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Choline enters the nutritional limelight
Janet Raloff

Body and mind both benefit from a dietary supplement called choline. Or so say health and nutrition stores and Web sites. They sell drinks, bars, and capsules with claims they'll enhance physical endurance and mental suppleness.

Soon, the grocery store may be studded with banner labels extolling products as good, if not excellent, sources of choline. Eggs, red meat, and a variety of fortified foods will probably be among the first to sport such tags.

Approved last month, these labeling claims are the first authorized under a new federal law. It permits food manufacturers to identify their products as a rich source of any nutrient that has previously been established to be necessary for good health.

Not permitted on those labels, however, is any statement of a specific health benefit. As such, few people would understand the reason for purchasing foods high in choline, a nutrient that remains well below the radar screen of most grocery shoppers.

Medical researchers, however, are exploring the effects of choline in various arenas. In fact, for several years there's been clear evidence that lack of choline can harm an individual's liver.

But more recent experiments in animals suggest that the compound can have more subtle benefits. A few scientists are, for example, investigating hints that extra choline in the adult diet boosts brainpower.

Generating far more excitement is evidence that supplemental choline given to a pregnant female can offer her offspring a wealth of life-long benefits. A growing number of rat studies indicate that choline enrichment in the womb can alter brain development in ways that facilitate learning later in life.

Prenatal choline may even guard the brain against toxic assaults and disease, not to mention senility and other neurodegenerative changes, notes Christina L. Williams, who heads the Department of Psychological and Brain Sciences at Duke University in Durham, N.C.

This may explain why the National Institute on Aging has been a major sponsor of studies investigating effects of prenatal choline enrichment. "After all," quips neuropsychologist H. Scott Swartzwelder of the Durham (N.C.) Veterans Affairs Medical Center, "aging begins at conception."

Integral ingredient

A chemical building block of every cell, choline plays an integral role throughout the body and throughout life. It's an ingredient of the membranes surrounding cells. It also transports a cholesterol carrier out of the liver and helps rid the blood of homocysteine, an amino acid that at high concentrations increases the risk of heart disease. Furthermore, choline is a precursor to molecules that relay signals between nerve cells, including those in the brain.

Though the liver synthesizes choline, it may not produce adequate amounts, at least from the food that some people in the United States eat. Recognizing that a shortage of choline in the diet causes liver damage, the Institute of Medicine (IOM) in Washington, D.C., established its first choline recommendations 3 years ago. This organization, which develops daily intake guidelines for vitamins and other nutrients, advocates eating about 0.5 gram per day.

Meeting IOM's dietary-intake goals, however, can be a hit-or-miss proposition since there is a dearth of data on how much choline most foods contain. Steven H. Zeisel's laboratory at the University of North Carolina in Chapel Hill has just begun a systematic assay to quantify the choline in commonly eaten U.S. foods. Performed for the Agriculture Department, the tests should yield data on 300 of the most popular items by January 2002 and 2,700 more over the following year.

New studies show, too, that prenatal nutrition may influence how much of the nutrient an individual requires. Moreover, IOM's nutrition guidelines were developed to prevent liver damage, whereas optimum health may require more choline.

Enriched diet

More than a decade ago, Williams and her husband, Warren H. Meck, also at Duke, began their studies of choline's impacts on rat brains.

Meck, a neuroscientist, had been enriching the diets of adult rats with choline in hopes that it might improve their performance in certain memory tests. He knew that choline is a building block of acetylcholine. A chemical that nerve cells use in signaling, it plays an important role in memory.

Recalls Williams, "I asked if he had considered administering choline early in development," when the brain structures central to memory were forming. He hadn't.

So, Meck and Williams launched a study in which they gave pregnant female rats water laced with choline. This supplementation roughly quadrupled the animals' normal choline intake. For a few weeks after birth, the pups received injections of additional choline.

The scientists then tested these offspring throughout their short lives on their recall of locations in a maze where the researchers had hidden food. The experiment measured whether the rats could remember뾞nd not revisit뾱ites they had already emptied as they sought out the remaining food during the day.

"We found that the prenatally supplemented animals clearly outperformed the others," Williams says. With repeated testing, scores improved for many of the animals in both the supplemented group and an unsupplemented group that served as a control. Yet even after 16 weeks of daily testing, she notes, the supplemented rats continued to make fewer errors than the others did.

One aspect of the results was even more startling, Williams notes. The more difficult the tests of memory and learning became, the bigger the apparent benefit of that prenatal enrichment. The best explanation is that the choline-supplemented offspring could "hold more information," Williams told Science News. "We know of no other treatment that increases memory size."

Her group and others have repeatedly confirmed the findings. "What's so amazing," Williams contends, is that the aptitude for learning in prenatally supplemented animals "is as good in old age as it was when they were young. They show no decline." In contrast, animals not supplemented prenatally with choline show signs of senility in old age. It appears that with supplementation, "we're building a better brain," she says.

Narrow window

Nuances in choline action are showing up. By narrowing the window of prenatal supplementation, Williams and others have identified only two small periods during which extra choline boosts a rat's intelligence. The first is from days 12 to 17 in gestation. This correlates roughly with the second half of a human pregnancy. The other window runs from 2 to 4 weeks after birth뾞 period that corresponds loosely with human infancy and toddlerhood.

Recently, scientists have begun delving into what underlies that first malleable period. It coincides with the formation of a complex network of choline-sensitive nerve cells that sends information to a region of the brain known as the hippocampus, Williams notes. This area is active in learning and memory.

Five years ago or so, Williams and other researchers asked Swartzwelder to look for signs that early choline exposure somehow changes the brain. Dubious that a week of prenatal enrichment could smarten animals, much less trigger detectable physiological changes, he nonetheless agreed to a pilot study.

The results changed his perspective.

In a hippocampal neuron, certain patterns of incoming chemical signals can trigger a response called long-term potentiation. During this response, newly arriving signals are more effective than under other conditions. The process helps cement memories by "promoting the encoding and consolidation of new information. It's the first step in learning," Swartzwelder explains.

Compared with hippocampal tissue from unsupplemented animals, brains primed with prenatal choline showed long-term potentiation more readily, Swartzwelder found. When he then turned to brains from animals whose mothers had been choline deficient, he found hippocampal circuits unusually resistant to the effect.

It appeared that choline is "powerful stuff," Swartzwelder recalls. But to make sure of his results, he repeated the analyses, using rats reared and treated by a different group of researchers. Again, he saw the same effect. Overall, the greater the prenatal exposure to choline, the larger the effect on the brain.

That was 2 years ago. Now, Swartzwelder is focusing on glutamate, a primary chemical messenger responsible for triggering long-term potentiation. Brain cells have specialized protein complexes, called NMDA receptors, that respond to glutamate. They don't promote long-term potentiation unless they receive closely timed signals from other brain cells (SN: 9/4/99, p. 149:

Swartzwelder's team has now shown that NMDA receptors in the brains of animals that received prenatal choline enrichment are unusually responsive to signals. This finding suggests that these animals might make memories more readily than others do.

Protecting neurons

Prenatal supplementation with choline can also protect the brain later in life. That finding, to be published soon in the Journal of Neuroscience, is "the wildest thing of all," Swartzwelder says.

His group and its collaborators find evidence that choline can influence the effects of a toxic drug. Prenatal supplementation protects neurons in the brains of adolescent rats from the cell death ordinarily associated with high doses of a drug that blocks the NMDA receptors.

Last year, prenatal choline supplementation in another study prevented memory defects following drug-triggered brain lesions. The researchers used a drug that induces convulsive epileptic seizures in rodents. Epileptic seizures not only damage the brain, but they also tend to impair memory and learning.

Gregory L. Holmes of Harvard Medical School's Center for Research in Pediatric Epilepsy in Boston and his colleagues administered the neurotoxic drug to rodents뾱ome of which had received prenatal choline supplementation뾞nd then monitored the animals' learning skills.

Using a standard test of spatial memory, the researchers daily released each rat into a pool of milky water and waited for the animal to find a stationary platform just beneath the surface. Animals that had not experienced seizures oriented themselves more quickly every day. This learning showed up in rats whether or not they had received prenatal choline supplementation.

After the experienced rats developed epilepsy, however, the pattern changed. When tested a week after seizures, prenatally supplemented animals remembered where the platform was and in succeeding days continued to improve their performance. But rats that had received no prenatal choline supplementation acted as if they had no memory of where the platform had been and showed less improvement in finding it during the following days.

If studies of people confirm an effect of prenatal choline on the brain's response to assaults after birth, Holmes' team wrote in the Nov. 15, 2000 Journal of Neuroscience, these findings "could lead to nutrition-based preventive strategies." The authors liken the possibility to the use of folate vitamins now routinely prescribed to pregnant women to prevent neural tube defects in the fetus.

Jan Krzysztof Blusztajn of Boston University, a coauthor on that paper, has been probing biochemical differences that arise from prenatal choline supplementation.

Three years ago, he showed that extra choline available during hippocampal development permanently modifies that area's efficiency in using the nutrient. When choline concentrations in the womb are low, the brain becomes "very frugal" with this nutrient, Blusztajn says, whereas the choline metabolism of animals that encounter an abundance in the womb "becomes quite wasteful." Prenatal conditions probably determine how much choline an adult requires.

His studies indicate that an overly frugal hippocampus may lead to problems. Its parsimony may leave little choline free to perform mentally demanding activities.

With a low stockpile of choline, production of the neurotransmitter acetylcholine may prove insufficient to carry out sustained, high-throughput communications between memory neurons. They just poop out and learning slows. However, Blusztajn reports that prenatally supplemented rats "have some sort of cognitive reserve뾵hich is probably also a biochemical reserve. It lets them sustain longer [choline-fueled] neurotransmission."

Improving memory

Evidence is emerging that choline supplementation in adulthood, too, may sometimes improve memory. This result comes from a study of people who, because of gastrointestinal problems, receive virtually all of their nutrition intravenously. Manufacturers don't regularly fortify with choline most nourishment that's administered intravenously.

"We now know that between 20 and 50 percent of patients receiving [intravenous] nutrition long-term develop liver disease," notes Alan L. Buchman of Northwestern University Medical School in Chicago. Some die; others may survive with transplants. In the September-October Journal of Parenteral and Enteral Nutrition, his team reports on a pilot study of 15 volunteers with gastrointestinal problems who were receiving intravenous nutrition. Signs of liver damage disappeared in those seven who had been randomly assigned to receive supplemental choline for 24 weeks.

The researchers also administered IQ and other tests to 11 participants. They initially scored below normal on verbal memory and visual memory tests. In the January-February Journal of Parenteral and Enteral Nutrition, the scientists reported that those scores improved "significantly" in the men and women receiving supplemental choline. This suggests, they said, that severe choline deficiency in adulthood may impair memory reversibly.

Zeisel is beginning several more human trials. In one, resembling the animal experiments, 80 pregnant women will be given specially prepared waffles and asked to eat one with each meal from about 15 weeks into their pregnancy until a month after their baby is born. Some of the women will get normal waffles, the rest will get ones fortified with either one egg or its choline equivalent in the form of soy lecithin.

When the women's babies are 10 and 12 months old, psychologists will test the infants' visual memory뾲he child's recall of where Mom's picture last appeared.

Minimum requirements

Zeisel has also just launched the first detailed analysis of how much choline people need for basic health. Eighty volunteers will be held "captive, " Zeisel says, for 71 days in a university metabolic ward. Everything they eat and excrete will be measured. The food뾯esembling heavily fortified milk shakes뾵ill initially carry a normal range of recommended nutrients. Then, all the participants will be switched to a cholinefree version.

They'll remain on that diet until enzymes indicative of liver damage begin appearing in their blood. At that point, Zeisel says, "we'll begin adding back increasing amounts of choline until we discover how much it takes to return each to normal."

Because the test will include men and women, blacks and whites, and premenopausal and postmenopausal women, it should determine whether particular groups differ in their needs.

Today, few people exhibit overt choline deficiency. Zeisel suspects, however, that at least some teeter on the brink of insufficiency. Because the best-known choline-rich foods tend to be animal products, especially ones high in fat, he worries that vegans and those who have successfully pared most fat from their diet may be vulnerable.

Don't be afraid of eating eggs despite their cholesterol, he chides. Their yolks are among the richest known natural sources of choline. A tall glass of skim milk offers as much choline as an egg does. And coming soon, predicts Gregory Paul, director of nutrition for Central Soya of Ft. Wayne, Ind., will be a host of foods뾬range juice, baked goods, and pasta뾣ortified with choline-rich soy lecithin.

So, keep an eye out for those new choline labels, Williams says; they'll help identify "what we call food for thought."


For a few unfortunate people, choline has a dark side. An inborn error of metabolism, trimethylaminurea, causes them to smell like rotting fish when they eat high-choline foods.

Sara D. Brown
Clinton, N.J.

Good point. New labeling that identifies foods rich in choline should help people with trimethylaminurea avoid those foods.뾌. Raloff

As a reader concerned about my cholesterol and fat intake, I was ready to throw away my container of egg substitute and buy a dozen eggs when I read the article. Then, I came to the third sentence of the next-to-last paragraph: ". . . a tall glass of skim milk offers as much choline as an egg does." So, I poured myself a glass of cold skimmed milk (and had a cookie).

Doris E. Gennaro
Gainesville, Fla.

The tabulation of choline content leaves one with the mistaken impression that only eggs and liver are choline rich. While soy lecithin is mentioned in passing as a manufacturing additive, soy is otherwise neglected in the text and chart. The CRC Handbook of World Food Legumes: Nutritional Chemistry, Processing Technology and Utilization (1989, D. Salunkhe, CRC Press) lists a value of 3.4 milligrams of choline per gram of soybean seeds. That's 289 mg of choline for an 85-g (3-oz) serving. Lentils contain 2.23 mg/g, or 200 mg per serving. Both values are comparable to the choline content of an egg. Considering that soy in the form of tofu, tempeh, or boiled beans comes free of cholesterol and rich in healthful compounds, concern for vegan health seems spurious, as does the market-driven notion of eggs as the perfect food.

John M. Vinopal
Berkeley, Calif.

The need for choline is certainly bolstered by recent studies. But nearly 50 years ago, nutrition maven Adelle Davis touted choline's merits. Though vilified by many in medicine and food production, her whole-food philosophy made sense to some of us. We sidestepped the anticholesterol bandwagon. Result at 61 years old: blood pressure, 110/70; HDLs, 77; triglycerides, 53. Thanks to all the brain food, we won't soon forget Davis.

David Rawlins
Pauma Valley, Calif.

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