As an essential nutrient, choline can help you to . . .

Fire Up Your
Mind’s Tree of Life

… by naturally synthesizing abundant amounts of
acetylcholine, the principal biomolecule for focus and concentration
By Will Block

A house is not a home unless it contains
food and fire for the mind as well as the body.

— Benjamin Franklin,
Poor Richard’s Almanac

A

s the evolutionary party began on our planet, choline was an early gift for life. Judging from newly emerging data, acetylcholine—a principal biomolecule for which choline is the precursor*—is ubiquitously expressed throughout the phylogenetic tree of life, even among organisms without nervous systems.1 This is surprising, given that acetylcholine is generally thought of as a neurotransmitter. Nevertheless, experimental evidence has shown that acetylcholine is widely expressed in pro- and eukaryotic** non-neuronal cells, where it operates as a local mediator and modulator of physiological functions. Scientists have found detectable levels of acetylcholine in bacteria, and in primitive organisms, such as blue-green algae, yeasts, fungi, protozoa, worms, and sponges . . . suggesting an extremely early appearance of acetylcholine in the evolutionary process.


*Choline is also used in the synthesis of the phospholipids, phosphatidylcholine and sphingomyelin, which are structural components of all human cell membranes.

†Referring to the evolutionary history of life on earth.

**Prokaryotes are a group of organisms that lack a cell nucleus, while eukaryotes are organisms whose cells contain complex structures inside the membranes.



Acetylcholine is ubiquitously
expressed throughout the
phylogenetic tree of life, even among
organisms without nervous systems.


3 Billion Years of Utility

It is astounding that acetylcholine shows up nearly 3 billion years ago given the age of the planet (~4.6 bya) and the appearance of life (~3.8 bya). And far from originating for purposes of neurotransmission, the initial use of acetylcholine was much more basic, having to do with fundamental aspects of cellular development and function. When neuronal tissue did finally evolve in living things (marine organisms and mollusks) about 500 to 400 million years ago, it may be that these cells merely took advantage of an already sophisticated, built-in cholinergic system and adapted it to their newfound need for neurotransmission.

Acetylcholine Is a Classic Neurotransmitter

In animals, acetylcholine represents one of the most quintessential neurotransmitters. And in humans, acetylcholine and its synthesizing enzyme, choline acetyltransferase, have been demonstrated in a variety of neuronal tissue types, including muscle cells. However, in immune cells, the non-neuronal cholinergic system is widely expressed, demonstrating the commonality of its non-neural role. A few years ago, a review was conducted by several German pharmacologists who examined the world’s scientific literature to see what roles acetylcholine may play in non-neuronal function. Here is their eye-opening conclusion, in their own words:2

. . . it becomes evident that the non-neuronal cholinergic system represents a most widely expressed and highly effective system created by nature to regulate or modulate basic cell functions. . . . It is fascinating to revise the role of acetylcholine [ACh] in biological systems by discriminating between non-neuronal and neuronal ACh. The non-neuronal cholinergic system, phylogenetically an extremely old system, is more widely distributed in biological systems than the neuronal system. The majority of human cells synthesize acetylcholine . . . We postulate that a picture will emerge showing that ACh plays an important role in the regulation of cellular homeostasis, comparable with its dominant role within the nervous system.


‡In bodily organs or systems other than the central or peripheral nervous systems.



It is astounding that acetylcholine
shows up nearly 3 billion years ago
given the age of the planet (~4.6 bya)
and the appearance of life (~3.8 bya).


The scientists are saying, in short, that we have long been overlooking a fundamentally important aspect of acetylcholine’s role in our physiology—a role that runs deeper and broader than we imagined.

Acetylcholine Helps Maintain Homeostasis

Before getting to some of the evidence supporting the authors’ conclusion, let’s look at its implications. Homeostasis is one of the key concepts of biology. It is the process by which an organism, or an organ, or a single cell, maintains equilibrium by adjusting its physiological processes to compensate for the effects of disruptive outside forces, such as changes in temperature or chemical composition, or assault by hostile microorganisms. Since homeostasis is necessary for the proper functioning, and ultimately the survival, of our cells, it’s fair to say that anything, such as acetylcholine, that plays an important role in that process is very important indeed. This suggests the obvious: that any nutritional precursor to such a vital compound—in this case, choline—should be high on our priority list.

An intriguing clue regarding the importance of acetylcholine is its universal appearance in nature. As previously stated, although we think of it primarily as a neurotransmitter, acetylcholine is found, more than any other such type of molecule, in a wide variety of creatures—including those that do not even have a nervous system.


This suggests the obvious: that any
nutritional precursor to such a vital
compound—in this case, choline—
should be high on our priority list.


Acetylcholine Is Vital for Cellular Function

All of this suggests that acetylcholine has played a vital role in the evolutionary history of life on earth, going back to the dawn of life, and that this role, remote from originating for purposes of neurotransmission, was much more basic than that, having to do with fundamental aspects of cellular development and function. When neuronal tissue did finally evolve in living things (shortly after the Cambrian explosion) about 500 to 400 million years ago, it may be that these cells merely took advantage of an already sophisticated, built-in cholinergic system and adapted it to their newfound need for neurotransmission.

The German authors cite evidence of a role of acetylcholine in such diverse non-neuronal cellular functions as mitosis (cell division), cell differentiation, organization of the cytoskeleton (the internal structural framework of the cell), cell-cell contact, secretion, absorption (of nutrients such as choline and amino acids), membrane development (especially choline-containing phospholipids); and metabolism.

Epithelial Cells Are Especially Important

Acetylcholine appears to be synthesized in the majority of human cells, the authors report. A particularly important role of acetylcholine in humans is in the function of epithelial cells. These are smooth, tightly packed cells that constitute the membranous lining, inside and outside, of most organs. They form the primary protective barrier against assault by potentially harmful substances, such as bacteria, viruses, and fungi, in their immediate environment. Epithelial cells are thus extremely important in maintaining homeostasis. They appear to be directly involved in regulation of the immune response, such as the release of antibodies to attack and destroy microbial invaders.


Dietary choline was necessary,
not only for survival during
the harsh times of glaciation in the
Middle Stone Age, but also
most likely to fuel and fire up our
predecessor’s minds for
escape from the mother continent
50,000 years ago.


Acetylcholine activity has been detected in epithelial cells of the human airway, the alimentary tract, the kidneys, the urogenital tract, the eyes, the placenta, and the skin, as well as in glandular tissue of the female breast. And it has been observed that the vast majority of epithelial cells contain both nicotinic and muscarinic receptors, the same kinds of specialized molecular receptors that are activated by acetylcholine in the nervous system. That cannot be a coincidence.

Choline and the Speed of Brain Evolution

As we now know, the non-neuronal functions of acetylcholine in one-celled life ultimately remain operative in complex life, even after neuronal properties develop. So for many reasons, dietary choline was necessary, not only for the survival of life during the harsh times of glaciation in the Middle Stone Age, but also most likely to fuel and fire up our predecessor’s minds for escape from the mother continent (“Out of Africa”) 50,000 years ago.


Choline may have contributed to the
speed with which human evolution
and complex knowledge was
furthered, and in the same area of
Africa, albeit between 100 and 75
thousand years ago.


Just as omega-3 fatty acids is now thought to have played an instrumental role in preserving human life on the planet (see “Did Shellfish Omega-3s Spur Brain Evolution?” in the April issue), choline may have contributed to the speed with which human evolution and complex knowledge was furthered, and in the same area of Africa, albeit between 100 and 75 thousand years ago (kya).

Supporting these conclusions, animal studies show that maternal prenatal choline supplementation promotes permanent enhancement of attention and spatial memory abilities in offspring. Conversely, dietary choline restriction during pregnancy impairs cognitive function in offspring. Has this been proven to be the case with humans? Although few studies have been done to date examining the correspondence between gestational choline concentrations and neurodevelopmental outcome in humans, so far there have been no findings of any clear correspondence between choline and IQ.3 Nevertheless, without question, the development of the fetal brain is influenced by nutrients such as docosahexaenoic acid (an omega-3 fatty acid) and choline.4

Ostrich Eggs for Breakfast

Bird eggs, which are rich in choline, have been valuable foodstuff since prehistory, in both hunting societies and more recent cultures where birds were domesticated. Hunter-gatherers in Africa’s Kalahari Desert use ostrich eggshells as water containers in which punctured holes and pouring lips enable their use as canteens. The presence of such eggshells with engraved hatched symbols dating from the Howiesons Poort period of the Middle Stone Age at Diepkloof Rock Shelter in South Africa suggests ostriches were an important part of human life as early as 60 kya.5 And even earlier, at 100 kya, according to another recent study judging from engraved ostrich eggshells from the Middle Stone Age levels at Blombos Cave, South Africa.6 Both of these studies provide evidence for symbolically mediated behavior, or “cognitively modern” human behavior, reflective of the kind of complex cognition advancement that the “Out of Africa” Diaspora required.

The Feds’ Lowball Criterion: Disease Prevention

Picture the following classic cartoon. The scene is a classroom filled with middle-aged adults who are enrolled in an adult education class, Economics 101. It is apparently the first day of class. As the initial lesson, the professor has just written on the blackboard, “Don’t spend more than you take in.” A heavyset guy with a somewhat porcine look raises his hand and says, “I don’t get it.” The cartoon’s caption reads, “Can You Spot the Congressman?”

Should we laugh or cry? It’s hard to say, when something so absurd is also so true.

Here’s something similarly absurd: the federal government’s recommendations for our daily intake of a variety of nutrients (mainly vitamins and minerals) have traditionally been designed merely to prevent the occurrence of deficiency diseases, not to maintain good, let alone optimal, health. That’s like feeding your dog just enough that he doesn’t bite your hand out of hunger, but not so much that he’d lick it out of love. You could do much better than that for your dog—and the government could do much better for you.


In 1998, the Food and Nutrition
Board of the Institute of Medicine
declared choline to be
an essential nutrient, because it must
be consumed in the diet in order to
meet our metabolic needs and
maintain good health.


But to be fair, the task in question is challenging, even in terms of establishing the minimal levels required for disease prevention. Beyond that lowball criterion, the task becomes much more difficult and contentious when the experts try to define the requirements for the ideal state of optimal nutritional health. After all, individuals vary greatly in their nutritional requirements, owing to many factors, such as heredity, gender, age, lifestyle choices, available foods, and general state of health. In the case of vitamin D, even geographic location is important (see “Vitamin D and Calcium Combat Cancer” in the August 2007 issue).

Choline Is an Essential Nutrient

So perhaps we should be sympathetic and cut the feds some slack . . . not on your life. Ironically, it may be that the feds didn’t do too bad a job, with the data they had, in recommending preliminary Adequate Intake (AI) values for an essential nutrient that is neither vitamin nor mineral. That’s choline, a nitrogenous alcohol obtained mainly—but rarely in adequate amounts—from milk, eggs, liver, and peanuts, which is the subject of this article.

Choline’s principal role in human physiology is as a precursor to several other important compounds:

  1. Phosphatidylcholine and sphingomyelin – These two phospholipids are important structural components of our cell walls. They also act as sources of certain compounds involved in cell-signaling functions, as do some other metabolites of choline. (Phosphatidylcholine is also known as lecithin.)

  2. Acetylcholine – This vital neurotransmitter activates all of our muscles. It’s also the principal facilitator of neuronal signals in those regions of the brain that are involved in learning, memory, and other cognitive functions (the cholinergic system). When acetylcholine is depleted in Alzheimer’s disease, the brain may “autocannibalize” its own neurons by taking choline from the phosphatidylcholine molecules in the cell walls. This helps alleviate one problem at the expense of another: degradation of the cell walls, which hastens the process of neuronal loss seen in Alzheimer’s patients. Thus it’s especially important to maintain adequate choline levels when cholinergic function may be impaired. (See “A Tale of Two Cholines,” May 2005.)

  3. Betaine – This oxidation product of choline is an important molecular donor of methyl groups (–CH3), which are involved in many important physiological processes, including the conversion of the harmful amino acid homocysteine to harmless methionine. (See “Choline Battles Homocysteine,” April 2005.)

Choline Deficiency Leads to Liver Dysfunction

In 1998, the Food and Nutrition Board (FNB) of the Institute of Medicine declared choline to be an essential nutrient, because it must be consumed in the diet in order to meet our metabolic needs and maintain good health. Choline is not considered a vitamin, however, because our bodies can produce small amounts of it via the enzymatic breakdown of phosphatidylcholine. In establishing daily AI values for choline, the FNB’s main criterion was the prevention of liver dysfunction, the primary consequence of choline deficiency.

In 2003, the Linus Pauling Institute (LPI) endorsed the FNB’s recommendations in the context of the following statement:7

Little is known regarding the amount of dietary choline required to promote optimum health or prevent chronic disease in humans. The Linus Pauling Institute supports the recommendation by the Food and Nutrition Board of 550 milligrams (mg)/day for adult men and 425 mg/day for adult women. . . . Little is known regarding the amount of dietary choline most likely to promote optimum health or prevent chronic disease in older adults. At present, there is no evidence to support a different intake of choline from that of younger adults . . .

The LPI report was peer-reviewed by Dr. Steven H. Zeisel, a professor of nutrition at the University of North Carolina at Chapel Hill. Dr. Zeisel, a leading authority on choline, serves on the Institute of Medicine’s Panel on Folate, Other B Vitamins, and Choline, which is responsible for recommending the AI values for these nutrients. He has published many research papers on choline, the latest of which changes the picture painted above.

The First Choline Study to Include Women

The new paper illustrates how difficult is the task that we’ve been discussing. Its title gives a hint: “Sex and menopausal status influence human dietary requirements for the nutrient choline.”8 Amazingly, this was the first study of choline requirements that included women, according to the authors; meaning that the existing AI value for women was established on theoretical grounds only.


So any advantage gained by larger
and more agile brains might not have
been enough, not without the higher
levels of nutrition provided by
shellfish for omega-3s and eggs for
choline enhancement.


The initial objective of the study was to evaluate the dietary requirements for choline in 57 healthy men and women (aged 18–70) and to investigate the consequences of choline deficiency. The ultimate objective was to refine the information on which the Institute of Medicine’s Food and Nutrition Board based its preliminary Adequate Intake values and, perhaps, to enable the calculation of a more relevant Estimated Average Requirement for choline, on which the Dietary Reference Intake (DRI, the final word) would be based.

Women’s Menopausal Status Makes a Big Difference

The details of how this study was conducted are mind-numbing, so let’s just cut to the chase. The researchers found, first of all, that 77% of men and 80% of postmenopausal women in their study developed subclinical liver or muscle dysfunction (causing no harm) when they were fed a choline-deficient diet [less than 50 mg per 70 kg (154 lb) of body weight per day] for 6 weeks. Remarkably, the rest seem to have done all right on this diet.

This organ dysfunction occurred, however, in only 44% of premenopausal women on the choline-deficient diet, perhaps because of their high levels of estrogen, which facilitates the synthesis of phosphatidylcholine. Since the body can obtain choline from phosphatidylcholine, having higher levels of the latter would reduce the need for choline from food or supplements.

The Old “Adequate Intake” May Be Too Low

The researchers also found that the current AI of 550 mg for men may be inadequate for some men, because 23% of the men in their study became choline-deficient (as evidenced by organ dysfunction) at that level of intake per 70 kg of body weight per day. The deficiencies were reversed when the men’s choline intake was increased to 825 mg per 70 kg of body weight per day.

Overall, 550 mg per 70 kg of body weight per day for men was sufficient to prevent or reverse organ dysfunction (disease prevention!) for 81% of the subjects in this study; the remaining 19% needed 825 mg per 70 kg of body weight per day, or the amount of choline in an ad libitum (no limitations) diet containing more than 550 mg per 70 kg of body weight per day. In the authors’ words, “This data should help inform the Institute of Medicine as they refine estimates for DRIs [Dietary Reference Intake] for choline.” Let’s hope so.

What About Optimal Health?

The question is, will the Institute of Medicine ever get beyond mere disease prevention and set its sights higher, on optimal health? Again, let’s hope so, but the new data discussed above are still in the disease-prevention realm.

Meanwhile, there is reason to believe that substantially higher amounts of choline—perhaps 2 to 3 g/day—may be essential for optimal health, especially in the elderly. Compared with younger people, the elderly show a greatly reduced bioavailability of choline to the brain after ingesting a single, substantial dose of it.9 A higher daily intake might compensate for that effect and could conceivably offer protection against neurodegenerative diseases such as Alzheimer’s.

The Light at the End of the Cave

Back during the time of the Middle Stone Age caves of South Africa 164 to 60 kya, the major problem our predecessors faced was the acquisition of adequate amounts of nutritious food. This was not guaranteed at a time when heavy glaciation elsewhere on the planet had resulted in a cooler and drier Africa, far less hospitable to plants, animals, and humans. So any advantage gained by larger and more agile brains might not have been enough, not without the higher levels of nutrition provided by shellfish for omega-3s and eggs for choline enhancement. Fortunately, for our own current Diaspora or breakout from the confines of the Food and Nutrition Board, we have the convenience of modern supplements. Do not be left behind.

References

  1. Kawashima K, Misawa H, Moriwaki Y, et al. Ubiquitous expression of acetylcholine and its biological functions in life forms without nervous systems. Life Sci 2007 May 30;80(24-25):2206-9.
  2. Wessler I, Kirkpatrick CJ, Racke K. The cholinergic ‘pitfall’: acetylcholine, a universal cell molecule in biological systems, including humans. Clin Exp Pharm Physiol 1999;26:198-205.
  3. Signore C, Ueland PM, Troendle J, Mills JL. Choline concentrations in human maternal and cord blood and intelligence at 5 y of age. Am J Clin Nutr 2008 Apr;87(4):896-902.
  4. da Costa KA, Rai KS, Craciunescu CN, Parikh K, Mehedint MG, Sanders LM, McLean-Pottinger A, Zeisel SH. Dietary docosahexaenoic acid supplementation modulates hippocampal development in the Pemt-/- mouse. J Biol Chem 2010 Jan 8;285(2):1008-15.
  5. Texier PJ, Porraz G, Parkington J, Rigaud JP, Poggenpoel C, Miller C, Tribolo C, Cartwright C, Coudenneau A, Klein R, Steele T, Verna C. A Howiesons Poort tradition of engraving ostrich eggshell containers dated to 60,000 years ago at Diepkloof Rock Shelter, South Africa. PNAS April 6, 2010;107 (14):6180-5.
  6. Henshilwood CS, d’Errico F, Watts I. Engraved ochres from the Middle Stone Age levels at Blombos Cave, South Africa. J Hum Evol 2009 Jul;57(1):27-47.
  7. Higdon J. Choline. Linus Pauling Institute, Corvallis, OR, 2003.
  8. Fischer LM, daCosta KA, Kwock L, Stewart PW, Lu TS, Stabler SP, Allen RH, Zeisel SH. Sex and menopausal status influence human dietary requirements for the nutrient choline. Am J Clin Nutr 2007;85:1275-85.
  9. Cohen BM, Renshaw PF, Stoll AL, Wurtman RJ, Yurgelun-Todd D, Babb SM. Decreased brain choline uptake in older adults. JAMA 1995;274(11): 902-7.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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