The Durk Pearson & Sandy Shaw^®Life Extension News^TMVolume 18 No. 2 • June 2015

SEE BELOW IN THIS SECTION ON CHOLINE:THE VAGUS NERVE, WITH ITS MAJOR NEUROTRANSMITTER BEING ACETYLCHOLINE,

DO YOU INGEST ENOUGH CHOLINE?

Are You One of the 92% of the Population that Does Not Consume the Adequate Intake of Choline Recommended by the Institute of Medicine? CHOLINE is an Essential Nutrient But Much More

An article in a food industry trade journal (Hutt. “Choline: the Silent Deficiency,”Prepared Foods, Jan. 2015) warns that Choline is the “Silent Deficiency” and cites Institute of Medicine data from 2007 to 2010 showing that 92% of Americans are not getting the recommended AI (adequate intake) of choline, 550 mg/day for men and 425 mg/day for women (more is recommended in the case of pregnant and lactating women). The article points out the opportunity for the food industry to “do well by doing good” (our words, not the article’s) by fortifying foods with choline. As they explain, the FDA allows a claim of a “good” source of choline for a product containing 75 mg of choline chloride or 137.5 mg of choline bitartrate per serving. To be permitted to say your product is an “excellent” source of choline, the FDA requires that the product contains twice this much per serving. The article goes on from there to discuss a number of health benefits from taking choline, typically (as in most trade publications) providing no references to the scientific literature on choline! Incredibly, the article claims that choline sales are not reported by companies that track the supplement market other than Nielsen/SPINS, which reported the combined sales of choline and inositol in 2012, with these sales in natural/mass channels reported to reach an unbelievably tiny $428,000. What gives? How can a nutrient as important as choline and ingested at such an officially estimated meager level by most Americans have escaped notice?

Chances are that you are not getting enough choline in your diet and, unless you take a choline supplement, you are not ingesting the AI recommended by the Institute of Medicine, an amount that (on the basis of the scientific literature) is on the low side of what would be optimal. Here are a few of the important health benefits provided by choline, some of which you have undoubtedly read about but others you are likely to have never heard of. You should know about these if you are not yet taking a choline supplement.

NOTE TO OUR READERS: In order to keep this newsletter from expanding beyond the bounds of a reader’s reasonable time to spare, we have not included much of what we had written up on beneficial effects of choline. More on that in a later newsletter!

CHOLINE FOR MEMORY AND LEARNING

One of the oldest known and studied effects of the cholinergic nervous system is its relation to learning and memory, with one early influential paper from 1974.¹ A later paper² showed that acetylcholine in the forebrain regulates adult hippocampal neurogenesis and learning. A recent paper³ reported that in a community-based population of nondemented individuals, participants in the Framingham Offspring Cohort (744 women and 647 men aged 36–83), higher concurrent dietary choline intake was related to better cognitive performance.

References

1. Drachman and Leavitt. Human memory and the cholinergic system. Arch Neurol.30:113–21 (1974).
2. Mohapel, Leanza, et al. Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning. Neurobiol Aging. 26:939–46 (2005).
3. Poly, Massaro, et al. The relation of dietary choline to cognitive performance and white-matter hyperintensity in the Framingham Offspring Cohort. Am J Clin Nutr.94:1584–91 (2011).

THE CHOLINERGIC NERVOUS SYSTEM IS THE MAJOR ANTIINFLAMMATORY PATHWAY

THE CHOLINERGICANTIINFLAMMATORY PATHWAY

A MAJOR REGULATOR OF INFLAMMATION

INFLAMMATION, A RECOGNIZED CAUSE OFCANCER, CARDIOVASCULAR DISEASE, AGE-ASSOCIATED DISEASES, ANDAGING ITSELF

An early (2007) review paper¹ on the cholinergic antiinflammatory pathway quoted Claude Bernard who thought that health was due to equilibrium in the “milieu interieur” by a “continuous and delicate compensation, established with the most sensitive of balances” (“Lessons on the phenomena of life common to animals and vegetables”). This early view foresaw in a simple sketch the new understanding of health that we have today and in which the cholinergic antiinflammatory pathway plays a major role in maintaining that “balance” of which Claude Bernard wrote.

The review¹ then discussed the emergence of the “cytokine theory of disease” in which defensive molecules, the inflammatory cytokines, produced by the immune system can cause the signs, symptoms, and damaging after effects of disease. The cholinergic antiinflammatory pathway is important in preventing the damage that can be caused by massive releases of these cytokines in response to various diseases. In one example, a major cytokine, TNF-alpha (tumor necrosis factor alpha) is released in response to gram-negative bacteria but excessive amounts of that release can cause septic shock. With the problem of antibiotic resistance increasingly making it difficult to treat septic shock, this condition has a high mortality rate.

The Vagus Nerve

An early discovery was that the vagus nerve served as a conduit for signals from the cholinergic nervous system to modulate the production of inflammatory cytokines. For example, the review¹ notes that, “an accidental discovery revealed that intracerebral administration of a molecule that inhibited TNF production also increased efferent vagus nerve activity and inhibited inflammation outside the CNS.” The mechanism responsible for this effect was found to be acetylcholine, the major vagus nerve neurotransmitter. Acetylcholine signals the inhibition of cytokine synthesis via the vagus nerve.

Galen

Keep in mind that this was an early review on a research area about to explode, and it continues to expand at a dramatic pace today. The review points to scientific evidence suggesting that signaling via the vagus nerve can affect many aspects of human health, noting specifically that sudden death, increased morbidity and mortality following cardiac surgery in hostile or depressed patients, and increased death rates in patients with sepsis or organ failure have been linked (as of the date this paper was published and supported by new evidence since then) to decreased vagus nerve activity. These are just three examples out of many medical conditions in which deficient vagus nerve activity plays an important role.

One of those mysteries that remains unexplained is noted at the end of the review, where it is mentioned that clinical antiinflammatory responses may be linked to the fat induced stimulation of the cholinergic antiinflammatory pathway as in the case of rats, using fish oil, soy oil, olive oil or other fats. And, now (to the review, “now” is 2007), the review says, a major source of systemic TNF during lethal challenges is the spleen, the source of Galen’s black bile. The review finishes by asking: How did the ancient Greeks know? (It may have simply been that the ancients noticed that when people had this black gunk emerging from the spleen, they were unlikely to survive.)

Reference

1. Tracey. Physiology and immunology of the cholinergic aniinflammatory pathway.J Clin Invest.117(2):289–96 (2007).

Choline Attenuates Immune Inflammation in Patients with Asthma

A 2010 paper² reported that, in a randomized study, 76 asthma patients were treated with 1500 mg of choline chloride twice daily + pharmacotherapy or with pharmacotherapy alone (pharmacotherapy was inhaled steroids and long-acting beta adrenergic agonist), with short acting beta adrenergic agonist given as needed. There was a significant decrease in symptom/drug use score of patients receiving choline from baseline, but no significant change in the symptom/drug use score from baseline in the standard pharmacotherapy alone group patients. Choline was also reported to significantly decrease peripheral eosinophil counts and Th2 response (the immune system activity that occurs during active disease) such as lower IL-4 levels and reduced TNF-alpha levels in the choline treated patients.

These results indicate activation of the cholinergic antiinflammatory pathway by treatment with choline in human asthma patients.

Reference

2. Mehta, Singh, et al. Choline attenuates immune inflammation and suppresses oxidative stress in patients with asthma.Immunobiology.215:527–34 (2010).

Dietary Choline and Betaine Intake Associated with Reduced Levels of Inflammatory Markers in Healthy Adults

In an early study (2008)³ in the runup of research following the discovery of the cholinergic antiinflammatory pathway, a cross sectional survey of 1514 men and 1528 women with no history of cardiovascular disease was carried out (the ATTICA Study). Compared with the lowest tertile of choline intake (<250 mg/d), participants who consumed >310 mg/d had, on average, 22% lower concentrations of C-reactive protein [with high levels linked to poor cardiovascular health], a commonly used measure of inflammation, 26% lower concentration of IL-6 (an inflammatory cytokine), and 6% lower concentration of tumor necrosis factor alpha, another inflammatory cytokine. (Similarly, those who consumed >360 mg/d of betaine had an average of 10% lower homocysteine levels, 19% lower C-reactive protein, and 12% lower concentrations of TNFalpha than did those who consumed <260 mg/day.)

This was an associational study, thus did not provide evidence for cause and effect. But it was an early study and much more was to come in later research to support these findings as having causal implications.

3. Detopoulou et al. Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study. Am J Clin Nutr. 87:424–30 (2008).

HEART FAILURE

A 2014 paper⁴ reported that chronic stimulation of the vagus nerve improved left ventricular function in a canine model of chronic mitral valve regurgitation. As the authors explain, autonomic dysregulation, failure of the systems regulating (for example) respiration and heart function, is characterized by activation of the sympathetic nervous system (adrenergic) and declining activity of the vagus (cholinergic) nerve and is an important contributor to the progression of heart failure. “One of the key features of chronic heart failure (CHF) is the autonomic sympathetic/parasympathetic (adrenergic/cholinergic) imbalance, which is usually characterized by excessive sympathetic drive accompanied by parasympathetic withdrawal.” They further explain that the use of inhibitors of sympathetic activity (such as beta adrenergic receptor blockers) is one of the ways that has been used to treat this problem but, “[o]n the other hand, reversing the sympathetic/parasympathetic imbalance by enhancing parasympathetic activity through vagal nerve stimulation (VNS) becomes an obvious potential therapeutic approach.”

In this study, dogs had mitral valve regurgitation induced experimentally and were treated with electrodes that stimulated the vagus nerve. The results showed improved contractile function and significant improvement (that is, reduced expression) of inflammatory markers such as C-reactive protein.

4. Yu, Tang, et al. Chronic vagus nerve stimulation improves left ventricular function in a canine model of chronic mitral regurgitation.J Transl Med. 12:302 (2014).

YOU MAY NEED MORE CHOLINE THAN THE AMOUNT RECOMMENDED BY THE INSTITUTE OF MEDICINE

New Study Reports Genetic Differences Between Ethnic and Racial Groups in Amount of Choline Required

The Institute of Medicine of the National Institute of Health defines the “adequate intake” (AI) for choline as 550 mg/day for men and 425 mg/day for women. Many Americans are said not to ingest the AI for choline, which can result in fatty liver, liver damage, muscle damage, and may promote eventual dementia. In this new paper,¹ scientists report that genetic differences (identified as single nucleotide polymorphisms, SNPs) between ethnic and racial groups indicate that the amount of choline required will differ between these groups. Seventy-nine humans were fed a low choline diet and 200 SNPs in 10 genes related to choline metabolism examined to determine associations with organ dysfunction. Some people on low choline diets presented with muscle damage, others with liver damage.

As the researchers note, the setting of dietary recommendations has not (or has rarely) considered genetic diversity in the need for daily intake of nutrients. They suggest that the simplest and safest way to deal with this is to set dietary recommendations at a level high enough to meet the needs of those with the greatest requirements. That may indeed be the simplest and safest way, but what these researchers probably have not considered is that dietary programs (school lunches, food stamps, etc.) are based upon these dietary recommendations and setting the level high enough to meet the needs of those with the greatest requirements would be quite a bit more expensive for these government programs than setting it at a level that would meet the requirements of the average American. Moreover, when you think of the case of choline, the foods that can supply it (eggs, dairy, and fish, for example) tend to be on the expensive side or perhaps on the yucky side (liver).

Add to the genetic variation the decreasing ability of older persons to transport choline into the brain² and it appears likely that a significant fraction of the populace may require a higher intake of choline than that recommended by the Institute of Medicine of the National Institute of Health, where experiments on nutrition are usually done on college students. A recent paper⁴ showed that a donor of peroxynitrite, a potent oxidant, as well as other oxidants, caused rapid dose-dependent inhibition of the sodium-coupled high-affinity choline transporters, suggesting one possible mechanism for the decreased choline transport in older persons.

It has also been reported that choline acetyltransferase, the enzyme needed to convert choline to acetylcholine, is inhibited by exposure to excitatory amino acids.³ Taurine and the antiinflamatory compounds naturally formed from it, taurine bromamine and taurine chloramine, are able to provide protection against these inflammatory excitatory amino acids and, hence, are likely to help prevent the suppression of choline acetyltransferase formation resulting from exposure to excitatory amino acids.

References

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1. da Costa, Corbin, Niculescu, et al. Identification of new genetic polymorphisms that alter the dietary requirement for choline and vary in their distribution across ethnic and racial groups. FASEB J.28:2970–8 (2014).
2. Cohen, Renshaw, Stoll, Wurtman, et al. Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study. 274(11):902–7 (1995).
3. Louzada et al. Taurine prevents the neurotoxicity of beta-amyloid and glutamate receptor agonists; activation of GABA receptors and possible implications for Alzheimer’s disease and other neurological disorders. FASEB J.18:511–8 (2004).
4. Cuddy, Gordon, et al. Peroxynitrite donor SIN-1 alters high affinity choline transporter activity by modifying its intracellular trafficking. J Neurosci.32(16):5573-84 (2012).

CHRONIC FATIGUE

Central Fatigue May Be Associated with Low Activity of the Vagus Nerve and Hence of Low Parasympathetic (Cholinergic) Nervous System Activity

Central fatigue is chronic fatigue, lasting six months or more, characterized by a persistent sense of tiredness, has been reported to generally correlate poorly with traditional markers of disease.¹ “In general, hypoactivity of the hypothalamic-pituitary-adrenal axis, autonomic nervous system alterations characterized by sympathetic overactivity and low vagal tone, as well as immune abnormalities, may contribute to the expression of CF [chronic fatigue].”¹ “Central fatigue generally correlates poorly with traditional markers of disease and is frequently associated with other psychosocial factors, such as depression, sleep disorder, anxiety, and coping styles, which suggests that dysregulation of the body’s stress systems may serve as an underlying mechanism of CF.”

For example, the authors explain that glucocorticoids, stress hormones, play an important role in the regulation of the sympathetic nervous system (SNS), restraining SNS responses after stress and under resting conditions. The paper suggests that although glucocorticoids are often considered immunosuppressive, it may be more accurate to call them immune modulators and that they can have important antiinflammatory effects via negative feedback to the immune system’s production of inflammatory cytokines. Thus, like the cholinergic antiinflammatory pathway, glucocorticoids help to keep the sympathetic nervous system under control.

Despite many attempts to pin down CF to specific immune abnormalities, to hypercortisolism or hypocortisolism, results have been inconsistent. However, the paper reports that a recent and robustly designed study² showed that “fatigue not only in its severe and chronic form, as in CFS [chronic fatigue syndrome], but also in its milder forms, is associated with increased inflammation, as indexed by elevated plasma C-reactive protein levels and white blood cell counts, even after adjusting for depressive status. This study further supports the notion that the symptom of fatigue, rather than a diagnosis of CFS itself, may be what is clinically associated with inflammation.”

References

1. Silverman, Helm, et al. Neuroendocrine and immune contributors to fatigue. PM R.2(5):338–346 (2010).
2. Raison, Lin, Reeves. Association of peripheral inflammatory markers with chronic fatigue in a population-based sample. Brain Behav Immun. 23:327–337 (2009) PubMed: 19111923.

ORGASM!!!

A 2005 paper¹ reported a study by fMRI of the brain regions activated during orgasm by vaginal cervical mechanical self-stimulation in women with spinal cord injury. A number of areas of the brain were activated during orgasm, with the authors concluding that, “the Vagus nerves provide a spinal cord-bypass pathway for vaginal-cervical sensibility and that activation of this pathway can produce analgesia and orgasm.” The authors comment that some patients, both men and women, who have spinal cord injury described an intensely sensitive to the touch area of skin near their injury and which when stimulated in the right way, can produce orgasm. Just an interesting little tidbit here. Too bad they didn’t try choline supplementation in some of these patients.

Reference

1. Komisaruk, Whipple. Functional MRI of the brain during orgasm in women. Annu Rev Sex Res.16:62–86 (2005).

BEST FOOD SOURCES FOR CHOLINE IF YOU CHOOSE TO GET IT FROM YOUR DIET

Your brain on choline.

The March 2004 USDA Database for the Choline Content of Common Foods tells you that the highest food sources for choline include egg yolk, raw, fresh (682.4 mg choline moiety/100 g of food), chicken liver, all classes, cooked, pan-fried (308.5 mg choline moiety/100 g of food), veal, variety meats and by-products, liver, cooked, pan-fried (411.0 mg choline moiety/100 g of food). Perhaps a more palatable source is one egg, whole, cooked, fried (272.6 mg choline moiety/100 g of food), while a hardboiled egg contained 225.2 mg choline moiety/100 g of food.

“Choline moiety” is choline contributed by free choline, phosphatidylcholine, phosphocholine, glycerophosphocholine, and sphingomyelin.

Inflamed By Love

A poem by Stendhal (Marie-Henri Beyle) includes this line:

“Love is like a fever which comes and goes quite independently of the will.”

Curiously, it appears that, although Stendahl could have known nothing about inflammatory cytokines, love is very likely to be like a fever in the sense of representing a state of systemic inflammation.

The researchers who published a recent paper¹were studying the possibility that social interactions of various types, particularly negative and competitive interactions, would be associated with heightened proinflammatory cytokines. Subjects were 122 healthy young adults who kept diaries for 8 days that described positive, negative, and competitive social interactions. Within 4 days they were subject to the Trier Social Stress Test in which oral fluids were collected before a laboratory-imposed stressor and at two time points after the stressor and analyzed for inflammatory markers.

The results showed that leisure time competitive activities did not correlate with increased proinflammatory cytokine levels, but competing for another’s attention, such as (the paper states this explicitly) a ROMANTIC PARTNER is correlated with increased proinflammatory cytokine levels as was academic/work-related (i.e. bringing home the bacon) competitive events. The authors propose that the leisure time competitive activities may be perceived as challenging rather than threatening, whereas competing for the attention of a romantic partner or competition in an academic/work-related situation might be considered threatening.

The authors’ analysis of the results are also interesting and consistent with what we know about the regulation of inflammation. They note that social stress increases sympathetic nervous system activity—for example, rodent models of social stress have been shown to increase sympathetic nervous system (SNS) activity, where SNS is based upon adrenergic neurotransmission, and to decrease parasympathetic activity (based upon cholinergic neurotransmission), which is inversely related to inflammation. The authors note, however, that only 522 competitive events (or an average of 4.28 per person) were reported and it would be helpful for looking at differences between different subtypes of competitive events if more participants were included.

Perhaps, then, the state of love that Stendahl called a “fever” might be mitigated by taking a supplement that increased parasympathetic nervous system activity, thereby reducing the hyperinflammatory state that love seems to induce in many as a response to the social stress it represents. It may seem strange to think of romantic “love” as a dysfunctional state that might be improved with appropriate “treatment” (in this case, a choline supplement or a cholinesterase inhibitor such as galantamine, which might help by increasing parasympathetic nervous system activity) but to many (if one is to judge by the book of love poems² by famous poets that included the Stendahl poem the state of love can be almost akin to insanity, with alternating periods of ecstasy and agony. In another place (forget where at the moment), rock star Ted Nugent was quoted as saying that love was like a “tire iron,” presumably meaning that his experience of it was a bit overwhelming. Try a choline supplement, Ted, it might make the experience less stressful, more like a rubber mallet than a tire iron.

A couple of speculations: We wonder whether what is called “lovesickness” might be similar to the form of sickness behavior observed in animals and humans when they are in an inflammatory state with high levels of proinflammatory cytokines. One other oddity is that prolactin, another stress hormone that has proinflammatory effects,¹ is released in large quantities during orgasm, adding yet another twist to the relationship between romantic love, sex, and inflammation.

References

1. Chiang, Eisenberger, et al. Negative and competitive social interactions are related to heightened proinflammatory cytokine activity. Proc Natl Acad Sci U S A.109(6):1878–82 (2012).
2. Love, a Book of Quotations,edited by Ann Braybrooks (Dover Publications, 2012).

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