Nutrigenomics - "Let Food be Thy Medicine and Medicine Be Thy Food." An Ancient Truth in Light of Fancy DNA Analyses

Researchers working in the field of nutrigenomics prioritize berries over pills and individuality over "one-size-fits-it-all approaches" - can they also tell us how to "eat away cancer"?

"Live longer, live stronger"... rings any bells? Anyone? Of course. That's the motto of Super Human Radio. So anyone, who has been listening to the Science Roundup over the past couple of weeks will  have heard it at least once. Now, while the "stronger" part of Carl Lanore's slogan is still largerly under-researched if you asked me, the nutritional angle, which does not appear in the slogan, but is still a major theme of the show is really taking off, these days. Nutrigenomics, i.e. the science of (a) how what we eat determines how our genes functions - keyword: epigenetics and (b) how our very individual genes determine how we're supposed to eat, is really talking off these days. Reason enough for me to invite you to take a peak at what we already know in terms of the modern version of the ancient

 "Let food be thy medicine and medicine be thy food."

One of the primary objectives researchers in the field have subscribed to is the battle against cancer. No other disease appears to be more suited to the modulating effect of the chemical compounds in foods, which is - and that's something you've heard on the Science Round Up several times, as well, capable of both preventing and inducing the instability of the DNA synthesis and gene expression that's finally causing our cells to play havoc.

Table 1: Epigenetic roles of nutrition in physiologic and pathologic processes (from Nepomuceno, originally based on Choi. 2010)

As Júlio César Nepomuceno writes in a recent paper which actually re-instigated my interest in the whole matter,

"[...t]he nutrients are able to affect the genome and its expression through the synthesis of nucleotides, prevention and repair of DNA damage, or through epigenetic mechanisms including methylation of histones, proteins responsible for chromatin structure that play an important role in regulating gene expression." (Nepomuceno. 2013)

Now, while all the cells in our bodies share an identical genome, there are many "epige‐ nomes", which are the unique  sets  of  epigenetic  instructions  for  establishing  and maintaining  lineagespecific expression profiles.

And it is at this cross-roads between the general and the specific where DNA methylation and histone acetylation which can be brought about by the foods we eat an the supplements we take will have more powerful effects than the latest blockbuster drug from the laboratories of Phizer, Merck, Bayer, and co. (Fuji. 2010).

The methylation / acetylation cycle: The genomic switchboard of your cells

Against that background, you as an avid listener and reader of SHR and the daily news and articles on the SuppVersity won't be surprised that nutrients that are part of the so-called "methylation cycle" are considered among the most important agents in nutrigenomics. It's their presence, adequate enzymatic conversion and use that ensures the integrity of the genome of each and every cell in your body and once the tightly controlled and constantly operating machinery is broken, cancer and - as more and more scientists believe "premature" aging and other diseases of epigenetic origin can ensue.

One (not Two!) Kiwi(s) A Day Keeps the Doctor Away. (learn more)

Despite the fact that the word methylation is tightly linked to all these pathologies, it's actually a completely unbiased process.

And while this should be self-evident, most of us need tabular overviews like the one to in table 1 to remind ourselves of the critical and for most of us highly beneficial effect folate, for example, had on our embryonic development, or - just another example - the epigenetic roots of the beneficial effects compounds such as curcumin, resveratrol or choline will have on obesity, inflammation or neurocognition.

In fact, the integrity of our DNA is under constant assault. Simple "mechanistic" errors during the replication process, electromagnetic radiation (from X-Rays to very low frequency EM), alkylating agents, spontanous mutations and the often-heard of reactive oxygen species threaten the integrity of each and every cell in our body leading (in the best case) to cell cycle arrest and apoptosis, in the worst case to mutations, cancer and genetic diseases. Moreover,

"[...c]urrent cancer models comprise those that are inherited through the germline and represent only  ∼5% of total cases of human cancers. These tumors originate because of mutational events. The remaining ∼95% originate as sporadic events and evolve as a result of exposure to the environment,  which  includes  exposure  to  both  environmental  contaminants  and  dietary agents. The multistage model of carcinogenesis identifies various phases, initiation, promotion, and progression, appears to be influenced by tissue microenvironment and organization." (Nepomuceno. 2013)

Yet, as frightening as it may see, these threats and the effects specific nutrients will have on their ability to harm us may  be our best chance to avoid cancer, premature aging. In fact, scientists argue that the age-increased susceptibility to cancer may actually be the results of an accumualtion of epigenetic changes, many of which could be ameliorated, if not prevented by dietary nutrients that will affect the profile of transcripts, which may - and this is where things get complicated - yet be modulated by inter-individual differences in our genetic make-up (Miller. ) - so-called polymorphisms, such as the "cancer gene" Carl and I have been talking about in the last installment of the Science Round Up in the context of Angelina Jolie's double-mastectomy (see table 2 for a selection of these polymorphism).

Table 2:Polymorphic genes, dietary components and cancer: possible candidates (Nepomuceno. 2013)

Now while scientists have already been successful (or they believe they were) in identifying dietary patterns that are associated with an increased and decreased risk of certain cancers. You have to keep in mind that these associations, as they were proposed by the experts from the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) are largely based on epedimiological data and will thus neither include the modulating effects of the said polymorphisms nor have the status of undebatable facts.

"Red meat will cause cancer!"

One of my favorite examples is the association between red meat intake and the development of cancer, of which th AICR researchers believe that there was a 15% to 20% increased risk of cancers of the colon and/or rectum per 100 grams of red meat or 50 g of processed meat consumed per day (is that true?).

Suggested Read: "Meat-Ology: A Brief Glance at the Latest Data on The Link Between Red Meat, Cooking Techniques & Prostate Cancer" - How bad is it?

If you take a close enough look at the respective papers and don't rely on the mainstream media coverage, exclusively, the American Cancer Society openly admits that

• the mutagens and carcinogens (heterocyclic amines and polycyclic aromatic hydrocarbons) in meat are produced by cooking meat at high temperatures and/or by charcoal grilling and that 
• the nitrates/nitrites and salt used to process meat contribute to the formation of nitrosamines, which are known mutagens and carcinogens in animals

and not "meat per se" are the true - or we should say "most likely" - mechanistic factors involved, here.

In the end, a similar "most likely" should also accompany the well-accepted conclusion from accumulating evidence on the beneficial effects of a diet that's high in fruits and vegetables after all, diets on the other end of the extreme are notorious for providing sub-optimal amounts of vitamin B12 and could thus also increase the risk for malfunctions in the methylation cycle and the subsequent development of cancer.

Tea, coffee and the other mainstream polyphenol sources

Contrary to the associations with vitamins, the influences polyphenols have on our overall and genetic health are actually a comparatively "novel" topic of scientific research. In fact, scientists argue that these common constituents of foods of plant origin and not the previously hailed vitamins are the major antioxidants in our diets. Vegetables and fruits like apple, grape, pear, cherry, and various berries contain up to 200–300 mg polyphenols per 100 g fresh weight and coffee, teas, cereals, chocolate, and dry legumes also contribute to the polyphenol intake.

Did you know that flavenols are only a subclass of polyphenols? They comprise a large and diverse family of compounds synthesized by plants. Flavonoid subclasses include anthocyanidins in berries and grapes, flavanols in tea, flavanones in citrus fruits, flavonols in onions, flavones in herbs and peppers, and isoflavones in soy.

In that, the term polyphenol is actually an umbrella term that comprises various powerful antioxidants such as flavonoids and stilbenes, many of which have been implicated in cancer prevention and the promotion human health without recognizable side effects, which are - even in such prominent cases like red wine, which contains a wide range of different polphenols - far from being completely understood. The recently mentioned negative effects of cholorogenic acid supplements on the glucose metabolism of rodents, are another example, where certain molucules - in this case chlorogenic acid - of which we believed that they were responsible for the beneficial health effect of coffee turn out to exert different or even downright hazardous effects, when they are administered in isolation.

Similar observations have been made for the classic anti-oxidant vitamins A, C and E and as of late vitamin D. Not everything that looks good on paper or works in the petri dish will also work in a complex organism and even fewer things did eventually make the translation from the bench to the bedside.

Table 3: Selected trials involving "classic" antioxidant vitamins esp. beta carotene (based on Tanaka. 2012)

For science the disappointment surrounding beta carotene (see table 3) was actually highly productive, Without the conflicting data on the real world effects of foods such as yellow-orange vegetables, green leafy vegetables, orange and yellow foods and all the other carotenoid-containing food items and the negative outcomes in the above cited studies, we would probably still lack an appropriate grasp of what carotenoids actually are.

A group of chemicals known as isoprenoid polyenes that are found in lipid-soluble form in the  yellow-orange-red pigments in all higher plants and some animals. Scientists further distinguish

Table 4: Sources, function, and effects of different carotenoids (Tanaka. 2012)

1. vitamin A precursors that do not pigment such as β-carotene;
    
2. pigments with partial vitamin A activity such as cryptoxanthin, β-apo-8'-carotenoic acid ethyl ester;
    
3. non-vitamin A precursors that do not pigment or pigment poorly such as violaxanthin and neoxanthin; and
    
4. non-vitamin A precursors that pigment such as lutein, zeaxanthin and anthaxanthin. 

As Tanaka points out, the specific form of the molecules, in particular their stereoisomerism (take a look at your left hand and compare it to the right one and you know what this is ;-) exerts a marked influence on the physical properties.

Vitamin C is vitamin C, is vitamin C, is ... useless?

While research on the different types of carotenes has made huge progress and scientists are finally grasping the notion that there is a difference between folic acid and its biologically active cousins, the one on the most prominent dietary anti-oxidant and it's proctetive effects on cancer stalls - with mainly negative outcomes:

If you add some reactive oxygen species to this mitochondrium, this will trigger beneficial, (mito-)hormetic adaptations, that could be blunted by too many antioxidants. Could be blunted, but what exactly is the latest evidence for the average individual or the corresponding rodent model (learn more)?

"Regarding the use of vitamin C in cancer patient the results were not promising. In a double- blind study 100 patients with advanced colorectal cancer were randomly assigned to treatment with either high-dose vitamin C (10 g daily) or placebo. Overall, these patients were in very good general condition, with minimal symptoms. None had received any previous treatment with cytotoxic drugs. Vitamin C therapy showed no advantage over placebo therapy with regard to either the interval between the beginning of treatment and disease progression or patient survival. Among patients with measurable disease, none had objective improvement.

On the basis of this and our previous randomized study, it can be concluded that high-dose vitamin C therapy is not effective against advanced malignant disease regardless of whether the patient has had any prior chemotherapy."

On the other hand, studies investigating the dietary intake of vitamin C as a part of the natural nutrient matrix ascorbic acid comes with in the vegetables and fruits in our diets (phenols, flavones, and terpenes, beta carotene, selenium), provides at least preliminary evidence that vitamin C intake may be more important for prevention of lung cancer than beta-carotene (e.g. Kromhout. 1987). The necessary amount of vitamin C to get the job done is yet not higher than 70mg (!) of ascorbic acid and almost certainly dependent (if not solely brought about) by the presence of phenols, flavones, and terpenes in the corresponding foods.

---

Bottom line: The examples of vitamin C and beta carotene show that our understanding of the complex interaction of chemicals with the ability to influence our health through epigenetic changes or the prevention of the latter is still limited. For the latter, which have been around for decades, we already know not one, but rather a mixture - and in that, a mixture at the right ratios - is necessary to see actual benefits.

"Does the Usefulness of Vitamin E Supplementation Depend on Your Activity level?" - Hitherto largely overlooked are the complex interactions of exercise and nutrient induced epigenetic changes, which may well determine the usefulness of antioxidant supplements (learn more)

That being said, the combination of gene essays, in-vitro, in vivo and epidemiological science under the beneath the rood of "nutrigenomics" must be considered one of the most promising research directions of the future. At the moment it's results are yet about as preliminary as the various definitions you will find, when you look around in the scientific community.

Most importantly, however, most of the reasonably reliable results this comparatively new branch of research has and is producing is simply confirming the stuff you've been learning on SHR and the SuppVersity about diet and nutrition over the past years and you can take my word for it: this is not going to go change much in the future.

References:

• Choi, Sang-Woon, Friso S. Epigenetics: A New Bridge between Nutritionand Health. Adv Nutr 2010;1: 8–16.
• Fujii T.M.M., Medeiros R., Yamada R. Nutrigenomics and nutrigenetics: important concepts for the nutrition science. J Brazilian Soc Food Nutr 2010;35(1): 149-166.
• Kromhout D. Essential micronutrients in relation to carcinogenesis. Am J Clin Nutr May 1987;45(5):1361-1367
• Milner JA, Romagnolo DF. Nutrition and Health: Bioactive Compounds and Cancer. Humana Press. 2010.
• Nepomuceno, J.C. Nutrigenomics and Cancer Prevention. In: Cancer Treatment - Conventional and Innovative Approaches. Rangel, L. (ed.). InTech. 2013.
• Tanaka T, Shnimizu M, Moriwaki H. Cancer Chemoprevention by Carotenoids, Molecules 2012;17: 3202-3242.

Old School Supplements - Choline: Stronger, Faster, Leaner & More Muscular, or Just Another Dumb-and-Barbell Story?

Image 1: You really get a hefty dose of the history of physical culture with volume 1 + 2 of Randy Roach's Muscle, Smoke & Mirrors; I must forewarn you, though: These books have addictive potential, so don't buy them, when you have other important things (beside training ;-) on your schedule.

If you are among my facebook friends, you will probably remember that I have received an amazing gift from my friend Carl Lanore, a few weeks ago: The first two books of Randy Roach's Muscle, Smoke & Mirrors (soon-to-be) Trilogy (Roach. 2008-2011). I am not a fan of muscle gossip, but these books are a really amazing resource for everyone with a vested interest in physical culture - just as Super Human Radio the "first radio station dedicated to promote physical culture is, by the way ;-)

My personal favorite in the first two volumes of Muscle Smoke & Mirrors is yet clearly the last third of the second volume about the history of dietary supplements. Aside from the notorious liver tabs and all sorts of "pro-diarrheal" protein supplements, stories about Joe Weider being willing to sell elephant shit, if only someone convinced him that it would further protein anabolism, and a lot of other informative and entertaining stuff, there was one supplement that has been largely forgotten by now that caught my interest - choline!

Choline is present in every human cell!

Although it does not carry the term "vitamin" in its name, choline is an essential water-soluble nutrient that is abundant in some of the typical old-school bodybuilding foods, such as calf liver, beef, eggs, chicken, turkey, sardines, cod, milk and a lot of those green vegetables, many people today believe they must have been invented by the vegans and vegetarians.

Are vitamin supplements bad for me? I have addressed the question in some detail in two previous blogposts in response to the ever resurfacing horror stories about vitamin E, selenium and prostate cancer (Part I), and the media hype around the results of the Iowa Women's Health Study (Part II). So before you bombard me with further questions, go and check out these and a couple of posts on hormesis, here at the SuppVersity ;-)

At first sight it may thus seem that the supplemental choline some of the pros took with each and every meal was at best a waste of time and money, if not a potential health hazard; after all, we are seeing all those horror news about potential negative side-effects from the overconsumption of all sorts of allegedly harmless vitamins pop up in the media in ever shorter time intervals, as of late.

Choline - essential, but already (over-)abundant?

To answer this question we will initially have to identify what choline does in our bodies. As the name that has been derived from the greek word for bile ("chole") implies, choline has been initially identified as a major component of the juices and cells of the pancreas and liver. Scientists realized only later that it is an absolutely essential constituent of each and every cell of our body, where choline with its fat-modifying properties increases the flexibility of the cell membranes and handles the in- and outflux of fat-based nutrients and waste products, respectively.

If we take into consideration that choline is also one of the rare trimethylated molecules in our diets and acts as an important methyl donor that is required for both, the proper activation and deactivation of genes, and as precursor to the neurotransmitter acetylcholine, it is hardly surprising that the list of mostly neurological and cardiological pathologies stemming from marginal or full-blown choline deficiency is endless:

Image 2: The purportedly dangerous cholesterol bombs, aka eggs, are among the #1 sources of dietary choline

• high homocysteine levels, cardiovascular disease, 
• high blood pressure, high triglyceride levels
• fatigue, insomnia, 
• memory and nerve problems,
• liver dysfunction, kidney failure
  (probably subsequent to a lack of phosphatidylcholine),
• impaired growth and failure to thrive,
• abnormalities in bone and red blood cell formation,
• infertility

If you take a look at your "scientifically formulated high potency B-vitamin supplement" *rofl* you may notice that despite getting 1000%-3000% of all sorts of B-Vitamins, chances are that it contains "only" 100% of the recommended daily allowance of choline (USDA recommendations):

Figure 1: The daily choline intake of most Americans is below the respective RDA, of which some scientists already speculate that it may already be too low. (USDA. 2011)

• 0-6 months: 125 mg
• 6-12 months: 150 mg
• 1-3 years: 200 mg
• 4-8 years: 250 mg
• males 9-13 years: 375 mg
• males 14 years and older: 550 mg
• females 9-13 years: 375 mg
• females 14-18 years: 400 mg
• females 19 years and older: 425 mg
• Pregnant females of any age: 450 mg
• Lactating females of any age: 550 mg

And though the "average" American today is working his way up towards a similar "weight class" as the heavy weight bodybuilders in Arnold's days, the disproportionally higher muscle mass of a bodybuilder as well as the 8,000-10,000kcal diets those big guys were consuming in the off season would suggest that they needed at least twice, maybe even thrice the amount of choline an average individual would consume. The "OSBDA", as in old-school bodybuilding daily allowance would thus have been roughly 1.5g of dietary choline, as it is contained in

• 15 eggs
• 10-11 eggs and 1lbs of chicken
• 1 cup of almonds, three cups of rice, 5 eggs, 1lbs of chicken and five ounces of liver

And while many of the pros probably got way more than those 1.5g of choline from their glutenous and ridiculously frequent meals, the increased oxidative damage due to the arduous workouts and use of certain "supplements" may well have exacerbated their need for a nutrient of which various epidemiological studies report a significant correlation with reduced levels of C-reactive protein (CRP), interleukin-6 (IL-6) and the tumor necrosis factor-alpha (TNF-alpha); the usual suspects, all of which  have been implicated as confounding, if not causative factors in almost every modern (e.g. Detoupolo. 2008, Rajaie. 2011).

Bigger, stronger, faster, leaner, ... what the pros said

For most, yet by probably not all competitive bodybuilders back in the day, improvements in heart and overall health were yet probably not the major incentive to ramp up their choline intake to levels, where the fishy smell your sweat, urine and other bodily fluids will develop when you ingest way too much choline eventually drowned out the foul protein farts, they got from the hardly digestible protein powders of the late 1970s. What they were looking for was the competitive edge:

1. Performing more reps and training at an even higher volume - With dietary / supplemental choline being a necessary precursor to acetylcholine, which in turn facilitates skeletal muscle contraction, it was only reasonable to assume that the 2-3x per day 2-3h marathon workouts some of the guys were performing, would increase the risk to deplete your choline levels so that the acetylcholine production would come to a standstill and your muscles would simply refuse to contract.
    
2. Greater protection and faster repair of muscle damage - Due to its established anti-oxidant effects and its status as an essential and functional constituent of the cell wall, it appears logical that adequate levels of choline would be necessary to both protect and repair skeletal muscle.
    
3. Increased leanness and vascularity - In view of the fact that it has been known since the early 1950s that choline's role in the oxidation of fatty acid goes well beyond serving as a source for the phospholipids that would carry them out of the liver and to the mitochondria of skeletal muscle and other metabolically active tissue (Artom. 1953). Even the assumption that choline supplementation will propel the oxidation of fatty acids, promote lower body fat levels and lead either directly (fat loss) or indirectly (reduced inflammation = reduced subcutaneous water) to a more vascular look, was far from being a bro-scientific 'dumb-and-barbell story'.

As you as an educated SuppVersity student know all too well, though, not everything that appears to make sense works and not everything that that works must necessarily have scientific research to back its efficiacy up - after all, the brocebo effect alone (cf. "Add 10kg to Your Bench With Brocebos") could have been responsible for a subjective decrease in fatigue (1), a decrease in muscle soreness (2) and a perceived increase in leanness and vascularity (3).

... what exercise and nutrition science says

Despite the last-named restraints and the unlikeliness that we will find a study on choline supplementation on 200lbs+ bodybuilders on a 8,000kcal/day+ diet, I guess, you will not mind, if we take a brief look at whether or not those "logical" benefits (#1-3, above) have actually been observed in peer-reviewed studies.

1. Potential effects of supplemental choline on training load / volume Van Allwörden et al. weer among the first scientists who tried to establish a connection between the long-established exercise induced decreases choline, exercise performance and fatigue (Van Allwörden. 1993). Just like Buchman et al. who report similar results in marathon runners (Buchman. 2000), Allwörden et al. had yet to acknowledge that the 0.2g/kg lecithin (a choline source) induced compensation of the 17% decrease in serum choline levels compared to the control group did not lead to increase the performance of the adolescent triathletes in their study. And though these results stand in contrast to a 1992 study by Sandage et al. which found a minimal increase in 10k running times in response to the ingestion of 2.8g of choline 1h prior to the run, most authors of pertinent reviews do acknowledge the theoretical merit of the hypothesis, but speculate that the decline in choline is rarely ever pronounced enough to for choline supplements to illicit immediate ergogenic benefits (e.g. Jäger. 2007; Penry. 2008). Long-term studies on potential downstream effects of decreased oxidative stress, improved cellular regeneration and utilization of fat soluble nutrients, on the other hand, are missing so that the preliminary answer to the question whether choline supplementation would allow you to train longer, or at an overall higher volume must be: Very unlikely!
    
2. Potential effects of supplemental choline on muscle damage, repair and growth While Michel et al. observed in isolated muscle cells that choline deficiency induced a cascade of changes in both the oxidative metabolism (downregulated), as well as the fatty acid composition of the cell membranes (Michel. 2011), which was characterized by a shift towards mono- and away from saturated fatty acids, it is somewhat far-fetched to use this as "evidence" for a potential beneficial effect of choline supplementation; after all, we are dealing with isolated, choline depleted muscle cells in a petri dish and cannot even say for sure whether a potentially hightened susceptibility of the monounsaturated fats in the cell wall will lead to an increase in skeletal muscle damage in response to strenuous exercise. Against the background that there is no other convincing scientific evidence that would suggest that supplemental choline - in the absence of dietary choline deficiency (or pathologies related to the latter, such as liver cirrhosis) - would make your muscle bullet proof, this is the 2nd purported benefit the real-world significance of which turns out to be more than questionable.
    
3. Potential effects of supplemental choline on fat loss and vascularity Interestingly enough, the "fat loss" hypothesis, appears to be the one with the most convincing scientific evidence to support it. In 2002, for example, Hongu and Sachan observed a shift towards increased fatty acid oxidation in 19 healthy women who participated in a combined carnitine + choline + exercise trial. Moreover, these substrate repartitioning effects were "sustained until wk 2 after cessation of choline plus carnitine supplementation and exercise" (Hongu. 2002). In a previous rodent trial a similar stack that included caffeine, carnitine and choline had lead to body fat reductions "similar to those due to mild exercise" (Hongu. 2000), an observation that would support a previous hypothesis of the authors stating that the combination of carnitine and choline favors an "incomplete oxidation of fatty acids and disposal of their carbons in urine as acylcarnitines in humans" and could thusly help to increase the absolute and relative amount fat loss on a diet. In view of the well-established lipolytic effects of caffeine a "CCC stack", i.e. caffeine + carnitine + choline, could thus in fact make a valuable addition to a sound exercise and diet regimen. Whether it would really make a visible difference, remains yet questionable.

What is the take away message from this article then? I guess, the best answer to this question would be eat your eggs, (organ-)meats, fish, nuts and veggies (and to avoid soy lecithin in supplemental or any other form) to satisfy your choline requirements naturally, in order to remain the "metabolically healthy, fat burning, muscle building machine" you should by now be with all those daily tips on health, exercise, nutrition and supplementation, here at the SuppVersity ;-)

References:

• von Allwörden HN, Horn S, Kahl J, Feldheim W. The influence of lecithin on plasma choline concentrations in triathletes and adolescent runners during exercise. Eur J Appl Physiol Occup Physiol. 1993;67(1):87-91.
• Artom, Camillo. Role of Choline in the Oxidation of Fatty Acids by the Liver. J. Biol. Chem. 1953 205: 101-111. 
• Buchman AL, Awal M, Jenden D, Roch M, Kang SH. The effect of lecithin supplementation on plasma choline concentrations during a marathon. J Am Coll Nutr. 2000 Nov-Dec;19(6):768-70.
• Detopoulou P, Panagiotakos DB, Antonopoulou S, Pitsavos C, Stefanadis C. Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study. Am J Clin Nutr. 2008 Feb;87(2):424-30. 
• Hongu N, Sachan DS. Caffeine, carnitine and choline supplementation of rats decreases body fat and serum leptin concentration as does exercise. J Nutr. 2000 Feb;130(2):152-7.
• Hongu N, Sachan DS. Carnitine and choline supplementation with exercise alter carnitine profiles, biochemical markers of fat metabolism and serum leptin concentration in healthy women. J Nutr. 2003 Jan;133(1):84-9.
• Jäger R, Purpura M, Kingsley M. Phospholipids and sports performance. J Int Soc Sports Nutr. 2007 Jul 25;4:5. 
• Penry JT, Manore MM. International Journal of Sport Nutrition and Exercise Metabolism 2008, 18(2):191-203
• Rajaie S, Esmaillzadeh A. Dietary choline and betaine intakes and risk of cardiovascular diseases: review of epidemiological evidence. ARYA Atheroscler. 2011 Summer;7(2):78-86.
• Roach, Randy. Muscle Smoke & Mirrors. Volume 1-2. AuthorHouse. 2008-2011.
• Sachan DS, Hongu N. Increases in VO2max and metabolic markers of fat oxidation by caffeine, carnitine, and choline supplementation in rats. J Nutr Biochem. 2000 Oct;11(10):521-6. 
• Sandage BW, Sabounjian RN, White R, Wurtman RJ: Choline citrate may enhance athletic performance. Physiologist 1992, 35(4):236. 
• USDA. FSRG Dietary Data Brief -- No. 9 –Dietary Intakes of Choline. 2011

Choline Deficiency, Its Consequences and How You Fix It | Part 2 of the "Common Nutrient Deficiencies, Their Health Consequences and How You Can Fix Them" Series

Don't you tell me there was no fancy cooking with the choline source #1, i.e. egg yolk! What about egg yolk on ricotta cauliflower ravioli filling, for example | get the recipe @ tastespotting.com

If you've read the last installment of this series, you can hardly be surprised that today, we are about to talk or rather I am about to write about choline. Choline is, as Wikipedia informs us, a water-soluble essential nutrient. Why choline is not officially called a "vitamin" is beyond me. "Experts" will still group it within the B-complex vitamins, anyway.

In my analyses in the series on nutrients other than cabohydrates that influence glucose control, you've read that the former, the "other", "real" B-vitamins are - in my humble opinion - totally overrated. Choline, which can come in various forms of quaternary ammonium salts all of which contain the caracteristic N,N,N-trimethylethanolammonium cation, on the other hand, it probably the most underrated micronutrient - not only for glucose control, by the way.

You can learn more about choline at the SuppVersity

Huge GH Spikes from GPC!?

Choline & Classic Bodybuilding

Improved Lipid Profile W/ Eggs

Caffeine, Choline, L-Car = Fat Loss

Choline Maximizes Carnitine Storage

Choline as a Nootropic?

One of the reasons choline has been depreciated is probably that it occurs in all the good foods of which scientists have been (falsely) telling you that you must not eat them for decades.

Figure 1: Eggs, or rather their fatty yolks, are a very good source of choline. One too few people appreciate for its nutritional density and too many people fear for its allegedly bad cholesterol content | learn why this is bullocks

Voilà, exhibit A (see Figure 1), an egg. The "bad" yolk of a single egg contains enough choline to "get you through the day" - whether that's also enough choline for optimal health is a question we are about to tackle later in today's installment of the Common Nutrient Deficiencies, Their Health Consequences and How You Can Fix Them" Series (you can browse through past and previous issues, here, if you have an RSS compatible web-browser).

The fact that generations of bodybuilders have been throwing away the yolks only to supplement with even more choline than they'd have gotten from their eggs does yet certainly tell you something about the importance of this nutrient.

But I am digressing, here. What we actually wanted to talk about is after all "normal" people, not bodybuilders. Normal people like the participants of the 2005 National Health and Nutrition Examination Survey (NHANES) among which only 2% of postmenopausal women consumed the recommended amount of for choline, and in general "mean choline intakes for older children, men, women and pregnant women are far below the Adequate Intake established by the IOM" (Zeisel. 1991).

When people don't get enough choline in their diets, and the amount of choline in their system declines, will eventually lose their ability to methylate homocysteine to methionine. The result, their plasma levels of homocysteine increase and heart disease, dementia and even cancer are lurking right around the corner.

Why is high plasma homocysteine bad? In spite of the fact that it is still questionable, whether homocysteine is causally involved in the etiology of heart disease (Brattström. 2000), the present evidence leaves little doubt that high homocysteine levels are a marker of increased risks for several chronic diseases and conditions including cardiovascular disease, cancer, cognitive decline and bone fractures (HSC. 2002; Wu. 2002; Seshadri. 2002; van Meurs. 2004).

Even in the absence of vitamin B6, and B12, of which everybody is talking these days, choline and its cousin betaine have the ability to lower homocysteine levels (Chiuve. 2007). In this context you should also keep in mind that (a) homocysteine levels and the development of the triage we call "metabolic syndrom" (obesity, diabetes, high cholesterol) and that (b) choline is "lost" (oxidized) during the methylation process -- the choline requirements of the average, meanwhile at least chubby US citizen are thus naturally higher than the RDA scientists have determined in a day and age, when a BMI of >30 was still the exception.

Figure 2: The maintenance of healthy homocysteine levels is only one of choline's many important effects.

Aside from being involved in the clearance of homocysteine, choline is also, and maybe even more importantly, used in the synthesis of the constructional components of your body's cell membranes and much more (see Figure 2, as well):

• Choline figures in cell signaling, where the choline-containing phospholipids, phosphatidylcholine and sphingomyelin, are precursors for the intracellular messenger molecules, diacylglycerol and ceramide. And with the platelet activating factor (PAF, an activator and mediator of many leukocyte functions, including platelet aggregation and degranulation, inflammation, and anaphylaxis) and sphingophosphorylcholine (regulate trafficing around / across the cell membrane; Ramstedt. 2002), there are two additional choline metabolites with important systemic functions.
• The transmission of never impulses is another, certainly one of the most important functions of choline or rather acetylcholine, an important neurotransmitter involved in muscle control, memory, and many other functions. No wonder that low choline levels have been associated with the progression of Alzheimer's and non-Alzheimer's dementia (Babic. 1999; Seshadri. 2002)

Apropos beyond methylation - choline can make up for a lack of folate! The often decried lack of folate intake (just as a reminder the folate fortfication program in the US made no one healthier - with one exception, maybe: The recommendations to increase folate intake for pregnant women/women of childbearing age has been relatively successful for preventing neural tube defects in infants) would be much less of an issue in the diabesity problem, if the average American consumed 2,200mg of choline per day. The same amount of choline that is which preserved the markers of cellular methylation and attenuated folate deficiency related DNA damage in a genetic subgroup of folate-compromised men in a 2010 study by Shin et al.

• The effects on lipid (fat) transport and metabolism are probably still totally underrated by both the public and certain parts of the medical establishment. The fat and cholesterol that's consumed in the diet is after all transported to the liver by lipoproteins (chylomicrons) which are built from phosphatidylcholine. If there is not enough choline to build these 'cholesterol shuttles' the fat and cholesterol will begin to accumulate in you liver. No wonder scientists have long discovered an intricate relationship between choline intakes, on the one hand, and the development of non-alcoholic fatty liver disease, on the other hand - in fact, more recent evidence suggests that millions of US citizens have been able to escape a non-alcoholic fatty liver only due to "good genes" that allow them to budget their insufficient choline intake better than others (Spencer. 2011).

In spite of the fact that a full-blown choline deficiency will impair your exercise performance, the provision of supplemental choline has not been shown to consistently produce meaningful increases in exercise performance (Penry. 2008). As a physical culturist, you should still keep in mind that intense exercise will increase your basal choline requirements of which the wise USDA says based on data of which the researchers say that its quality "varies widely across studies", with the most significant sources of potential sources being over- or underreporting of portion sizes and frequency of intake, omission of foods, and inaccuracies related to the use of food composition tables. Accordingly Yates et al. add for consideration:

Table 1: High choline foods for omnivores and vegetarians; choline content in milligrams / 100g | data adapted from nutritiondata.com

"Therefore, the values reported by nationwide surveys or studies that rely on self-report may be somewhat inaccurate and possibly biased. Food composition databases that are used to calculate nutrient intake from self-reported and observed intake data introduce errors due to random variability, genetic variation in the nutrient content, analytical errors, and missing or imputed data.

In general, when nutrient intakes for groups are estimated, the effect of errors in the composition data is probably considerably smaller than the effect of errors in the self-reported intake data (NRC, 1986). However, it is not known to what extent this is true for folate, biotin, pantothenic acid, or choline." (Yates. 1998)

That's bad, because the first signs of liver damage in humans (beginning NAFLD if you will) occur after only 3 weeks on a choline deficient diet (Zeisel. 1991). In view of the fact that doses of safe therapeutic doses go into the 8-10 gram range and considering the fact that the total amount of choline in foods is not exactly exorbitantly high, it would appear prudent to follow the "more is better principle", when it comes to choline-rich foods (see Table 1 and bottom line for suggestions | Didn't find the food you were looking for? Try the official USDA Overview).

Don't go overboard on supplements! When it comes to supplementation, on the other hand, you better be careful not do overdo it. While choline is generally relatively benign, it can produce side effects that range from increased potassium and magnesium requirements over depressive like symptoms (a general sluggishness) to vomiting and, in some people, acne-like skin rashes. Dosages in the below 3g per day range do yet generally appear to be tolerated very well. In the long term the phospholipid bound forms of choline can yet produce quite nasty depressive-like side-effects - another reason to prefer the cheap and effective citrates and tartrates if you are just "supplementing" your diet or looking for the metabolic effects, primarily.

Unless you are following a no fat diet, the use of dietary supplements to cover your baseline requirements of 500-600mg (I am deliberaterly not using the ostensibly "accurate" RDA, here) shouldn't  be necessary - at least if you eat your healthy eggs every day ;-)

Choline as a "metabolic activator" and diet aid!?

If you mimic the old-school body- builders and have your choline supps with meat, this will increase the retention & effects of carnitine.

If you remember my previous article on the relatively unknown "CCC-Stack" which consists of caffeine, carnitine, and... you guessed it, choline you will yet remember that doubling your intake with 500mg of choline tartrate or citrate had quite remarkable effects on the metabolism (learn more | for metabolic purposes I would prefer the citrate and tartrate forms over the expensive phospholipid bound version of choline, which may have its advantages, though, when it comes to brain-related effects).

Moroever, a recent study from the Zagazig and the Mansura University in Egypt suggests that choline alone, will produce quite impressive weight loss effects - even in the absence of the "fat liberator" caffeine and the "fat transporter" carnitine, i.e. the other "C"s in the CCC stack.

The study, Elsawy, Abdelrahman and Hamza conduted investigated the effects of choline supplementation on body mass reduction and leptin levels among female taekwondo and judo athletes in the pre-competition phase (Elsawy. 2014).

Figure 3: Relative changes in lipid oxidation, body fat (%), body mass and strength parameters in female athletes during contest prep with (choline) and without (control) 2x2g of supplemental choline in their meals (Elsawy. 2014)

Twenty-two female athletes (15 taekwondo and 7 judo athletes) were selected from different weight
categories and divided into two groups, according to weight. The players in the experimental group consumed their choline supplements (2x2.0g of choline bitartrate) daily with meals for one week.

I guess the results actually speak for themselves. As expected, the experiment revealed significant differences between pre- and post-competition measurements of free plasma choline, and urine choline levels. The significantly higher fat loss, on the other hand, is something even the researchers did not necessary expect to see. In view of the reduction in malondyaldehyde (MDA = lipid oxidation) and the increase in carnitine retention and effects you've read about in a previous SuppVersity article ("Choline Maximizes Carnitine Retention + Effects" | read more) it is yet eventually not surprising that the choline group lost more body fat without suffering significant reductions in strength and lean mass.

Eat three of these or combine two of them: One whole eggs, 4oz of shrimp, or 5oz scallop, 5oz chicken, 5oz turkey

Eat four of these or combine four of them: 4oz cod, 1.5 cups of collard greens, 1.75 cups of Brussel sprouts, 1.75cups of broccoli, 5oz tuna, 5oz salmon, 6oz beef, 6 oz saridines

Eat five of these or combine one of each 2cups of swiss chard, 2cups of cauliflower, 2cups of asparagus, 2.25cups of spinach, 2cups green peas, 2.5 cups cabbage, 2 cups of Shiitake mushrooms

Other foods with choline, of which you'd yet probably have to eat too much to get to your SRI (SuppVersity recommended intake for adults) of 500-600mg are green beans and bok choy (5% of SRI per cup), summer squash, miso and tomatoes (1-2% of SRI per cup)

Bottom line: I am well aware that the fat loss effects, I deliberately mentioned last are probably the "sexiest" benefits choline has to offer. Compared to the conservation of liver, brain and heart hearth for which you "just" have to make sure that you consume enough of the foods in the list to the left, the ability of supplemental choline to promote fat loss and conserve lean mass and strength in "average Janes" (read more) and competitive athletes (Figure 3) is actually quite pathetic.

Speaking of "pathetic" the notion that eggs would be bad for you, because they contain cholesterol is probably even more pathetic than the notion that being ripped was more attractive than being healthy. In view of the fact that the amount of highly bioavailable choline in a single egg can cover 20%-35% (depending on its size) of your daily choline demands, having an egg for breakfast is nothing you should consider, but rather something you should simply do! The increase in choline intake, the beneficial effects on your cholesterol particle and phospholipid profile and the increase in HDL-driven lipid reverse-transport are after all something you don't want to sacrifice on the altar or unwarranted prejudices and in blind obedience to dietary guidelines of which more and more researchers say that they "are not benefiting the public as a whole and may actually have negative nutritional implications." (Herron. 2004)

References:

• Babic, T. "The cholinergic hypothesis of Alzheimer’s disease: a review of progress." Journal of Neurology, Neurosurgery & Psychiatry 67.4 (1999): 558-558.
• Brattström, Lars, and David EL Wilcken. "Homocysteine and cardiovascular disease: cause or effect?." The American journal of clinical nutrition 72.2 (2000): 315-323.
• Elsawy, Gehan, Osama Abdelrahman, and Amr Hamza. "Effect of Choline Supplementation on Rapid Weight Loss and Biochemical Variables Among Female Taekwondo and Judo Athletes." Journal of Human Kinetics 40.1 (2014): 77-82.
• Herron, Kristin L., and Maria Luz Fernandez. "Are the current dietary guidelines regarding egg consumption appropriate?." The Journal of nutrition 134.1 (2004): 187-190.
• HSC: Homocysteine Studies Collaboration. "Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis." Jama 288.16 (2002): 2015-2022. 
• Penry, Jason T., and Melinda M. Manore. "Choline: an important micronutrient for maximal endurance-exercise performance?." International journal of sport nutrition and exercise metabolism 18.2 (2008): 191.
• Ramstedt, Bodil, and J. Peter Slotte. "Membrane properties of sphingomyelins." FEBS letters 531.1 (2002): 33-37.
• Seshadri, Sudha, et al. "Plasma homocysteine as a risk factor for dementia and Alzheimer's disease." New England Journal of Medicine 346.7 (2002): 476-483. 
• Shin, William, et al. "Choline intake exceeding current dietary recommendations preserves markers of cellular methylation in a genetic subgroup of folate-compromised men." The Journal of nutrition 140.5 (2010): 975-980.
• Spencer, Melanie D., et al. "Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency." Gastroenterology 140.3 (2011): 976-986.
• van Meurs, Joyce BJ, et al. "Homocysteine levels and the risk of osteoporotic fracture." New England Journal of Medicine 350.20 (2004): 2033-2041.
• Wu, Lily L., and James T. Wu. "Hyperhomocysteinemia is a risk factor for cancer and a new potential tumor marker." Clinica Chimica Acta 322.1 (2002): 21-28.
• Yates, Allison A., Sandra A. Schlicker, and Carol W. Suitor. "Dietary reference intakes: the new basis for recommendations for calcium and related nutrients, B vitamins, and choline." Journal of the American Dietetic Association 98.6 (1998): 699-706. 
• Zeisel, STEVEN H., et al. "Choline, an essential nutrient for humans." The FASEB journal 5.7 (1991): 2093-2098.