INSIDERSALT: HOW DID IT EVER

BECOME PALEO?

THE

Vol. 7, Issue 3

DICING UP LEAKY GUT

SUNSHINE AND VITAMIN D

FEND OFF THE BONK

LOREN CORDAIN, PH.D., PROFESSOR EMERITUS

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of Medicine.8 The authors of this paper concluded that:

“1.65 million deaths from cardiovascular causes that occurred in 2010 were attributed to sodium consumption above a reference level of 2.0g per day...”

DIETARY SOURCE OF SALT2

GRAMS/DAY

Added in processed foods 7.2Table salt and cooking use 1.4Naturally occuring in foods 1.0

TOTAL 9.6

If we convert 2.0g of sodium consumption per day into salt (NaCl), it translates into 5.0g of salt per day. The typical U.S. diet contains a whopping 9.6g. The high salt foods below are commonly consumed by Standard American Dieters, but are by no stretch of the imagination Paleo.

SALT: HOW DID IT EVER BECOME PALEO? A benefit of being recognized as one of the Founders of the contemporary Paleo Diet movement is that many fledgling authors of Paleo Diet Cookbooks and related writings send me complimentary copies of their books. I am grateful to receive them, as they provide me an informed window into the thought stream of many current Paleo Diet advocates.

However, a disturbing notion has now crept into virtually all of these books: salt is OK. Recipe after recipe seems to include either salt or sea salt as a key ingredient. Whoa! Where the heck did this idea come from? Certainly not from the peer review scientific articles1-7 which preceded and defined the modern Paleo Diet concept, indicating that added salt was never part of humanity’s original fare. Perhaps this erroneous belief has been promoted by popular, non-scientific Paleo bloggers? I don’t know, but it is time to set the record straight - added salt, be it sea salt or otherwise, definitely should not be part of contemporary Paleo Diets.

THE EVIDENCE

For those of you whom are new to the Paleo Diet, I have written many articles including Sea Salt: Between

the Devil and the Deep Blue Sea and Celtic Sea Salt (Sel

Gris): Not Even a Pinch Paleo, demonstrating how salt consumption has multiple adverse effects upon our health and wellbeing. These same concepts are well outlined in The Paleo Answer, The Paleo Diet (Revised), and

The Paleo Diet for Athletes.

A comprehensive worldwide study regarding the link between dietary salt and health recently (Aug 2014) was published in the prestigious New England Journal

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The list below shows the top ten sources of salt in the U.S. Diet.9 You can see that by consuming fresh fruits, fresh vegetables, fresh meats, fresh or frozen fish and seafood, and nuts at every meal, you will go a long way in reducing your salt intake. Fresh, “living,” real foods are naturally low in salt, so why take health promoting nutritious foods and spoil a good thing by adding salt or sea salt to the recipe. After just a week or two your palate will become accustomed to the delicious flavor of real, “living” foods with no added salt.

FOOD IS IT PALEO?

Breads and Rolls Not PaleoCold Cuts and Cured Meats Not Paleo

Pizza Not Paleo

Poultry Can be Paleo (if not processed)

Soups Can be Paleo (if not processed)

Sandwiches Not PaleoCheese Not Paleo

Pasta Dishes Not Paleo

Meat Dishes Can be Paleo (if not processed)

Traditional Snacks Generally not Paleo

The adverse health effects of a high dietary salt (NaCL) intake are well established and have been known for decades in both the scientific and lay literature. Whether your salt comes from sea salt, table salt or salt in processed foods the resultant undesirable health effects remain the same. The table to the left lists both well recognized and more obscure diseases and conditions caused by high salt consumption.

WELL RECOGNIZED DISEASES

MORE OBSCURE DISEASES

High Blood Pressure (Hypertension)

Ménière’s Disease (Ear ringing)

Stroke InsomniaOsteoporosis Motion SicknessKidney Stones Asthma

Stomach Cancer Exercise Induced Asthma

The best advice I can give you is that if you have purchased one of the Paleo Diet Cookbooks, if the recipe calls for sea salt or salt - don’t add it!

Cordially,

Loren Cordain, Ph.D., Professor Emeritus

For sources see References: Section I

SUNSHINE AND VITAMIN DStarting in the summer of 1974, I worked as a lifeguard at Sand Harbor Beach on Lake Tahoe’s pristine North Shore for the next 20 consecutive summers. Besides experiencing some of the greatest times of my life, I took in a lot of sunshine - to say the least! Back in the 70s there were only two brands of suntan lotions (Coppertone and Sea & Ski) because “sunscreens” had yet to be invented. There were no sun blocking agents in either lotion, and we used them mainly to moisturize our skin. No one on our lifeguarding crew worried about skin cancer, and if anybody got too much sun, they simply sat beneath an umbrella on the lifeguard tower. In the day, our goal was not to avoid the sun, but rather to get the deepest, darkest tan possible. We also wore short shorts and Vuarnet sunglasses. Times and styles have changed considerably since then (thank heavens), but one big difference today that may produce adverse health effects is the near universal application of sunscreen lotions.

I still spend my summers at Sand Harbor, but no longer as a lifeguard. Very few beachgoers still have deep tans like they did back in the 70s, and sunscreens are to be found in every beach bag because “everyone knows that sunscreens prevent skin cancer.” Just like the milk industry’s campaign to convince us that milk drinking prevents osteoporosis, sunscreen manufacturers have promoted the myth that sunscreens prevent cancer. In a recent review paper, Dr. Berwick from the University of New Mexico Cancer Center, summarized the most recent scientific findings on sunscreens, “ Sunscreens protect against sunburn . . .Thus far, no rigorous human evidence has shown that sunscreens prevent the major types of skin cancer: cutaneous melanoma and basal cell carcinoma.” If the truth be known, melanoma risk is actually increased with sunscreen use because they allow you longer exposure to the sun without burning.

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The part of sunlight which causes damage to our skin is called ultra violet (UV) radiation. This spectrum is divided into two sections: UVA and UVB. Most of the sunlight which reddens our skin causing sunburn is UVB. Consequently, almost all sunscreens employ one or more ingredients in their formula to block UVB to various degrees. Until recently, few sunscreens blocked UVA. Although, it hasn’t been completely settled, a consensus in the scientific community now indicates UVA sunlight is the chief cause of melanoma. Consequently, if your sunscreen only blocks UVB and not UVA, it most likely increases the risk for melanoma.

Given this scenario, you might think that the best sunscreen would be one that blocks both UVB and UVA equally. Unfortunately this conclusion is erroneous and would actually end up increasing your risk of dying from numerous cancers. Sunlight exposure has a paradoxical effect that is both good and bad. Chronic, long term exposure to the sun such as what lifeguards and other outdoor workers experience frequently is protective from melanomas and many other cancers, whereas intermittent, infrequent intense burning followed by little sun exposure may promote this deadly form of skin cancer and many other cancers.

Blocking UVB sunlight turns out to be a very poor idea because this spectrum of light stimulates vitamin D production in our skin. Sunscreens which block UVB suppress the synthesis of vitamin D, one of the most powerful anticancer substances our body produces. In the past 20 years compelling evidence reveals that low vitamin D blood status increases the risk for 16 cancers, many autoimmune diseases, cardiovascular disease, type 2 diabetes, hypertension, mental illness, osteoporosis, and susceptibility to infectious disease. So what is the solution? How can you and your children enjoy a nice sunny summer day outdoors and not get sunburnt, but still benefit from the sun’s healthful vitamin D boosting effects?

If we look to the evolutionary template along with a little common sense and some modern technology, we can easily overcome this problem. The first thing you’ve got to do is to change your mindset - sunlight is not harmful but rather is incredibly healthful providing we get it in a “U” shaped dose (not too little and not too much). My wife Lorrie and I have been taking our boys to the beach every summer of their lives. None has ever had a severe sunburn, and every one of them gets as “brown as berries” by summer’s end. Here’s our strategy. At the beginning of summer, we apply lotion liberally for the first few days, preferably with sunscreens containing both UVA and UVB blockers and a moderate SPF value (say 8 to 15). As the boys gradually tan we simultaneously reduce the sunscreen quantity and SPF value. After a week to 10 days, when they are tan, we pay little attention to sunscreens anymore. We encourage them to sit under beach umbrellas or put on their shirts if they are hot or have had too much sun. A similar strategy will work for adults depending upon your skin color and initial tan. The key here is moderation and to gradually increase your exposure. The best protection from excessive sunlight is not sunscreens, but rather shade, hats and light clothing.

I’ve made my point - regular sunlight exposure is one of the most healthful habits we can get into because it

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increases our blood levels of vitamin D, which in turn reduces our risk for almost every disease and illness in the western world. But the question that now arises is how much sun do we need? This is first dependent upon how much pigmentation you have in your skin. People with more pigment need almost twice the time in the sun as do those with less pigment to achieve similar blood concentrations of vitamin D.

The Paleo DietThe table to the left shows blood levels of vitamin D and their classification. Lifeguards and other outdoor workers can achieve blood concentrations that top out at about 60 ng/ml. But you really don’t need values this high. Most experts agree that values higher than 30 ng/ml will significantly reduce your risk for cancer and all of the other diseases associated with low vitamin D status. The good news is that daily sunlight exposure in the summertime for short periods 15-30 minutes will rapidly boost your blood levels of vitamin D above 30 ng/ml. The bad news is that it is virtually impossible to do this with diet alone because almost all real foods that we commonly eat contain little or no vitamin D.

VITAMIN D SUPPLEMENTATION

For most of us, regular sunlight exposure is a luxury that is difficult or impossible to come by on a year round basis. Obviously, our hunter gatherer ancestors did not have this problem. Consequently, you will need to supplement your diet with vitamin D3 capsules. If we look at the official governmental recommendation for vitamin D intake (between 400 and 600 IU), it is woefully inadequate, and represents a complete failure in public health policy. The most recent human experiments show that blood levels of 30 ng/ml could never be achieved with vitamin intakes between 400 and 600 IU. In fact, 400 IU does not raise insufficient blood concentrations of vitamin D one iota.

The majority of men, women and child in the U.S. maintain blood levels of vitamin D which are either deficient or insufficient. Hence, one of the best strategies you can take with adopting The Paleo Diet is to supplement daily with vitamin D3 if you are unable to get sunshine on a regular basis.Most vitamin D experts agree that daily supplementation of at least 2,000 IU of vitamin D3 is necessary to achieve blood levels of 30 ng/ml or greater. People who have never supplemented with vitamin D, and who have had little sunlight exposure for years, may need 5,000 IU per day.

Cordially,

Loren Cordain, Ph.D., Professor Emeritus

For sources see References: Section II

DICING UP LEAKY GUTI’m often asked what it means to have leaky gut, how to identify if you have it, and how to alleviate symptoms of leaky gut. Let me break it down. When the cells lining the gastrointestinal tract become compromised leading to increased intestinal permeability (e.g. a leaky gut), it allows the gut contents (food and microorganisms) to chronically interact with the immune system. Accordingly, many immunologists now believe that increased intestinal permeability represents an initial environmental trigger for autoimmune diseases in genetically susceptible individuals.1-5

A leaky gut also allows entry of a compound called lipopolysaccharide (LPS), found in gut gram negative bacteria, into the bloodstream. Systemically, LPS may produce a chronic low level inflammatory condition called endotoxemia, which is increasingly being recognized as an underlying factor in insulin resistance, the metabolic syndrome, cardiovascular disease and obesity.6 - 9

A number of commonly consumed foods including cereal grains, legumes, alfalfa sprouts, hot chili peppers, potatoes, and alcohol are known to increase intestinal permeability.10 One of the least appreciated foods which may compromise intestinal function and promote a leaky gut, however, are tomatoes.

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In the U.S., we eat a lot of tomatoes and tomato products. In the table below you can see that that the per capita consumption for all tomato food items comes in at 85.7 pounds per year, per person.

US PER CAPITA CONSUMPTION OF TOMATOES AND TOMATO PRODUCTS

ITEM POUNDS (LBS.)

Fresh Tomatoes 18.5Processed Tomatoes (total) 67.2

Tomato Sauces 23.5Tomato Paste 12.1

Canned Whole Tomatoes 11.4Ketchup 10.1

Tomato Juice 10.1TOTAL 85.7

One element in many foods including potatoes, beans, legumes and alfalfa sprouts, that causes increased intestinal permeability and a leaky gut are saponins. These soap like compounds disrupts all cell membranes (including those lining the gut) causing them to either break or form holes (pores) in the membrane. The primary saponin in tomatoes which causes a leaky gut is called alpha tomatine. The table below shows the concentration of alpha tomatine in a variety of tomatoes and tomato food products.

Note that smaller and unripe tomatoes have markedly increased levels of alpha tomatine, whereas this compound is barely detectable in a standard ripe, red tomato. In contrast, ketchup, green salsa, pickled green tomatoes and cherry tomatoes are all potent sources of alpha tomatine.

ALPHA TOMATINE CONCENTRATIONS 9MG/KG) IN TOMATOES AND TOMATO FOOD PRODUCT

ITEM ALPHA TOMATINE (MG/KG)

Unripe small immature green 548Unripe medium immature green 169

Pickled green tomatoes (Brand A) 71.5Unripe pickled green 28

Green salsa 27.5Sundried red tomatoes 21

Unripe green large 16Unripe large immature green 10

Sungold cherry tomatoes 11Fried green tomatoes 11

Microwaved green tomatoes 11Yellow cherry tomatoes 9.7

Ketchup 8.6Red sauce 5.7

Yellow pear cherry tomatoes 4.5Tomato juice 2.8

Red cherry tomatoes 2.7Condensed tomato soup 2.2

Red pear cherry tomatoes 1.3Medium yellow tomatoes 1.3Large yellow tomatoes 1.1

Stewed canned tomatoes 1.1Ripe red beefsteak tomato 0.9

Green zebra tomatoes 0.6Roma 0.4

Standard red ripe tomato 0.3

Although tomatoes typically have lower concentrations of glycoalkaloids (alpha tomatine) than potatoes (alpha solanine and alpha chaconine), alpha tomatine in tomatoes is more effective than potato glycoalkaloids in disrupting the intestinal membrane and promoting a “leaky gut.” The adverse effects of alpha tomatine from

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tomato foods are dose dependent - meaning that the more you eat, the worse are the effects. A few slices of ripe red tomato in a salad probably will have minimal or no adverse effects upon your intestinal or immune system function. But a diet high in unripe, green tomatoes, green salsa, and ketchup should be avoided.

In addition to alpha tomatine, tomatoes contain another anti-nutrient called tomato lectin which rapidly crosses the gut barrier and enters our bloodstream. Hence, unripe tomatoes and certain tomato products may be rich sources of both saponins and a lectin which may compromise intestinal function and promote a “leaky gut.” Furthermore, a convincing body of literature from animal studies shows that alpha tomatine from tomatoes is a powerful stimulator of the immune response - so much so that it is employed in vaccines as an adjuvant, a substance which increases the potency of the vaccine. The crucial issue here is how much alpha tomatine you consume. At low dietary concentrations, this tomato chemical probably has little or no effect in most healthy people. However, I cannot say the same for autoimmune disease patients.

You can learn more about the adverse effects of tomato consumption in individuals with autoimmune disease in The Paleo Answer.

Cordially,

Loren Cordain, Ph.D., Professor Emeritus

For sources see References: Section III

FEND OFF THE BONK I’m often asked how endurance athletes go about replenishing their energy when their reliance pre-Paleo focused upon carbohydrates as their primary source of fuel. Qualitative differences among processed foods and “real” living foods are nutritionally important for optimizing athletic performance. 70% of the food in the typical endurance athlete’s diet comes from four foods: 1) refined sugars, 2) refined cereal grains, 3) refined vegetable oils and 4) dairy products. These foods have low nutrient (vitamin and mineral) density compared to the traditional foods our species have always consumed including fresh vegetables, fruits, fresh meats (grass produced are superior to grain produced), poultry, free ranging eggs, lamb, pork, and nuts and seeds.

During endurance exercise, muscle cells utilize two major substrates, glycogen and intramuscular triglyceride (IMT). Both fuels represent labile sources of ATP for working muscles. At 70 - 80% of VO2 max, IMT represents the major fuel source. As exercise intensity progresses to 90 - 100% of VO2 max, intramuscular glycogen and glucose become the preferred energy source because they require less oxygen on a molar basis. Both metabolic pathways are absolutely essential in high level endurance performance such as the marathon.

As Joe Friel and I have outlined in our The Paleo Diet

for Athletes, numerous recent scientific studies show that IMT stores and utilization via beta oxidation pathways as just as crucial if not more so than glycogen metabolism at the exercise intensities typical for long term (many hours) endurance performance. Accordingly, exercise physiologists have shown that higher fat, lower carbohydrate diets which stress the beta oxidation pathways result in higher muscle stores of IMT. The Paleo Diet for Athletes details how both metabolic pathways must be maximized before, during, and after exercise. Good Paleo sources of dietary carbohydrate to maximize muscle glycogen storage are: sweet potatoes, yams, bananas, fresh fruit, fruit juices and dried fruit. These carbs yield a net metabolic acidosis as opposed to refined sugars, grains and processed foods which ultimately end up depleting muscle glutamine stores.

In a nutshell, there are four basic reasons why the Paleo Diet enhances athletic performance:

1. BRANCHED CHAIN AMINO ACIDS

First, The Paleo Diet is high in animal protein which is the richest source of the branch chain amino acids - valine, leucine and isoleucine. Branch chain amino acids are different from other amino acids that collectively make up protein in that they are potent stimulants for building and repairing muscle. This information is quite new and has only been reported in the scientific literature in the past few years. But the dig is this - these amino acids work best when consumed in the post-exercise window. Lean meats and fish are far and away the greatest source of branch chain amino acids. A 1,000 calorie serving of lean beef provides 33.7 grams of branch chain amino acids whereas the same serving of whole grains supplies a paltry 6 grams.

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Because most endurance athletes focus on starches (breads, cereals, pasta, rice, potatoes) and sugars at the expense of lean meats, particularly following a hard workout, there are precious few muscle-building branch chain amino acids in their diets. By consuming high amounts of lean protein (and hence branch chain amino acids), athletes can rapidly reverse the natural breakdown of muscle that occurs following a workout and thereby reduce their recovery time and train at a greater intensity at the next session. Replacing starches with lean meats now makes perfect sense and explains the athletes’ near-universal report of improved recovery with these dietary recommendations.

2. BLOOD ACIDITY VS. ALKALINITY

In addition to stimulating muscle growth via branch chain amino acids, a Paleo Diet for athletes simultaneously prevents muscle protein breakdown because it produces a net metabolic alkalosis. All foods, upon digestion, report to the kidney as either acid or alkali (base). The standard American diet (SAD) is net acid producing because of its high reliance upon acid-yielding grains, cheeses and salty processed foods at the expense of base-producing fruits and veggies.

The athlete’s body is even more prone to blood acidosis due to the by-products of exercise. One way the body neutralizes a net acid producing diet is by breaking down muscle tissues. Because a Paleo Diet for athletes is rich in fruits and veggies, it reverses the metabolic acidosis produced from a typical grain- and starch-laden athlete’s diet and thereby prevents muscle loss.

3. TRACE NUTRIENTS

Fruits and veggies are also rich sources of antioxidant vitamins, minerals and phytochemicals and together with lean meats (excellent sources of zinc and B vitamins) promote optimal immune system functioning. The refined grains, oils, sugars and processed foods that represent the typical staples for most athletes are nearly devoid of these trace nutrients. From the training logs of numerous athletes we found the frequency and duration of colds, flu and upper respiratory illnesses are reduced when they adopt the Paleo Diet. A healthy athlete, free of colds and

illness, can train more consistently and intensely and thereby improve performance.

4. GLYCOGEN STORES

One of the most important goals of any athletic diet is to maintain high muscle stores of glycogen, a body fuel absolutely essential for high-level performance. Dietary starches and sugars are the body’s number one source for making muscle glycogen. Protein won’t do and neither will fat. Athletes and sports scientists have known this information for decades. Regrettably, they took this concept to extremes, and high-starch, cereal-based, carbohydrate-rich diets were followed with near fanatical zeal 24 hours a day, 7 days a week.

It is a little known fact, but similar to the situation with branch chain amino acids, glycogen synthesis by muscles occurs most effectively in the immediate post-exercise window. Muscles can build all the glycogen they need when they get starch and sugar in the narrow time window following exercise. Eating carbs all day long is overkill, and actually

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serves to displace muscle-building, lean proteins and alkalinity-enhancing, nutrient-dense fruits and veggies that are needed to promote muscle growth and boost the immune system.

But how can you prevent becoming glycogen depleted and bonk? By maximizing IMT and utilizing beta oxidation pathways during exercise, intramuscular glycogen stores can be conserved, thereby allowing greater exercise intensity towards the end of an endurance race wherein many athletes glycogen stores are depleted.

Perhaps the most important refinement made to the original Paleo Diet for Athletes was the recognition that consumption of starches and simple sugars is only necessary and useful during exercise and in the immediate post-exercise period. We also found certain carbohydrates are more effective than others in restoring muscle glycogen, particularly specific types of sugar such as glucose and net alkaline-producing starches found in bananas, potatoes, sweet potatoes and yams.

The world of endurance nutrition is ever changing. Athletes who adopt the Paleo lifestyle are typically leaner, healthier and experience no performance decline. Remember, the adverse nutritional and health effects of refined sugars, refined grains, refined vegetable oils and processed foods does not discriminate amongst athletes or the general population. The Paleo Diet’s nutritional superiority compared to high carb diets, the Mediterranean Diet and diabetic diets is immeasurable.

You can learn more about how The Paleo Diet can benefit athletes from all walks of life in The Paleo Diet

For Athletes.

Cordially,

Loren Cordain, Ph.D., Professor Emeritus

For sources see References: Section IV

REFERENCES: SECTION I1. Eaton SB, Konner M. Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med. 1985 Jan 31;312(5):283-9

2. Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, O’Keefe JH, Brand-Miller J. Origins and evolution of the western diet: Health implications for the 21st century. Am J Clin Nutr 2005;81:341-54.

3. Frassetto L, Morris RC Jr, Sellmeyer DE, Todd K, Sebastian A. Diet, evolution and aging--the pathophysiologic effects of the post-agricultural inversion of the potassium-to-sodium and base-to-chloride ratios in the human diet. Eur J Nutr. 2001 Oct;40(5):200-13.

4. Cordain L. The nutritional characteristics of a contemporary diet based upon Paleolithic food groups. J Am Neutraceut Assoc 2002; 5:15-24.

5. Gotshall RW, Mickleborough TD, Cordain L. Dietary salt restriction alters pulmonary function in exercise-induced asthmatics. Medicine and Science in Sports and Exercise, 2000;32:1815-19.

6. Mickleborough TD, Cordain L, Gotshall RW, Tucker A. A low sodium diet improves indices of pulmonary function in exercise-induced asthma. Journal of Exercise Physiology Online 2000;3(2).

7. Frassetto LA1, Morris RC Jr, Sellmeyer DE, Sebastian A. Adverse effects of sodium chloride on bone in the aging human population resulting from habitual consumption of typical American diets. J Nutr. 2008 Feb;138(2):419S-422S.

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8. Mozaffarian D, Fahimi S, Singh GM, Micha R, Khatibzadeh S, Engell RE, Lim S, Danaei G, Ezzati M, Powles J; Global Burden of Diseases Nutrition and Chronic Diseases Expert Group. Global sodium consumption and death from cardiovascular causes. N Engl J Med. 2014 Aug 14;371(7):624-34.

9. Centers for Disease Control and Prevention (CDC). Vital signs: food categories contributing the most to sodium consumption - United States, 2007 - 2008, February 7, 2012.

REFERENCES: SECTION II1. Autier P, Doré JF, Eggermont AM, Coebergh JW. Epidemiological evidence that UVA radiation is involved in the genesis of cutaneous melanoma. Curr Opin Oncol. 2011 Mar;23(2):189-96.

2. Autier P. Sunscreen abuse for intentional sun exposure. Br J Dermatol. 2009 Nov;161 Suppl 3:40-5.

3. Autier P, Boniol M, Doré JF. Sunscreen use and increased duration of intentional sun exposure: still a burning issue. Int J Cancer. 2007 Jul 1;121(1):1-5.

4. Berwick M. The good, the bad, and the ugly of sunscreens. Clin Pharmacol Ther. 2011 Jan;89(1):31-3.

5. Binkley N, Novotny R, Krueger D, Kawahara T, Daida YG, Lensmeyer G, Hollis BW, Drezner MK. Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab. 2007 Jun;92(6):2130-5.

6. Burnett ME, Wang SQ. Current sunscreen controversies: a critical review. Photodermatol Photoimmunol Photomed. 2011 Apr;27(2):58-67.

7. Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, Kinkeldei J, Boehm BO, Weihrauch G, Maerz W. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008 Jun 23;168(12):1340-9.

8. Field S, Newton-Bishop JA. Melanoma and vitamin D. Mol Oncol. 2011 Feb 3. [Epub ahead of print]

9. Forouhi NG, Luan J, Cooper A, Boucher BJ, Wareham NJ.

Baseline serum 25-hydroxy vitamin D is predictive of future glycaemic status and insulin resistance: The MRC Ely prospective study 1990-2000. Diabetes. 2008 Oct;57(10):2619-25.

10. Garland CF, Garland FC, Gorham ED. Epidemiologic evidence for different roles of ultraviolet A and B radiation in melanoma mortality rates. Ann Epidemiol. 2003 Jul;13(6):395-404.

11. Gore F, Fawell J, Bartram J. Too much or too little? A review of the conundrum of selenium.J Water Health. 2010 Sep;8(3):405-16.

12. Gorham ED, Mohr SB, Garland CF, Chaplin G, Garland FC. Do sunscreens increase risk of melanoma in populations residing at higher latitudes? Ann Epidemiol. 2007 Dec;17(12):956-63.

13. Holick MF. Vitamin D and sunlight: strategies for cancer prevention and other health benefits. Clin J Am Soc Nephrol 2008;3:1548-54.

14. Holick MF. Optimal vitamin d status for the prevention and treatment of osteoporosis. Drugs Aging. 2007; 24(12):1017-29.

15. Holick MF, Chen TC: Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008 Apr;87(4):1080S-6S.

16. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr. 2005 Feb;135(2):317-22.

17. Kumar J, Muntner P, Kaskel FJ, Hailpern SM, Melamed ML. Prevalence and associations of 25-hydroxyvitamin D deficiency in US children: NHANES 2001-2004. Pediatrics. 2009 Sep;124(3):e362-70.

18. Melamed ML, Kumar J. Low levels of 25-hydroxyvitamin D in the pediatric populations: prevalence and clinical outcomes. Ped Health. 2010 Feb;4(1):89-97.

19. Mohr SB, Garland CF, Gorham ED, Grant WB, Garland FC. Relationship between low ultraviolet B irradiance and higher breast cancer risk in 107 countries. Breast J. 2008 May-Jun;14(3):255-60

20. Moyal DD, Fourtanier AM. Broad-spectrum sunscreens provide better protection from solar ultraviolet-simulated

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radiation and natural sunlight-induced immunosuppression in human beings. J Am Acad Dermatol. 2008 May;58(5 Suppl 2):S149-54.

21. Plum LA, DeLuca HF. Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov. 2010 Dec;9(12):941-55

22. Sharief S, Jariwala S, Kumar J, Muntner P, Melamed ML. Vitamin D levels and food and environmental allergies in the United States: Results from the National Health and Nutrition Examination Survey 2005-2006. J Allergy Clin Immunol. 2011 Feb 15.

23. Vieth R. Why the optimal requirement for vitamin D3 is probably much higher than what is officially recommended for adults. J Steroid Biochem Mol Biol 2004; 89-90:575-9.

REFERENCES: SECTION III1. Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011 Jan;91(1):151-75.

2. Fasano A. Surprises from celiac disease. Sci Am. 2009 Aug;301(2):54-61.

3. Visser J, Rozing J, Sapone A, Lammers K, Fasano A. Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms. Ann N Y Acad Sci. 2009 May;1165:195-205.

4 Joscelyn J, Kasper LH. Digesting the emerging role for the gut microbiome in central nervous system demyelination. Mult Scler. 2014 Jul 28. pii: 1352458514541579. [Epub ahead of print]

5. Vaarala O. Is the origin of type 1 diabetes in the gut? Immunol Cell Biol. 2012 Mar;90(3):271-6.

6. Cani PD, Osto M, Geurts L, Everard A. Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity. Gut Microbes. 2012 Jul-Aug;3(4):279-88.

7. Geurts L, Neyrinck AM, Delzenne NM, Knauf C, Cani PD.Gut microbiota controls adipose tissue expansion, gut barrier and glucose metabolism: novel insights into molecular targets and interventions using prebiotics. Benef Microbes. 2014 Mar;5(1):3-17.

8. Everard A, Cani PD. Diabetes, obesity and gut microbiota. Best Pract Res Clin Gastroenterol. 2013 Feb;27(1):73-83.

9. Jayashree B, Bibin YS, Prabhu D, Shanthirani CS, Gokulakrishnan K, Lakshmi BS, Mohan V, Balasubramanyam

M. Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes.Mol Cell Biochem. 2014 Mar;388(1-2):203-10.

10. Cordain, L. The Food - Autoimmune Disease Connection. In: Cordain, L., The Paleo Answer, John Wiley and Sons, New York, NY, 2012, pp. 161-179.

11. Bies C, Lehr CM, Woodley JF. Lectin-mediated drug targeting: history and applications. Adv Drug Deliv Rev. 2004 Mar 3;56(4):425-35

12. Carreno-Gómez B, Woodley JF, Florence AT. Studies on the uptake of tomato lectin nanoparticles in everted gut sacs. Int J Pharm. 1999 Jun 10;183(1):7-11.

13. Francis G, Kerem Z, Makkar HP, Becker K. The biological action of saponins in animal systems: a review. Br J Nutr. 2002 Dec;88(6):587-605.

14. Friedman M, Levin CE. Alpha tomatine content in tomato and tomato products determined by HPLC with pulsed amperometric detection. J Agric Food Chem 1995;43:1507-1511.

15. Gabor F, Bogner E, Weissenboeck A, Wirth M. The lectin-cell interaction and its implications to intestinal lectin-mediated drug delivery. Adv Drug Deliv Rev. 2004 Mar 3;56(4):459-80.

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22. Naisbett B, Woodley J. The potential use of tomato lectin for oral drug delivery: 4. Immunological consequences. Int J Pharm 1995;120:247-254.

23. Stoll LL, Denning GM, Weintraub NL. Endotoxin, TLR4 signaling and vascular inflammation: potential therapeutic targets in cardiovascular disease. Curr Pharm Des. 2006;12(32):4229-45

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3. Jonsson T, Granfeldt Y, Erlanson-Albertsson C, Ahren B, Lindeberg S. A Paleolithic diet is more satiating per calorie than a Mediterranean-like diet in individuals with ischemic heart disease. Nutr Metab (Lond). 2010 Nov 30;7(1):85

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8. Frassetto LA, Shi L, Schloetter M, Sebastian A, Remer T.Established dietary estimates of net acid production do not predict measured net acid excretion in patients with Type 2 diabetes on Paleolithic-Hunter-Gatherer-type diets. Eur J Clin Nutr. 2013 Sep;67(9):899-903.

9. Jönsson T, Granfeldt Y, Lindeberg S, Hallberg AC.Subjective satiety and other experiences of a Paleolithic diet compared to a diabetes diet in patients with type 2 diabetes. Nutr J. 2013 Jul 29;12:105.

10. Fontes-Villalba M, Jönsson T, Granfeldt Y, Frassetto LA, Sundquist J, Sundquist K, Carrera-Bastos P, Fika-Hernándo M, Picazo O, Lindeberg S. A healthy diet with and without cereal grains and dairy products in patients with type 2 diabetes: study protocol for a random-order cross-over pilot study - Alimentation and Diabetes in Lanzarote -ADILAN. Trials. 2014 Jan 2;15(1):2

11. Mellberg, C., Sandberg, S., Ryberg, M., Eriksson, M., Brage, S., Larsson, C., et al. (2014). Long-term effects of a Palaeolithic-type diet in obese postmenopausal women: a 2-year randomized trial. European Journal of Clinical Nutrition. doi:10.1038/ejcn.2013.290