohydrate diet results in consistently lower cortisol concentrations suggesting that the ratio of protein to carbohydrate in the human diet is a regulatory factor for steroid hormone blood levels (97).
The type of protein that is eaten during childhood (12 months to 6 years old) affects the age of puberty. Higher total protein and higher animal protein are associated with an early growth spurt during puberty and early onset of menstruation whereas a higher intake of vegetable protein is associated with later onset of puberty (98).
Amazingly, the foods a mother eats during pregnancy can result in lifelong effects on her children. Studies have demonstrated that cortisol levels in the 28 to 30 year old children of mothers who ate a high-protein, low-carbohydrate diet in late pregnancy are higher by 5.6% per portion of maternal meat/fish consumption per day and lower by 3.3% per portion of maternal green vegetable consumption per week (99). Children of mothers who ate 14 to 16 meat or fish portions per week during their pregnancy demonstrated 22% higher average cortisol blood concentrations in a stress test performed in their adulthood. Children of mothers who ate at least 17 portions of meat or fish per week showed 46% higher average cortisol blood concentrations at the age of 36 years. The effects of a high-protein, low-carbohydrate diet in late pregnancy also showed up in increased response to psychological stress in the adult offspring (100).
Additionally mothers who eat a high-animal-protein, low-carbohydrate diet during pregnancy have children who show higher blood pressures at 27 to 30 years of age. Children of mothers who ate higher amounts of meat and fish in the second half of pregnancy had higher systolic blood pressures as adults. Mothers who consumed higher amounts of fish but not meat during pregnancy had children with higher diastolic blood pressure. These associations were independent of maternal blood pressure, body size and smoking habits during pregnancy (101).
Consuming more animal-sourced foods during pregnancy, especially meat products, increases the risk of the child becoming an overweight adult, especially for female offspring (102).
It is thought that the effects of animal protein ingestion during pregnancy on blood pressures and weight may be due to chemical pollutants in meat such as EDCs (endocrine-disrupting chemicals) (103). EDCs can alter the function of many hormones. They are ubiquitous in modern environments and can be found in foods, clothing, fragrances, pharmaceuticals, personal care and cleaning products, pesticides and plastics. And they are fat soluble so they accumulate in animal fat, another reason to reduce our intake of animal products (104,105,106,107).
Time to take a break! The second installment on this topic will look at hazards in meat that are acquired during the lifetime of a meat animal or in the processing of the meat. See the blog called “Why is Eating Meat So Damaging to Human Health? Part Two: Acquired Hazards of Meat”.
1 Pan, A., Sun, Q., Bernstein, A.M., Schulze, M.B., Manson, J.E., Stampfer, M.J., Willett, W.C., Hu, F.B. Red Meat Consumption and Mortality: Results from Two Prospective Cohort Studies. Arch Intern Med. 2012 Apr 9; 172(7): 555-563.
2 Rashmi, S., Cross, A.J., Graubard, B.I., Leitzmann, M.F., Schatzkin, A. Meat intake and mortality: a prospective study of over half a million people. Arch Intern Med. 2009 Mar 23; 169(6): 562–571.
3 Zong, G., Li, Y., Wanders, A.J., et al. Intake of individual saturated fatty acids and risk of coronary heart disease in US men and women: two prospective longitudinal cohort studies. BMJ. 2016 Nov 23;355:i5796.
4 Chen, M., Li. Y/, Sun. Q., et al. Dairy fat and risk of cardiovascular disease in 3 cohorts of US adults. Am J Clin Nutr. Nov 2016; 104(5): 1209-1217.
5 Song, M., Fung, T., Hu, F.B., et al. Association of Animal and Plant Protein Intake With All-Cause and Cause-Specific Mortality. JAMA Intern Med Oct 2016; (10): 1453-1463.
6 Barbour, M.F., Ashraf, F., Roberts, M.B., et al. Association of dietary protein, animal and vegetable protein with the incidence of heart failure among postmenopausal women. Circulation Nov 2016; 134, No. suppl 1.
7 Wang, D., Campos, H., Baylin, A. Red meat intake is positively associated with non-fatal acute myocardial infarction in the Costa Rica Heart Study. Br J Nutr. 2017; 118: 303-311.
8 Esselstyn, C.B., Gendy, G., Doyle, J., Golubic, M., Roizen, M.F. A Way to Reverse CAD? J Fam Pract. 2014 Jul; 63(7):356-364b.
9 Campbell, T.C., Parpia, B., Chen, J. Diet, Lifestyle, and the Etiology of Coronary Artery Disease: the Cornell China Study. Am J Cardiol. 1998 Nov 26; 82(10B):18T-21T.
10 Esselstyn, C.B., Ellis, S.G., Medendorp, S.V., Crowe,T.D. A Strategy to Arrest and Reverse Coronary Artery Disease: A 5-year Longitudinal Study of a Single Physician’s Practice. J Fam Pract. 1995 Dec; 41(6):560-568.
11 Ornish, D., Brown, S.E., Scherwitz, L.W., Billings, J.H., Armstrong, W.T., Ports, T.A., McLanahan, S.N., Kirkeeide, R.L., Brand, R.J., Gould, K.L. Can Lifestyle Changes Reverse Coronary Heart Disease? The Lifestyle Heart Trial. Lancet. 1990 Jul 21; 336(8708):129-133.
12 Sieri, S., Chiodini, P., Agnoli, C., et al. Dietary Fat Intake and Development of Specific Breast Cancer Subtypes. J Natl Cancer Inst 2014 Apr 9;106(5). pii: dju068.
13 Tabung, F.K., Steck, S.E., Zhang, J., Ma, Y.,Liese, A.D. et al. Longitudinal Changes in the Dietary Inflammatory Index: An Assessment of the Inflammatory Potential of Diet over Time in Postmenopausal Women. Eur J Clin Nutr 2016 Dec; 70(12): 1374–1380.
15 Wick, J.Y. Diverticular disease: Eat your fiber! Consult Pharm. 2012 Sep; 27(9): 613-618.
16 Dilzer, A., Jones, J.M., Latulippe, M.E. The Family of Dietary Fibers: Dietary Variety for Maximum Health Benefit. Nutrition Today. 2013 May/June; 48(3):108-118.
17 World Cancer Research Fund. Food, nutrition, physical activity, and the prevention of cancer: A global perspective. American Institute of Cancer Research. Washington, DC: 2007
18 Hung, H.C., Joshipura, K.J., Jiang, R., et al. Fruit and vegetable intake and risk of major chronic disease. J Natl Cancer Inst. 2004; 96(21):1577-1584.
19 Slavin, J.L., Lloyd, B.. Health benefits of fruits and vegetables. Adv Nutr. 2012;3 (4):506-516.
20 Dauchet, L., Amouyel, P., Hercberg, S., Dallongeville, J. Fruits and vegetable consumption and risk of coronary heart disease: a meta-analysis of cohort studies. J Nutr. 2006:136(10):2588-2593.
21 He, F.J., Nowson, C.A., Lucas, M., MacGregor, G.A. Increased consumption of fruit and vegetables is related to a reduced risk of coronary heart disease: meta-analysis of cohort studies. J Hum Hypertens. 2007:21(9):717-728.
22 Boeing, H., Bechthold, A., Bub, A., Ellinger, S., Haller, D., et al. Critical review: vegetables and fruit in the prevention of chronic diseases. Eur J Nutr. 2012;51: 637-663.
23 Hui, C., Qi, X., Qianyong, Z., Xiaoli, P., Jundong, Z., Mantian, M. Flavonoids, flavonoid subclasses and breast cancer risk: a meta-analysis of epidemiologic studies. PLoS One. 2013;8(1):e54318.
24 Romagnolo, D.F., Selmin, O. Flavonoids and cancer prevention: a review of the evidence. J Nutr Gerontol Geriatr. 2012; 31(3):206-238.
25 Juge, N., Mithen. R,F,, Traka. M. Molecular basis for chemoprevention by sulforaphane: a comprehensive review. Cell Mol Life Sci. 2007; 64(9):1105-1127.
26 Gonzalez-Castejon, M., Rodriguez-Casado, A. Dietary phytochemicals and their potential effects on obesity: a review. Pharmacol Res. 2011; 64(5):438-455.
27 Davinelli, S., Sapere, N., Zella, D., Bracale, R., Intrieri, M., Scapagnini, G. Pleiotropic protective effects of phytochemicals in Alzheimer’s Disease. Oxid Med Cell Longev. 2012; 2012:386527.
28 Mythri, R.B., Bharath, M.M. Curcumin: a potential neuroprotective agent in Parkinson’s disease. Curr Pharm Des. 2012;18(1):91-99.
29 Spencer, J.P. Flavonoids and brain health: multiple effects underpinned by common mechanisms. Genes Nutr. 2009; 4(4):243-250.
30 Williams, R.J., Spencer, J.P. Flavonoids, cognition, and dementia: actions, mechanisms, and potential therapeutic utility for Alzheimer disease. Free Radic Biol Med. 2012:52(1):35-45.
32 Rizzo, N.S., Jaceldo-Siegl, K., Sabate, J., Fraser,G.E. Nutrient Profiles of Vegetarian and Nonvegetarian Dietary Patterns. J Acad Nutr Diet. 2013 Dec; 113(12):1610-1619.
34 Ley, S.H., Sun, Q., Willett, W.C., Eliassen, A.H., Wu, K., Pan, A., Grodstein, F., Hu, F.B. Associations between red meat intake and biomarkers of inflammation and glucose metabolism in women. Am J Clin Nutr. 2014 Feb; 99(2):352-360. 27.
35 Seah, J.Y., Gay, G.M., Su, J., Tai, E.S., Yuan, J.M., Koh, W.P., Ong, C.N., van Dam, R.M. Consumption of Red Meat, but Not Cooking Oils High in Polyunsaturated Fat, Is Associated with Higher Arachidonic Acid Status in Singapore Chinese Adults. Nutrients. 2017 Jan 31; 9(2).
36 Vogel, R.A., Corretti, M.C., Plotnick, G.D. Effect of a single high-fat meal on endothelial function in healthy subjects. Am J Cardiol. 1997 Feb 1; 79(3):350-354.
37 Rosenkranz, S.K., Townsend, D.K., Steffens, S.E., Harms, C.A. Effects of a high-fat meal on pulmonary function in healthy subjects. Eur J Appl Physiol. 2010 Jun; 109(3):499-506.
38 Qiao, L., Feng,Y. Intakes of heme iron and zinc and colorectalcancer incidene: A meta-analysis of prospective studies. Cancer Causes Control 2013; 24(6): 1175-1183.
39 Ward, M.H., Cross, A.J., Abnet, C.C., Sinha, R., Markin, R.S., Weisenburger, D.D. Heme iron from meat and risk of adenocarcinoma of the esophagus and stomach. Eur J Cancer Prev. 2012 Mar; 21(2):134-138
40 Atamna, H. Heme, iron, and the mitochondrial decay of ageing. Ageing Res Rev. 2004; 3(3):303-318.
41 Cross, A.J., Pollock, J.R., Bingham, S.A. Heme, not protein or inorganic iron, is responsible for endogenous intestinal N-nitrosation arising from red meat. Cancer Res 2003; 63(10: 2358-2360.
42 Bingham, S.A., Hughes, R., Cross, A.J. Effect of white versus red meat on endogenous N-nitrosation in the human colon and further evidence of a dose response. J Nutr. 2002 Nov; 132(11 Suppl):3522S-3525S.
43 Joosen, A.M., Kuhnle, G.G., Aspinall, S.M., Barrow, T.M. et al. Effect of processed and red meat on endogenous nitrosation and DNA damage. Carcinogenesis. 2009 Aug; 30(8):1402-1407.
44 Bao, W., Rong, Y., Rong, S., Liu, L. Dietary iron intake, body iron stores, and the risk of type 2 diabetes: a systematic review and meta-analysis. BMC Med. 2012 Oct 10; 10:119.
45 Zacharski, L. R., Chow, B., Howes, P. et al. Decreased Cancer Risk After Iron Reduction in Patients With Peripheral Arterial Disease: Results From a Randomized Trial. J Natl Cancer Inst. 2008; 100:1-7.
46 Cook, J.D. Adaptation in iron metabolism. Am J Clin Nutr. 1990 Feb; 51(2):301-308.
47 Miret, S., Simpson, R.J.,McKie, A.T. Physiology and molecular biology of dietary iron absorption. Annu Rev Nutr. 2003; 23:283-301.
48 Salvioli, S., Capri, M., Bucci, L., Lanni, C., Racchi, M. et al. Why do centenarians escape or postpone cancer? The role of IGF-1, inflammation and p53. Cancer Immunol Immunother. 2009 Dec; 58(12):1909-1917.
49 Brahmkhatri, V.P., Prasanna, C., Atreya, H.S. Insulin-Like Growth Factor System in Cancer: Novel Targeted Therapies. BioMed Research International 2015; 2015(2015) Article ID 538019, 24 pages
50 Renehan, A.G., Zwahlen, M., Minder, C., O’Dwyer, S.T., Shalet, S.M., Egger, M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet. 2004 Apr 24; 363(9418):1346-53.
51 Kleinberg, D.L., Wood, T.L., Furth, P.A., Lee, A.V. Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions. Endocr Rev. 2009; 30(1):51-74.
52 Kaaks, R. Nutrition, insulin, IGF-1 metabolism and cancer risk: a summary of epidemiological evidence.
Novartis Found Symp. 2004;262:247-260.
53 Ngo, T.H., Barnard, R.J., Tymchuk, C.N., Cohen, P., et al. Effect of diet and exercise on serum insulin, IGF-I, and IGFBP-1 levels and growth of LNCaP cells in vitro (United States). Cancer Causes Control. 2002 Dec; 13(10):929-35.
54 Allen, N.E., Appleby, P.N., Davey, G.K., Key, T.J. Hormones and diet: low insulin-like growth factor-I but normal bioavailable androgens in vegan men. Br J Cancer. 2000 Jul; 83(1):95-7.
55 Allen, N.E., Appleby, P.N., Davey, G.K., Kaaks, R., Rinaldi, S., Key, T.J. The associations of diet with serum insulin-like growth factor I and its main binding proteins in 292 women meat-eaters, vegetarians, and vegans. Cancer Epidemiol Biomarkers Prev. 2002 Nov; 11(11):1441-8.
56 Ornish, D., Weidner, G., Fair, W.R., Marlin, R., Pettengill, E.B., Raisin, C.J. et al. Intensive lifestyle changes may affect the progression of prostate cancer. J Urol. 2005 Sep; 174(3):1065-9; discussion 1069-70.
57 Baxter, R.C. IGF binding proteins in cancer: mechanistic and clinical insights. Nature Reviews Cancer 2014: 14, 329–341
58 Levine, M.E., Suarez, J.A., Brandhorst, S. et al. 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. 2014; 19:407-417.
61 Velasquez, M.T., Ramezani, A., Manal, A., Raj, D.S. Trimethylamine N-Oxide: The Good, the Bad and the Unknown. Toxins (Basel) Nov 2016; 8(11): 326.
62 Koeth, R.A., Wang, Z., Levison, B.S., Buffa, J.A., Org, E., Sheehy, B.T., et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine. May 2013; 19 (5): 576–585.
63 Tang, W.H.W., Wang, Z., Levison, B.S., Koeth, R.A., Britt, E.B. et al. Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk . N Engl J Med 2013; 368:1575-1584
64 Mente, A., Chalcraft, K., Ak, H., Davis, A.D., Lonn, E. et al. The Relationship Between Trimethylamine-N-Oxide and Prevalent Cardiovascular Disease in a Multiethnic Population Living in Canada. Can J Cardiol. 2015 Sep; 31(9):1189-1194.
65 Qi, J., You, T., Li, J., Pan, T., Xiang, L., Han, Y., Zhu, L. Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies. J Cell Mol Med. 2018 Jan; 22(1):185-194.
66 Xu, R., Wang, Q, Li, L. A genome-wide systems analysis reveals strong link between colorectal cancer and trimethylamine N-oxide (TMAO), a gut microbial metabolite of dietary meat and fat. BMC Genomics. 2015; 16 Suppl 7:S4.
67 Bae, S., Ulrich, C.M., Neuhouser, M.L., Malysheva, O., Bailey, L.B., Xiao, L., Brown, E.C., Cushing-Haugen, K.L., Zheng, Y., Cheng, T.Y., Miller, J.W., Green, R., Lane, D.S., Beresford, S.A., Caudill, M.A. Plasma choline metabolites and colorectal cancer risk in the Women’s Health Initiative Observational Study. Cancer Res. 2014 Dec 15; 74(24):7442-7452.
68 Mondul, A.M., Moore, S.C., Weinstein, S.J., Karoly, E.D., Sampson, J.N., Albanes, D. Metabolomic analysis of prostate cancer risk in a prospective cohort: The alpha-tocolpherol, beta-carotene cancer prevention (ATBC) study. Int J Cancer. 2015 Nov 1; 137(9):2124-2132.
69 Oellgaard, J., Winther, S.A., Hansen, T.S., Rossing, P., von Scholten, V.J. Trimethylamine N-oxide (TMAO) as a New Potential Therapeutic Target for Insulin Resistance and Cancer. Curr Pharm Des. 2017; 23(25):3699-3712.
70 Tangvoranuntakul, P., Gagneux, P., Diaz, S., Bardor, M., Varki, N., Varki, A., Muchmore, E. Human uptake and incorporation of an immunogenic nonhuman dietary sialic acid. Proc Natl Acad Sci U S A. 2003 Oct 14; 100(21):12045-12050.
71 Alisson-Silva, F., Kawanishi, K., Varki, A. Human risk of diseases associated with red meat intake: Analysis of current theories and proposed role for metabolic incorporation of a non-human sialic acid. Molecular Aspects of Medicine. 2016; 51: 16–30
72 Ji, S., Wang, F., Chen, Y., Yang, C., Zhang, P.,Zhang, X., Troy, F.A. Developmental changes in the level of free and conjugated sialic acids, Neu5Ac, Neu5Gc and KDN in different organs of pig: a LC-MS/MS quantitative analyses. Glycoconjugate Journal February, 2017; 34(1): 21-30.
73 Samraj, A.N., Läublia, H, Varki, N., Varki, A. Involvement of a non-human sialic acid in human cancer. Front Oncol. 2014 Feb 19; 4:33.
74 Samraj, A.N., Pearce, O.M.T., Läubli, H., Crittenden, A.N., Bergfeld, A.K., Banda, K., Gregg, C. J., Bingman, A.E., et al. A red meat-derived glycan promotes inflammation and cancer progression. PNAS January 13, 2015; 112 (2): 542-547.
75 Pallavi, R., Pelici, G.M. Insights into the beneficial effect of caloric/ dietary restriction for a healthy and prolonged life. Front Physiol. 2012 Aug 9;3:318.
76 Dirks, A.J., Leeuwenburgh, C. Caloric restriction in humans: potential pitfalls and health. Mech Ageing Dev. 2006 Jan;127(1):1-7.
77 Gallinetti, J., Harputlugil, E., Mitchell, J.R. Amino acid sensing in dietary-restriction-mediated longevity: Roles of signal-transducing kinases GCN2 and TOR. Biochem J. 2013 449(1):1 – 10.
78 Nakagawa, S., Lagisz, M., Hector, K.L., Spencer, H.G. Comparative and meta-analytic insights into life extension via dietary restriction. Aging Cell. 2012 11(3):401 – 409.
79 Fontana, L., Partridge, L., Longo,V.D. Extending healthy life span–from yeast to humans. Science. 2010 328(5976):321 – 326.
80 Yan, L., Lamb, R.F. Amino acid sensing and regulation of mTORC1. Semin Cell Dev Biol. 2012 23(6):621 – 625.
81 Wang, X., Proud, C.G. Nutrient control of TORC1, a cell-cycle regulator. Trends Cell Biol. 2009 19(6):260 – 267.
82 Melnik, B.C. Leucine signalling in the pathogenesis of type 2 diabetes and obesity. World J Diabetes. 2012 3(3):38 – 53.
83 Chang, A.R., Lazo, M., Appel, L.J., Gutiérrez, O.M., Grams, M.E. High dietary phosphorus intake is associated with all-cause mortality: results from NHANES III. Am J Clin Nutr. 2014 Feb; 99(2):320-327.
84 Ritz, E., Hahn, K., Ketteler, M., Kuhlmann, M.K., Mann, J. Phosphate additives in food–a health risk. Dtsch Arztebl Int. 2012 109(4):49 – 55.
85 Calvo, M.S., Uribarri, J. Public health impact of dietary phosphorus excess on bone and cardiovascular health in the general population. Am J Clin Nutr July 2013; 98(1): 6–15.
86 Gutiérrez, O.M. The Connection between Dietary Phosphorus, Cardiovascular Disease, and Mortality: Where We Stand and What We Need to Know. Adv Nutr. 2013 Nov; 4(6): 723–729.
87 Xiao, Y., Peng, C., Huang, W., et al. Circulating fibroblast growth factor 23 is associated with angiographic severity and extent of coronary artery disease. PLoS One. 2013; 8(8):e72545.
88 Ozkok, A., Kekik, C., Karahan, G.E., et al. FGF-23 associated with the progression of coronary artery calcification in hemodialysis patients. BMC Nephrol. 2013; 14:241.
89 Calvo, M.S., Tucker, K.L. Is phosphorus intake that exceeds dietary requirements a risk factor in bone health? Annals of the New York Academy of Sciences; Ann. N.Y. Acad. Sci. ISSN 0077-8923.
90 Karp H., Ekholm, P., Kemi, V., Itkonen, S., Hirvonen, T., Närkki, S., Lamberg-Allardt, C. Differences among total and in vitro digestible phosphorus content of plant foods and beverages. J Ren Nutr. 2012 Jul; 22(4):416-422.
91 León, J.B., Janeen, L.D., León, B., Sullivan, C.M., Sehgal, A.R. The Prevalence of Phosphorus-Containing Food Additives in Top-Selling Foods in Grocery Stores. J Renal Nutr July 2013; 23(4): 265–270.
92 Karp H1, Ekholm P, Kemi V, Hirvonen T, Lamberg-Allardt C. Differences among total and in vitro digestible phosphorus content of meat and milk products. J Ren Nutr. 2012 May; 22(3):344-349.
93 Anderson, K.E., Rosner, W., Khan, M.S., New, M.I., Pang, S.Y., Wissel, P.S., Kappas, A. Diet-hormone interactions: protein/carbohydrate ratio alters reciprocally the plasma levels of testosterone and cortisol and their respective binding globulins in man. Life Sci. 1987 May 4; 40(18):1761-8.
94 Rossow, L.M., Fukuda, D.H., Fahs, C.A., Loenneke, J.P., Stout, J.R. Natural bodybuilding competition preparation and recovery: a 12-month case study. Int J Sports Physiol Perform. 2013 Sep ;8(5):582-592.
95 Slag, M.F., Ahmad, M., Gannon, M.C, Nuttall, F.Q. Meal stimulation of cortisol secretion: a protein induced effect. Metabolism. 1981 Nov; 30(11):1104-1108.
96 Gibson, E.L., Checkley, S., Papadopoulos, A., Poon, L., Daley, S., Wardle, J. Increased salivary cortisol reliably induced by a protein-rich midday meal. Psychosom Med. 1999 Mar-Apr;61(2):214-224.
97 Anderson, K.E., Rosner, W., Khan, M.S., New, M.I., Pang, S.Y., Wissel, P.S., Kappas, A. Diet-hormone interactions: protein/carbohydrate ratio alters reciprocally the plasma levels of testosterone and cortisol and their respective binding globulins in man. Life Sci. 1987 May 4; 40(18):1761-1768.
98 Günther, A.L., Karaolis-Danckert, N., Kroke, A., Remer, T., Buyken, A.E. Dietary protein intake throughout childhood is associated with the timing of puberty. J Nutr. 2010 Mar; 140(3):565-571.
99 Herrick, K., Phillips, D.I., Haselden, S., Shiell, A.W., Campbell-Brown, M., Godfrey, K.M. Maternal consumption of a high-meat, low-carbohydrate diet in late pregnancy: relation to adult cortisol concentrations in the offspring. J Clin Endocrinol Metab. 2003 Aug; 88(8):3554-3560.
100 Reynolds, R.M., Godfrey, K.M., Barker, M., Osmond, C., Phillips, D.I. Stress responsiveness in adult life: influence of mother’s diet in late pregnancy. J Clin Endocrinol Metab. 2007 Jun; 92(6):2208-2210.
101 Shiell, A.W., Campbell-Brown, M., Haselden, S., Robinson, S., Godfrey, K.M., Barker, D.J. High-meat, low-carbohydrate diet in pregnancy: relation to adult blood pressure in the offspring. Hypertension. 2001 Dec 1; 38(6):1282-1288.
102 Maslova, E., Rytter, D., Bech, B.H., Henriksen, T.B., Rasmussen, M.A., Olsen, S.F., Halldorsson, T.I. Maternal protein intake during pregnancy and offspring overweight 20 y later. Am J Clin Nutr. 2014 Oct; 100(4):1139-1148.
103 Janesick, A.S., Shioda, T., Blumberg, B. Transgenerational inheritance of prenatal obesogen exposure. Mol Cell Endocrinol. 2014 Dec; 398(1-2):31-35.
104 Ismail-Beigi, F., Catalano, P.M., Hanson, R.W. Metabolic programming: fetal origins of obesity and
metabolic syndrome in the adult. Am J Physiol Endocrinol Metab 2006; 291:E439-440.
105 Grun, F., Blumberg, B. Minireview: the case for obesogens. Mol Endocrinol 2009; 23:1127-1134.
106 Janesick, A., Blumberg, B. Minireview: PPARgamma as the target of obesogens. The Journal of steroid
biochemistry and molecular biology 2011; 127:4-8.