New discoveries of important beneficial effects of choline …

Choline Detoxifies and Protects
… by decomposing lipid hydroperoxides and suppressing metabolic syndrome
By Durk Pearson & Sandy Shaw®


Choline Uptake in the Brain Decreases with Age

Choline has long been known as an important nutrient for the body and brain;1a for example, choline is used to make the neurotransmitter acetylcholine, which is (among other things) important for memory and focus as well as for muscular contraction. As you can see, Professor Coyote is excited by his detection of these effects (see cartoon). Importantly, choline uptake in the brain decreases with age.1 Following choline ingestion, “[b]rain cytosolic choline-containing compounds increased substantially in younger subjects (mean increase, 60%; p < .001 vs. baseline). Older subjects showed a much smaller increase in brain choline-containing compounds (mean, 16%; p < .001 v. the increase in younger subjects.”1

We originally formulated a choline formulation to help improve our memory, focus, and concentration by increasing our brains’ supplies of choline and cofactors, years before this paper was published showing the age-associated decrease in choline uptake by the brain. Our new formulation, containing no sugars, is an improvement on a long-lived good idea.

Choline Serves Many Functions

“A factor contributing to the special vulnerability of cholinergic neurons to loss with age or in dementia may be their need to use a limited supply of choline for multiple and competing purposes. In these cells, choline is not only the precursor of the neurotransmitter acetylcholine, it is also the precursor of phosphatidylcholine [a component of and essential to the function of cell membranes] and sphingomyelin, phospholipids that are both essential structural constituents of all cell membranes and sources of second-messenger molecules used in receptor-mediated intraneuronal signaling.”1 It is known, for example, that when supplies of choline are low, phosphatidylcholine in cell membranes is broken down to free choline for other more urgent uses. In fact, as reported in another paper,1b “[d]espite the presence of a pathway for endogenous synthesis of choline, a choline-deficient diet impairs growth, memory, and hepatic [liver], renal [kidney], and pancreatic functions in mammals.”

Choline Plays an Important Role in Gene Regulation

Choline has also long been known to be a vital part of the body’s system of methylation by which genes can be turned on or off. Methylation of the histones surrounding DNA reduce access to the underlying genetic material, while demethylation of the histones increases access to the underlying genetic material. For example, systemic hypomethylation (decreased methylation) and local hypermethylation (increased methylation) of areas of DNA containing tumor suppressors are associated with an increased cancer risk by reducing the ability of transcription factors to turn on the tumor suppressors. “DNA methylation is influenced by the availability of choline, and common genetic polymorphisms [slightly different versions of the same gene] have major effects on the dietary requirement for this nutrient.”1a “It is now clear that as much as 50% of the population may have genetic polymorphisms that increase dietary methyl requirements, of which choline is a major source, leaving them susceptible to choline deficiency.”1a

Current Government Recommended AIs (Adequate Intakes) of Choline Set Too Low

Interestingly, when the current AIs (adequate intakes) for choline were set by the Food and Nutrition Board of the Institute of Medicine in 1998,5 it was not known whether there were large numbers of people who were choline deficient and it was assumed that less than 5% of the population would be affected by genetic variations that increase their requirement for choline.1a This is far less than the up to 50% now estimated to be affected by such genetic variations (see paragraph above). Hence, the current AIs — 425 mg/day for women, 450 mg/day for pregnant women, 550 mg/day for lactating women, and 550 mg/day for men — were likely to have been set too low, possibly far too low. (In fact, according to new analysis of the NHANES dietary intake survey data, the majority of the population is actually consuming choline at levels far below the meager current dietary recommendations!)1a To make matters worse, human nutritional requirements are usually determined by experiments on healthy young adults, such as college students, and rarely includes subjects over 50 years old.

Anti-Inflammatory Effects of Choline

Choline and the cholinergic nervous system have also long been known to have potent anti-inflammatory effects. As chronic low-level inflammation is a causative factor in cardiovascular disease and cancer, as well as many other diseases (for example, Rheumatoid arthritis and osteoarthritis), the anti-inflammatory effects of choline are of considerable importance. In cell culture studies, one paper1c reported that exogenous addition of phosphatidylcholine significantly inhibited inflammatory processes in three models of inflammation. In the ATTICA study, “subjects whose diets were rich in choline and betaine had the lowest levels of several inflammatory markers, including C-reactive protein (CRP), homocysteine, interleukin-6, and tumor necrosis factor. These findings were significant after adjusting for various sociodemographic, lifestyle, and clinical characteristics of the participants.”1a More recently, findings from the Nurses’ Health Study included that “those with the highest consumption of dietary choline had improved plasma levels of biomarkers for inflammation, including adiponectin, high molecular-weight adiponectin, resistin, and CRP.”1a

New evidence for important brain protective and anti-aging effect of choline

New Evidence Now Shows That Choline Detoxifies Lipid Hydroperoxides

Lipid oxidation is a major mechanism in aging and a variety of diseases associated with increased oxidative stress, including cardiovascular disease and cancer. A new paper2 now reports evidence supporting the previously suggested but unproven hypothesis that choline and ethanolamine (functional groups of the phospholipids phosphatidylcholine and phosphatidylethanolamine) are able to decompose the highly unstable oxidation products hydroperoxides into more stable hydroxyl lipids that pose a reduced oxidative risk. “… ethanolamine was not as effective as choline in decomposing the lipid hydroperoxides.”2 “Consequently, the system [food or biological systems] with addition of choline, ethanolamine, or phospholipids will have less chance to accumulate lipid hydroperoxides and will show low peroxide values.”2

It had previously been suggested that the antioxidant protection provided by amines choline and ethanolamine could be due to an ability to decompose lipid hydroperoxides, but this new paper is said to be the first to clearly demonstrate that this is the case. In the brain, which contains a much larger quantity of highly unsaturated lipids than other organs, protection against lipid peroxidation is of particular importance.

New: Choline may help suppress the metabolic syndrome

Support for the Idea That Metabolic Syndrome May Be Caused by Increased Sympathetic (Adrenergic) and Decreased Parasympathetic (Cholinergic) Activity Rather Than Changes in the Activity of the Hypothalamic-Pituitary-Adrenal Axis

A very exciting new study3 reports that the metabolic syndrome (which includes high waist circumference, high serum triglycerides, high blood pressure, high serum glucose, and low high-density lipoprotein cholesterol) may be a result of increased sympathetic (adrenaline, noradrenaline) and decreased parasympathetic (cholinergic) nervous system activity rather than, as has been supposed, to changes in the hypothalamic-pituitary-adrenal axis. If supported by additional research, these findings suggest that decreasing adrenergic activity and increasing parasympathetic activity (as would be expected with choline supplementation) could be a way to decrease or reverse metabolic syndrome.

The new study3 involved 1883 participants aged 18–65 years. As reported by the authors, in response to stress, the autonomic nervous system and the hypothalamic-pituitary-adrenal axis are both centrally activated. “Persistent (over)activation of these stress systems could lead to metabolic alterations, such as high blood pressure, serum triglycerides, serum glucose, waist circumference, and low high-density lipoprotein (HDL) cholesterol.”3 The authors report inconsistent findings concerning the relationship between salivary morning cortisol (an indicator of hypothalamic-pituitary-adrenal axis activity) and components of the metabolic syndrome. Similarly, data concerning the relationship between heart rate variability (increased by cholinergic — also called parasympathetic — nervous activity) and metabolic syndrome have been inconsistent, though “[m]ore evidence is present for a negative relationship between parasympathetic nervous system (PNS) activity and the metabolic syndrome.”1aa The researchers, therefore, decided to study, using multiple extensive measures of the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis activity in a large cohort, to what extent these two stress systems are involved in metabolic syndrome.

The results showed that the CAB, a measure reflecting reciprocal sympathetic nervous system activation and parasympathetic nervous system inhibition, significantly decreased the odds of metabolic system, where higher CAB “was negatively associated with the number of metabolic dysregulations and all individual components of the metabolic syndrome (except for HDL cholesterol).” The awakening cortisol, which reflects sympathetic nervous system (SNS) and PNS coactivation through the HPA axis, did not associate with any of the metabolic measures.

The authors found that “decreased PNS and increased SNS activity were associated with metabolic syndrome and its components, whereas HPA axis measures were not.” “… a pattern of parallel high SNS and low PNS activity was most strongly associated with metabolic syndrome. In contrast, a pattern of low SNS activity and low PNS activity or high SNS activity with high PNS activity did not show association with the metabolic syndrome.” These results suggest to us that choline supplementation to help increase parasympathetic nervous system activity might be a way to reduce the risk of metabolic syndrome or perhaps even to treat it.

Choline in the Treatment of Asthma Choline Attenuates Immune Inflammation and Suppresses Oxidative Stress in Patients with Asthma

While on the subject of new findings about choline, we also report here the results of a 2010 paper showing that choline may be a valuable adjunct therapy for asthma patients.4 The study reports that conventional therapeutic interventions such as inhaled corticosteroids or inhaled corticosteroids combined with a long-acting beta-agonist (increasing beta adrenergic activity) are associated with systemic side effects that limit their use.

The researchers studied the effect of adding choline (1500 mg twice daily of oral choline chloride) to supplement the usual pharmacotherapy and compared the results to pharmacotherapy alone (inhaled corticosteroids plus long-acting beta agonist, formoterol fumarate). In both groups, a short acting beta agonist, levosalbutamol sulphate, was given as and when required. The addition of choline to the pharmacotherapy was found to reduce bronchial hyperreactivity and to reduce airway inflammation caused by histamine and slow-reacting substance of anaphylaxis as compared to the pharmacotherapy alone.

The authors conclude that “[i]t [choline] can be used as an adjunct therapy for asthma patients.”


1. Cohen et al. Decreased brain choline uptake in older adults. JAMA 274(11):902-7 (1995).
1a. Zeisel and da Costa. Choline: an essential nutrient for public health. Nutr Rev 67(11):615-23 (2009).
1aa. Interestingly, increased heart rate variation is a positive marker for better heart health, and one paper reported that heart rate variability is associated with polymorphic variation in the choline transporter gene. See Park et al. Fruit, vegetable, and fish consumption and heart rate variability: the Veterans Administration Normative Aging Study. Am J Clin Nutr 89:778-86 (2009) and Neumann et al. Heart rate variability is associated with polymorphic variation in the choline transporter gene. Psychosom Med 67(2):168-71 (2005).
1b. Bjelland et al. Choline in anxiety and depression: the Hordaland Health Study. Am J Clin Nutr 90:1056-60 (2009).
1c. Treede et al. Anti-inflammatory effects of phosphatidylcholine. J Biol Chem 282(37):27155-27164 (2007).
2. Pan et al. Choline and ethanolamine decompose lipid hydroperoxides into hydroxyl lipids. J Am Oil Chem Soc 87:1235-45 (2010).
3. Licht et al. Increased sympathetic and decreased parasympathetic activity rather than changes in hypothalamic-pituitary-adrenal axis activity is associated with metabolic abnormalities. J Clin Endocrinol Metab 95:2458-66 (2010).
4. Mehta et al. Choline attenuates immune inflammation and suppresses oxidative stress in patients with asthma. Immunobiology 215:527-34 (2010).
5. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Vitamin B12, Folate, Pantothenic Acid, Biotin, and Choline. National Academy Of Sciences, Washington DC: Food and Nutrition Board, Institute of Medicine National Academic Press; 1998:390-422.

© 2011 Durk Pearson & Sandy Shaw

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