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DO YOU INGEST ENOUGH CHOLINE? The Durk Pearson & Sandy Shaw® Life Extension News Volume 18 No. 2 • June 2015

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 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 CHOLINERGIC
ANTIINFLAMMATORY PATHWAY

A MAJOR REGULATOR OF INFLAMMATION

INFLAMMATION, A RECOGNIZED CAUSE OF
CANCER, CARDIOVASCULAR DISEASE, AGE-
ASSOCIATED DISEASES, AND
AGING 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

  1. 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.

  1. 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.

  1. 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).

Education is the Key to Good Health!

Information provided for educational purposes only!

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*The products and statements made about specific products on this web site have not been evaluated by the United States Food and Drug Administration (FDA) and are not intended to diagnose, treat, cure or prevent disease. All information provided on this web site or any information contained on or in any product label or packaging is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should not use the information on this web site for diagnosis or treatment of any health problem. Always consult with a healthcare professional before starting any new vitamins, supplements, diet, or exercise program, before taking any medication, or if you have or suspect you might have a health problem.
*Any testimonials on this web site are based on individual results and do not constitute a guarantee that you will achieve the same results.

 

Choline in Brain Function and Sleep

Choline in Brain Function and Sleep 
Acetylcholine (made from choline) is an important part of regulatory pathways in sleep and many cognitive functions.

By Durk Pearson & Sandy Shaw

Areview in Neuron1 described the function of acetylcholine (a ubiquitous neurotransmitter) in the brain as follows: “Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity, and coordinates firing of groups of neurons.” Its many effects make acetylcholine “an essential mechanism underlying complex behaviors.”1 Further, they propose a common theme for the activities of acetylcholine: “that acetylcholine potentiates behaviors that are adaptive to environmental stimuli and decreases responses to ongoing stimuli that do not require immediate action.”

The complex interaction between the cholinergic nervous system and the dopaminergic system includes regulation by cholinergic interneurons through muscarinic cholinergic receptor signaling as critical components in striatum-dependent decision making, which also involves dopaminergic signaling for the detection of rewarding stimuli.2 Cholinergic interneurons “can regulate the duration, magnitude, and spatial pattern of activity of striatal neurons, potentially creating an attentional gate that facilitates movement toward salient stimuli.”1 Moreover, as noted in the review,1 “the function of striatal cholinergic interneurons is also impaired in patients with movement disorders involv[ing] the dopaminergic system, such as Parkinson’s and Huntington’s disease …”

References

  1. Picciotto et al. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 76:116-28 (2012).
    2. Mark et al. Cholinergic modulation of mesolimbic dopamine function and reward. Physiol Behav. 104:76-81 (2011).

Circadian Rhythm of the Cholinergic Nervous System

As described in another paper,7 “[t]here is [] a pronounced circadian rhythm in the activity of the cholinergic system, upon which sleep, waking, and fundamental aspects of learning depend. These rhythms may deteriorate with aging, and sleep disturbance is a particular problem in AD [Alzheimer’s disease].” The authors focused upon the differences between the effects of administering cholinergic agonists during specific times of day. As they explain, “[t]he cholinergic system is regulated for increased transmission during waking and motor activity and decreased transmission (in general, during sleep, with brief, localized increases during rapid eye movement (REM) sleep. The elements of the cholinergic system—synaptic acetylcholine (ACh), stored ACh, acetylcholinesterase (AChE) activity and cholinergic receptors—are coordinated to achieve this end.” The experiments were done using cats.

In the cortex of the cats, ACh was reported to be doubled during quiet waking and nearly tripled when cats were activated by listening to tapes of singing birds. By contrast, during REM sleep, ACh was doubled in the cortex and tripled in the hippocampus. Thus, as has been reported elsewhere, ACh release is increased during waking, motor activity, and REM sleep.

As also reported in paper #7, cholinergic stimulation during the night in humans has effects similar to that seen in the animal studies. Cholinergic stimulation during NREM (non-REM) sleep induces awakenings and decreases in sleep time and efficiency, while cholinergic activity can enhance REM sleep. The authors describe studies that suggest that cholinergic inactivity during non-REM sleep may be a critical link in the consolidation of declarative memory (that includes word lists and places). Specific studies on galantamine (described in detail) did not find significant changes in the Pittsburgh Sleep Quality Index, did not find increased insomnia/sleep problems as compared to patients on placebo, but there was a suggestion of increased REM sleep activity (nightmares) at 24 mg/day. The authors7 note that the key to avoid unwanted cholinergic effects on sleep with cholinesterase inhibitors is to note their half-life (about 7 hours with galantamine)—indicating the period of increase and decrease of cholinergic activity—so as not to be increasing cholinergic activity excessively during sleep. With a 7 hour half-life, twice daily administration of immediate-release galantamine with meals, thus covers the normal waking day (data on file, Janssen Pharmaceutica Products LP, 2004) Low-dose choline taken by late afternoon should not have these effects.

  1. Davis and Sadik. Circadian cholinergic rhythms: implications for cholinesterase inhibitor therapy. Dement Geriatr Cogn Disord. 21:120-9 (2006).

Cholinergic Mechanisms for REM Sleep Control

“Rapid eye movement (REM) sleep is a distinct high frequency oscillation arousal state that has been linked to several aspects of brain function including developmental maturation of the brain, modification of synaptic plasticity and memory formation, as well as regulation of metabolic functions.”6 “Of particular importance are clusters of putative cholinergic neurons within the pedunculopontine (PPN) and laterodorsal tegmental (LDT) nuclei that have been characterized as ‘REM-on’ neurons because of increased firing during REM sleep. The combined data obtained from in vivo, lesion, transection, and pharmacological studies have suggested that these putative cholinergic ‘REM-on’ neurons in the brainstem are critically important for the generation and maintenance of the REM sleep state via widespread projections to the thalamus, brainstem, and specifically to the anterior pons.”6

The authors of paper #6 explain that various lesion and anatomical studies have suggested that the dorsal subcoeruleus (SubCD) area of the brain plays a major role in the production of REM sleep atonia (muscle paralysis) via descending projections to the medulla and spinal cord. The researchers performed experiments on SubCD brain slices to study the effects of the cholinergic agonist carbachol on SubCD brain activity, finding that carbachol “exerts a predominantly inhibitory role on fast synaptic glutamatergic activity and a predominantly excitatory role on fast synaptic GABAergic/glycinergic activity in the SubCD.” They conclude by hypothesizing that during REM sleep, cholinergic “REM-on” neurons that project to the SubCD induce an “excitation of inhibitory interneurons and inhibition of excitatory events leading to the production of coordinated activity in the SubCD projection neurons,” in which this coordination may be essential for the production of REM sleep.

This provides a sample of the complexity of sleep research at the molecular level and the contribution of the cholinergic nervous system to REM sleep. The authors remind readers that brain slices do not have sleep-wake cycles and, therefore, this is a limitation of the study. The work thus reveals the details of biochemical interactions in the SubCD at the molecular level but these do not provide the wider picture available with the addition of sleep-wake cycles that also involve other areas of the brain.

  1. Heister et al. Cholinergic modulation of GABAergic and glutamatergic transmission in the dorsal subcoeruleus: mechanisms for REM sleep control. Sleep. 32(9):1135-47 (2009).

The Cholinergic Nervous System as a Major Regulator of Inflammation

The parasympathetic nervous system is regulated by acetylcholine and plays a major role in modulating inflammation induced by the immune system in response to pathogens and inflammatory cytokines released in the process of tissue repair. In a severe form of runaway inflammation, sepsis resulting from infection has a high mortality rate. The vagus nerve, carrying cholinergic signals, is an important part of the parasympathetic nervous system anti-inflammatory activity via the conveyance of information to and from the brain. For example, in a model of endotoxemia (bacterial infection releasing endotoxins that stimulate release of inflammatory cytokines), “electrical stimulation of the vagus nerve significantly reduced serum and liver TNF [tumor necrosis factor, a major inflammatory cytokine] levels, prevented development of haemodynamic shock and improved survival without significantly altering IL-10 [an antiinflammatory cytokine] or corticosterone serum levels.”3

As reported in paper #3, “[s]uppression of inflammation in the brain and in the periphery can be achieved by enhancing cholinergic signaling by administration of acetylcholinesterase inhibitors. The acetylcholinesterase inhibitor galantamine, acting through a central mechanism, has been shown to attenuate serum TNF and IL-6 and improve survival in a murine [mouse] model of endotoxaemia.” Choline, as the precursor to the production in the body and brain of acetylcholine, is also able to enhance cholinergic signaling. “This mechanism could explain the association between high choline dietary intake with reduced pro-inflammatory markers in serum.”3

In fact, an editorial in a 2008 issue of the American Journal Of Clinical Nutrition4 commented on the finding of a paper in that issue that higher dietary intakes of choline and betaine decreased biomarkers of inflammation and was of the same magnitude as those reported for the Mediterranean Diet as a whole. (This was an epidemiological study; thus, this was an association that didn’t by itself prove causality.) Still, the author titled his editorial, “Is there a new component of the Mediterranean diet that reduces inflammation?”

  1. Rosas-Balina and Tracey. Cholinergic control of inflammation. J Intern Med. 265:663-79 (2009).
    4. Zeisel. Is there a new component of the Mediterranean diet that reduces inflammation? Am J Clin Nutr. 87:277-8 (2008).
Information provided for educational purposes only. *These statements have not been evaluated by the FDA. These products are not intended to diagnose, treat, cure, or prevent any disease.
*The products and statements made about specific products on this web site have not been evaluated by the United States Food and Drug Administration (FDA) and are not intended to diagnose, treat, cure or prevent disease. All information provided on this web site or any information contained on or in any product label or packaging is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should not use the information on this web site for diagnosis or treatment of any health problem. Always consult with a healthcare professional before starting any new vitamins, supplements, diet, or exercise program, before taking any medication, or if you have or suspect you might have a health problem.

For Focus & Clarity, Reach for Choline, Not Caffeine

Memory, focus and clarity of thought and mind are vital daily functions. The various stressors of the day and countless challenges that face us can be daunting. Usually people reach for caffeine to achieve that extra boost, but often are left disappointed because that caffeine infusion only lasts for a certain period of time. After that high wears off, people can feel like they’re running on empty which is never good, but there is another solution; a natural solution.

After more than 20 years of research from scientists all over the world, Durk Pearson and Sandy Shaw, two top research scientists, developed Mind, which uses a natural approach to keeping your mind running at maximum proficiency. Acetylcholine (ACh) helps your mind with retention and alertness. These two things are crucial for our daily activities, but in order to obtain the right amount needed, people would have to eat too much food. In addition, caffeine doesn’t help produce more acetylcholine, so Pearson and Shaw developed Mind. They created Mind in a well-balanced formula of choline and B-5 to help create more acetylcholine.

Using Mind as a dietary supplement can potentially boost your memory and mental clarity. Studies show that more acetylcholine in the brain correlates with improved memory retention and the speed at which you retain that information. With today’s fast-paced world, it’s even more important to have a clearer mind in order to learn and remember important material.

Caffeine only works for a short period of time and doesn’t provide the best results in a healthy way. In fact, too much coffee and or soda pop can leave you drained and jittery, and cigarettes can lead to a whole other slew of problems like heart disease and lung cancer. So, choose Mind the next time you need a boost to help you navigate the many challenges of life and feel safer knowing it’s a healthier, more natural solution to improving memory and mental sharpness.

To your health!
The Life Priority Team

Life Extension Scientists Durk Pearson & Sandy Shaw

Feed Your Head

DURK: Everything that happens in your brain, every memory, every thought, every emotion, every innovation, every “wow, that’s great!” is a result of the release of neurotransmitters. Neurotransmitters are not drugs; they are natural substances made by nerve cells in your brain that transmit messages from one nerve cell to another across the synapse that divides them. That’s why they are called neurotransmitters. They are made the nutrients in your diet, but there is a very good chance that even if you have a good diet, you’re not getting the optimum amount of the raw materials that your brain can use to make neurotransmitters.

The three most important neurotransmitters have been known for a long time: acetylcholine, noradrenaline, and dopamine. Acetylcholine is involved in memory and organization, the way you order things in your mind, the way you retrieve them in an orderly manner. It’s also involved in focus and concentration. A good example of what happens if you don’t have enough cholinergic activity can be found in a person who has taken the psychoactive drug atropine or any other anticholinergic drug. In many respects, they resemble someone with Alzheimer’s disease.

The latter are people who have suffered extensive damage to their cholinergic nervous system: they lose their memories, lose their focus, and lose their ability to concentrate.

What do you do to improve your cholinergic memory? Take choline and Vitamin B5. The vitamin B5 (also known as pantothenate) acts to convert the choline to acetylcholine more efficiently. Now there’s a very good reason to take choline as you get older, because as you get older the ability of your blood-brain-barrier to actively transport choline from your bloodstream into your brain drops dramatically. By the time you’re in your 60’s most people have perhaps 20 or 30 percent of their young adult capability of transporting choline from the blood stream into your brain.

SANDY: You can compensate for this by taking a choline supplement, choline plus vitamin B5, making it possible for more choline to be transported into your brain.

DURK: And if you don’t do this, something very unfortunate happens as you get older. The cholinergic system is a “use it or lose it” type system; that is, it requires continuous cholinergic stimulation to release neurotrophic growth factors. Without neurotrophic growth factors the cholinergic nerves start dying off. In fact, in order to make acetylcholine as you get older, your brain will start cannibalizing other brain cells for the choline contained in the cell membranes as phosphatidylcholine. Eventually, you start losing your cholinergic nervous system. You don’t notice the results of this immediately. Typically, it takes about an 80 percent neuron loss before people notice that they are doing more than just slowing down. Their memory isn’t quite as quick as it used to be or as sharp; it takes more time to do things. As time goes on, simple memory tasks become more and more difficult. So to keep your mind working properly especially as you get older or especially if you’re working very hard, like cramming for a test, you need more of these raw materials to make acetylcholine.

WILL: What is a good amount of choline and vitamin B5 to compensate for the loss, especially with age?

DURK: The U.S. Government asked the Institute of Medicine to determine whether choline was an essential nutrient or not. And they found that, yes, it is an essential nutrient for human beings; you can make a limited amount in your liver, but that’s not enough even when you’re young.

SANDY: They determined that about 550 mg a day would be required for a male adult.

DURK: And 425 mg for an adult female. However, all their data was derived from young college students who acted as subjects in medical experiments. They didn’t consider the fact that as people get older, their ability to transport choline into the brain, which is a major user of choline, is impaired. We think people should start out, for the first week, taking about 1 g of choline, and 2/3 of a gram of pantothenate each day. During the second week, these amounts should be doubled to 2 grams of choline and about a 1 1/2 gram of pantothenate per day. And in the third week, go to 3 grams of choline a day and a couple of grams of pantothenate per day. Now, it wouldn’t harm you to immediately jump to 3 grams per day. It’s just that you might possibly end up with a little constipation or tension headache because acetylcholine is what makes your muscles contract as well. If you take too much too fast, quicker than your body can adapt to the increased amount, you may end up with excessive muscle tension. The first symptom of this muscle tension is usually a stiff neck. I might add that choline is also important for cardiovascular health as well. One of the major risk factors for somebody dying of a heart attack is the inability of their heart to slow down rapidly after exercise. This pulse rate reduction is due to cholinergic stimulation by the vagus nerve. If you don’t have enough choline in your diet, you may be at increased risk for this particular problem.

SANDY: Acetylcholine is also involved in the relaxation of arteries. Which is another one of the things that deteriorates in the development of atherosclerosis; arteries simply do not dilate properly and as a result, your ability to control blood pressure is reduced.

DURK: In fact, the mechanism by which acetylcholine helps dilate arteries is by turning on an enzyme called nitric oxide synthetase found in the lining of the arteries. This enzyme turns the amino acid arginine into nitric oxide which then causes the arteries to dilate. That’s the same mechanism that gives you erections as well. Acetylcholine is involved in muscular contraction. You may think that if you have very intense and prolonged muscle contraction, like running a marathon, you might run low on choline and not be able to make the optimum amount of acetylcholine? And the answer to that is, absolutely yes.

SANDY: In long marathons, choline resources are limited.

DURK: It has been found that giving marathon runners choline, which is completely legal under athletic association rules, that you can run a marathon a little bit faster. And that is a lot when the time separating the winner from the second best may only be a matter of seconds. So especially as you get older you want to be sure you’re providing your brain with adequate amounts of choline and vitamin B5 to be sure you can make acetylcholine to help maintain youthful type mental function, rather than slowly tapering off into the sunset.

WILL: We reported recently on a paper in the American Journal of Clinical Nutrition that showed a correspondence between choline deficiency and high homocysteine levels.

DURK: Yes, in fact choline is involved in converting homocysteine back into cysteine. Homocysteine, you think of toxic byproducts as being something that oil refineries or automobiles make when they burn fuel. Yes, they make toxic byproducts, but, surprise, surprise, your own body makes toxic byproducts as well. And one of them is homocysteine. And in fact, choline can act as a methyl group donator to turn homocysteine, which can cause atherosclerosis and is associated with strokes, back into cysteine, which is a useful antioxidant nutrient amino acid, unlike homocysteine which is pro-oxidant and is causally involved in causing an increase in the incidents of strokes as well as hypertension.

WILL: Moving over to the other two neurotransmitters.

DURK: Noradrenaline is nature’s natural speed. It is your “get up and go” juice. But unlike speed, it doesn’t cause free radical damage that burns out the neurons in your brain. Noradrenaline, if you have enough of it you’re full of energy, you’re excited, you’re self confident. If you don’t have enough of it…

SANDY: You can be depressed, but you’re certainly going to be having less energy, less drive. You may just lose interest in doing most things.

DURK: If you have a hard time getting out of bed in the morning and maybe even feel like you’d like to go jump out a window, except its too much trouble, chances are you’re suffering from an inadequate supply of noradrenaline. Now, if you’re seriously depressed you do need to go see a doctor because there are a lot of other things that could be responsible. Such as hypothyroidism or some things that are a lot more complicated like too much cortisol being produced.

But in the case of people who, getting older, don’t have the spring to their mental step they did when they were teenagers, it’s because their noradrenaline levels drop off with age. And noradrenaline also causes the release of neurotrophic factors that help the noradrenergic nerve grow as well. So again, it’s a case of “use it or lose it.” Fortunately, you can make noradrenaline from either the essential amino acid tyrosine or the nonessential amino acid phenylalanine. You also need the help of some essential nutrients, specifically vitamin B6, C, and the mineral copper. And a lot of people are deficient in copper; a lot of people aren’t getting the RDA of copper. So its not surprising that the number one complaint people bring to their physicians is they just don’t have enough energy. And part of it may be because they’re only getting 6 hours of sleep a night, and part of it may be because they’re getting older and they’re making less noradrenaline.

Now in our formulations, we use phenylalanine rather than tyrosine because you cannot convert tyrosine into a neuromodulator called beta-phenethylamine. Neuromodulators modulate the effect of neurotransmitters, they turn up the effects or turn them down. Beta-phenethylamine turns up the effects of noradrenaline and by giving the person a phenylalanine, vitamin B6, copper, vitamin C combination, we’re actually able to give people the system of nutrients that their brain can use to make more beta-phenethylamine and more noradrenaline. So if you’re “get up and go” has “got up and went”, get yourself one of our formulations with the phenylalanine and the necessary nutrient cofactors to make it into noradrenaline.

WILL: Would you say that beta-phenethylamine is kind of a kick start modulator?

DURK: It sure is, and in fact it is thought to be involved in the mechanism, the euphoria of being in love. Beta-phenethylamine levels do go up when people are in love, but I’ll also add that it’s found in chocolate. Chocolate is probably your richest food source of it. But you can make the stuff in your brain if you have adequate phenylalanine (not tyrosine), vitamin B6 and adequate copper which we provide in all of our phenylalanine-containing formulations. Now, noradrenaline works very well in conjunction with caffeine. That first cup of coffee you drink in the morning gives you a real lift. It makes you work faster and harder and more accurately and with less effort. Yet, by the middle of the afternoon, drinking another cup of coffee may just make you space out, jittery, nervous, bad tempered. What’s going on here is pretty simple. There are two mechanisms by which caffeine works. One is that it antagonizes adenosine receptors and this is something we won’t get into, but it is one of the mechanisms by which caffeine keeps you awake. Another is that it makes you release noradrenaline in your synapses and also makes you more sensitive to noradrenaline because it preserves the effect of the second neurotransmitter, cyclic AMP.

SANDY: It’s called the second messenger.

DURK: Noradrenaline crosses the synaptic gap, and the reason it produces a signal in the receiving nerve is that is causes the production of cyclic AMP, the second messenger. Caffeine slows the rate at which the cyclic AMP is destroyed. Just like Viagra® slows the rate at which nitric oxide-stimulated cyclic GMP is destroyed. And so you get a stronger message. If you take a little bit of caffeine along with the phenylalanine and cofactors combination, you get a much better lift, and much longer lasting lift than taking just the caffeine alone. In fact, Sandy and I always take our choline formulation and our phenylalanine plus cofactors plus a little bit of caffeine formulation before we do any lectures and that’s the reason we’re able to remember all of this stuff and put it together in a way people can understand.

SANDY: We’ve discovered by experience that getting up far earlier than we normally do in the morning and having to do television shows during which you’re lucky if you get two minutes, you have to talk very fast, and have answers to questions. Meaning, you can’t spend any time thinking about the answers. Do this all day and it totally fatigues you; you’re depleting your supply of neurotransmitters like acetylcholine and noradrenaline and you just don’t have the ability to do a very good job of answering questions real fast. So that is originally how we developed these formulas, in order to help us to perform better while we were on publicity tours for our first book, Life Extension: A Practical Scientific Approach.

DURK: We developed a choline formulation back in the late 1970’s and it had a dramatic effect on Sandy. We started writing the book in ’78 and didn’t yet have a word processor so we were typing all of this stuff up. I literally had to take scissors and cut Sandy’s stuff apart and reassemble it in a different order. What she said was right but not well organized and it was literally cut and paste. Naturally, Sandy got a bit pissed off about that but once she started taking the choline supplement it was like everything flowed in the proper order. It was all organized when it came out of her fingers to the typewriter.

SANDY: It was effortless. It was one of those things that if you’re a writer and the words are flowing it just feels completely differently than when you’re writing and it feels as though you’re squeezing the last toothpaste out of the tube.

DURK: We had our choline formulation for the first tour for Life Extension, but we had not yet developed the phenylalanine plus cofactors formulation. And after 5 weeks on the road doing all those TV and radio shows, newspaper, magazine interviews, boy our get up and go, got up and went. So we decided to figure out what was going on; we were using noradrenaline a heck of a lot faster than we were able to make it. So we fixed that by providing the right formula to enable us to make more and the next tour was so much easier.

SANDY: It was easier to do a good job all day and we felt better at the end of the day, we weren’t as fatigued.

WILL: How much phenylalanine do you recommend people take on a daily basis? Or is it dependent upon what they’re doing?

DURK: Well, it depends on what they’re doing. For example, I particularly like a version of our formulation which has green tea polyphenols in it that are potent antioxidants, and have some psychoactive effects, they make colors brighter, make you feel cheerful, they’re a natural upper. In addition, it has phenylalanine and cofactors and 40 mg of caffeine which is the same amount you would get in a Coke®, which is actually about 50 mg. It’s the same amount you have in two cups of green tea. I normally use about 2 servings a day. One as soon as I get up, and the other in mid-afternoon when I start slowing down. But if I’m doing something really complex and mind numbing, like filing out my income tax with schedule A, B, C, D, E and F, I’ll use more. When I’m doing something really mind numbing like that or writing for a deadline, I may consume 5 or 6 servings a day. However, you don’t want to take it too close to bedtime or you are not going to get to sleep.

Now if you don’t like the effects of caffeine, we have our formulation, which has the phenylalanine and cofactors, but no caffeine. There are some people who are sensitive to caffeine and don’t like it. If we have to do a lecture at 10 o’clock at night, we’re certainly not going to take caffeine because we won’t get to sleep that night, but we will take phenylalanine along with our choline plus vitamin B5 formulation.

WILL: I’m curious, has anyone every attempted to determine the essentiality of phenylalanine or tyrosine, and set daily values? And if not, why not?

DURK: Well, tyrosine is an essential nutrient. And phenylalanine can be converted to tyrosine in your body so that is not considered an essential nutrient because you can replace it with tyrosine. However, as I mentioned tyrosine doesn’t help you make beta-phenethylamine. Scientists conducted a double-blind, placebo-control study on human beings that were subjected to very long hours of hard work; they were basically taking a test for several hours. They found that the tyrosine was an anti-fatigue agent that didn’t produce an excitatory effect, it didn’t act as an upper whereas the phenylalanine acted both for anti-fatigue and as an upper. So we prefer the phenylalanine for that reason.

WILL: You recommend between 1 and 3 grams of choline plus cofactors per day. What are your recommendations for phenylalanine plus cofactors?

DURK: For phenylalanine, it depends on the individual. Any where from half a gram to 3 grams per day. And I might add the choline plus vitamin B5 formulation can be taken at any time, including with food though of course, if the food remains in your stomach while being digested for awhile, there will be a delay before the choline is absorbed. In the case of the phenylalanine plus cofactors supplement, for best effects you want to take that on an empty stomach because other large amino acids in the diet can interfere with the passage of phenylalanine across the blood brain barrier.

SANDY: Certain amino acids compete to be carried across and there is limited capacity for carrying them.

DURK: For example, if you eat a big hamburger you could easily get yourself a half a gram of phenylalanine, however its likely to put you to sleep rather than waking you up because there are other things in there like the amino acid tryptophan that will interfere with phenylalanine crossing the blood brain barrier and that acts as a sedative. So you want to take phenylalanine on an empty stomach.

WILL: What about dopamine?

DURK: Now dopamine is closely related to noradrenaline; dopamine is involved in memory and motor coordination and…

SANDY: And it’s also involved importantly in reward. Whenever you do something that makes you feel good about doing it; that is due to release of dopamine.

DURK: In fact, the reason that opiates are rewarding is that they cause the release of dopamine in part of your brain. You might think that everything that’s going to give increased amounts of dopamine is going to be potentially addictive. The answer to this is, “no, it isn’t” and for a very simple reason. The dopamine can be made from tyrosine and phenylalanine, so when you take our phenylalanine plus cofactors you’re able to make more dopamine too. And why isn’t this addictive? It has very simply been a normal part of the diet for a billion years. The bugs have been worked out. When you take something like opium, which hasn’t been a part of the diet, you can get into trouble, like addiction. When you take phenylalanine, you’re not going to have that problem because all of those problems are buried back about a billion years. A good example of what happens when you don’t have enough dopamine is Parkinson’s disease. In addition to problems with memory, the person is very unhappy because their reward system isn’t working, and further, they lack adequate motor coordination. In general, there is a real detriment in the quality of life. And again, this is something that happens gradually as you get older. You don’t start getting Alzheimer’s disease or Parkinson’s the day you’re diagnosed.

SANDY: Actually, you have to have about 80% destruction of the dopamine neurons before you notice any symptoms of Parkinson’s. So what that means is that by the time Parkinson’s shows up, you’ve already suffered the majority of the damage you’re going to experience.

DURK: And our formulations can be helpful in getting you off stimulants such as cocaine, because cocaine works by causing a release of noradrenaline and blocking the synaptic reuptake and recycling of dopamine. So you only temporarily have more noradrenaline and dopamine. The problem is very simple: cocaine doesn’t help you make any more neurotransmitters, and so you get the same effect, you have to take more and more and more.

SANDY: Your supply gets depleted in addition to the free radical damage that takes place. And when you deplete your noradrenaline and dopamine supply you suffer a crash, the notorious crash that takes place for people who use cocaine or speed. And at that point, people can become extremely depressed and it’s a very serious problem.

DURK: In fact we knew a very talented rock singer who wrote very energetic, speedy music and he was hooked on methamphetamine, and he knew it was killing him. He asked us if we knew anything that could help. He didn’t like the effects of caffeine at all, so we suggested the use of phenylalanine and suggested that this might help him use less. He surprised us by going off meth entirely. He was able to kick speed and continue to write energetic music through the use of phenylalanine. We certainly don’t want to guarantee that will happen to everyone, but if you’re using stimulants, I might suggest that the phenylalanine formulations might really help you reduce the amount you’re taking or help you find something you like better.

WILL: Are there any other neurotransmitters worth mentioning?

DURK: Yes, nitric oxide which is made from arginine. In fact, it is a neurotransmitter. Acetylcholine, noradrenaline, and dopamine have been known for three quarters of a century, whereas knowledge of nitric oxide as a neurotransmitter is much more recent. It’s important in learning and memory and the mechanism by which a short term memory is turned into a long turn memory has only been known for about 15 years. And nitric oxide is also involved in learning a new motor sequence; for example, if you want to learn to play golf you want to have plenty of arginine in you.

SANDY: Nitric oxide is also needed to allow your arteries to dilate, to widen, in order to allow more blood flow. This is the way your body is able to adjust blood flow to areas that need more such as muscles during muscle activity.

The Durk Pearson & Sandy ShawLife Extension NewsTM

UNSUNG SUPERFOODS: HEALTHFUL FOODS YOU SHOULD INCORPORATE INTO YOUR DIET (AND HOW TO ENJOY THEM)

from the Chicago Tribune

04-20-09

Step aside, blueberries, spinach and broccoli. It’s time to give unsung superfoods a chance.

Many of us tend to eat what we know and what we can pronounce and prepare. But mixing things up helps add more healthful micronutrients and phytochemicals into our diets, said Mary Russell, director of nutrition services at the University of Chicago Medical Center.

Trying little-known foods also gets you into ethnic grocery stores, farmers markets and local markets that focus on sustainable, local food, Russell said. “That’s where you can learn from others how to buy, prepare and use unusual foods.”

To help steer your cart in a new direction, try incorporating these 10 healthful foods that you probably aren’t eating – but should be – into your diet.

Kamut

An ancient relative of durum wheat, kamut increasingly is used as an alternative to regular wheat. It has 20 to 40 percent more protein and is higher in lipids, amino acids, vitamins and minerals. Moreover, it can be tolerated by some with sensitivities to regular wheat. Kamut can be found in some packaged pastas, bread, cereals and crackers.

Try it: Kamut is usually found in the bulk section of supermarkets. Substitute it for wheat berries or rice or mix with sauteed peppers and onions. For breakfast, mix a half-cup with diced apples, raisins, walnuts and a touch of cinnamon and honey.

Dandelion greens

One of the first vegetables to come to the farmers market – and your yard – in the spring, dandelion greens are low in calories and high in fiber. But a serving (1 cup) of these dark, leafy greens also has more vitamin A than a cup of cantaloupe and more calcium than spinach, said dietitian Jodi Greebel, president of Citrition, a nutritional counseling practice in New York City. They’re also high in iron, other vitamins (including vitamin C), potassium and folate.

Try them: They’re somewhat bitter so you might not want to toss them in salads. Instead, try cooking them with something sweet – say a chicken or pasta dish with tomatoes – or adding nuts and dried fruit, Greebel said. Or saute with garlic and pepper.

Grapefruit

Grapefruit is in peak season through April and its juice boasts more nutrients per calorie than 100 percent apple, grape, pineapple and prune juice. Each serving (1 cup of juice) gives you more than 100 percent of your daily recommended vitamin C, which helps neutralize free radicals that can damage cells and lead to infection, aging and disease. It can boost the performance of some medications – but it can interfere with others – so check with your doctor if you take prescription drugs.

Try them: Top with a spoonful of maple syrup, or a dash of cinnamon, nutmeg or cloves, or use as a topping on cereal, waffles, pancakes or in a yogurt parfait.

Tempeh

Made from fermented soybeans, this traditional Indonesian food looks strange but it may ease symptoms of menopause because it contains phytochemicals such as isoflavones and saponins, said Russell. The soy protein and isoflavones also might reduce the risk of heart disease and some cancers.

Try it: Slice and saute. Its nutty, mushroom flavor can be used in soups, salads and sandwiches, according to author Jonny Bowden in “The 150 Healthiest Foods on Earth.”

Seaweed

Sea vegetables are rich in vitamins, minerals and trace elements. The kelp family (kombu, wakame and arame) is an excellent source of iodine and has about four times the iron of beef. Arame has more than 10 times the calcium as milk. Nori, the seaweed wrapped around sushi rolls, contains protein, calcium, iron, potassium and more vitamin A than carrots. If you’re taking medications, check with your doctor.

Try it: Try sushi or maki rolls. Or cut nori strips into pieces and sprinkle on salads, Russell suggested. Put kelp in a shaker and use instead of salt. Add to soups. Or mix it with olive oil or tamari and use as a seasoning.

Avocados

Don’t shun this creamy fruit because of the fat content. Avocados have good, unsaturated fats which help with growth and development of the central nervous system and the brain. They’re packed with nearly 20 vitamins, minerals and phytonutrients. And they play well with others; when you eat an avocado, it helps the body absorb more fat-soluble nutrients, such as alpha- and beta-carotene, as well as lutein, from other foods.

Try them: Use avocado in place of mayonnaise. Add it to smoothies, salad, salsa, soups or sandwiches.

Dried plums (prunes)

These little gems are “a mouthful of rich sweetness,” said dietitian and nutrition therapist Victoria Shanta Retelny of Chicago. High in antioxidants, they also have twice as much potassium as bananas; potassium can help keep blood pressure in check.

Try them: Retelny loves to dip them in dark chocolate or she purees them, then tops them with a dollop of plain yogurt and cinnamon.

Chia seeds

The little seeds that blossom into low maintenance pets – or the bizarre new Chia Obama – are actually nutrient-dense whole grains with omega-3 fatty acids. “They have among the highest antioxidant activity of any whole food, outdistancing even fresh blueberries,” doctors Michael Roizen and Mehmet Oz wrote in “You: Staying Young.” Studies also have shown they can level out blood sugar spikes. Roizen and Oz recommend two daily doses of about 20 grams of seeds each.

Try them: Use like flax seeds. “Sprinkle chia seeds in oatmeal or cereal for breakfast, or add them to salads, smoothies or baked goods such as muffins or brownies,” said natural health expert Jordan Rubin.

Beets

The deep red color can be a little intimidating, but earthy beets give us fiber, iron and vitamin C. “Plus, they contain betacyanin, a powerful cancer-fighting agent that has been shown to help prevent colon cancer,” said dietitian Gloria Tsang, founder of the online nutrition community Healthcastle.com. They also contain antioxidants that have been shown to lower total cholesterol while increasing HDL (good) cholesterol.

Try them: Try marinating steamed beets in fresh lemon juice, olive oil and fresh herbs. Grate raw beets onto salads, soups or any other dish. Or simply roast them with other veggies, Tsang suggested. But don’t cook beets too long, because their anti-cancer activity is diminished by heat.

Pumpkin

Though fresh pumpkin is available only in the fall and winter, canned products are just as healthful, Tsang said. “A serving of pumpkin (1 cup) has nearly 3 grams of fiber, and is packed with beta carotene – an antioxidant that can help improve immune function and reduce the risk for cancer and heart disease,” she said.

Try it: Cut fresh peeled pumpkin into chunks and roast with a bit of olive oil, salt and pepper, Tsang suggests. Or drop a generous scoop of canned pumpkin into plain pancake batter, or make a soup from canned pumpkin, chicken broth and fat-free half-and-half.

Energy Drinks and Mental Fitness

Healthy Energy Drinks and Mental Fitness

Life Priority teamed up with life extension scientists, Durk Pearson & Sandy Shaw® to market and develop a full line of healthy products called Designer Foods to improve and enhance your cognitive function, which spans not only memory, but attention, learning, problem solving, decision making, and reasoning.

Each new day presents challenges that, if not met and overcome, may leave you less fit mentally to control your life . . . to achieve your financial goals . . . to set the stage for pursuing your personal happiness.

By starting each day with a cool, refreshing glass of delicious LIFT™ (or LIFT Caps™) or Mind™ or Muscle Memory™), you can embrace a lifelong “Mental Fitness” program.

Life Priority healthy drink mixes, many of which are healthy energy drink mixes. These include the LIFT™ family mentioned above, all of which employ the amino acid phenylalanine, a precursor to an important memory molecule, noradrenaline, and your brain’s version of adrenaline. They also include the necessary enzyme cofactors vitamin B6, vitamin C, copper, and folic acid, along with natural flavors.

These formulations are based on the nutrient choline, which is the important memory nutrient involved in concentration and focus.* As we age, choline becomes less bioavailable, with serious consequences for memory function.

The “Mental Fitness” drinks are great-tasting, natural, fruit-flavored citrus cooler containing choline and essential nutrient cofactors plus the important amino acid taurine. Use Mind to help preserve and protect your memory function.*

Supplements for Memory “Loss”

Over time, the effects of too little sleep, aging, and the stress of a busy life can impair both your cognitive and memory functions. It may seem as if your memory has been “lost.” While many try to combat these effects with stimulants like caffeine, these only provide a temporary lift, and come with a host of unwanted side effects. Instead of masking the symptoms, why not improve the underlying problems instead? Try our Productive Sleep drink with choline.

Our formulas are carefully tested to ensure that they are safe and meet your needs. Often taking cues from historical findings, our scientists use their knowledge of the human body to create formulas based on scientific studies. They give real results.

Instead of settling for poorly designed energy drinks or caffeine pills that provide only a short burst of energy followed by a mental crash, consider products that have been developed using real science. Other sources can leave you feeling jittery, and carry the threat of weight gain from all the extra sugar and calories these drinks usually contain. If you rely on products like caffeine, you may also experience the symptoms of addiction. With Life Priority products, these are concerns you no longer have to consider. We carefully test all products to ensure that as long as the proper dosage recommendations are followed, you will notice no negative side effects from their use.

Drink Mixes

Nutrient Drink Mixes are a delicious way to supplement your diet with additional vitamins, minerals and amino acids necessary for enhanced cognitive, physical and sexual function. When mixed with water or your favorite beverage, they’re a convenient and efficient way to fuel your body, helping you feel and perform at your very best.

Life Priority   offers a wide variety of formulations for increased energy, mood and sleep enhancement, improved sexual function, weight loss, HGH release, and “Smart Nutrients” for cognitive enhancement and creative mental energy. Just choose the formula (or two) that’s right for you. We think you’ll be pleasantly surprised at how delicious, convenient and effective they are. At Life Priority, we offer a variety of “smart nutrients” from several different formulators. When mixed with water or your favorite beverage, they’re a convenient and efficient way to fuel your body, helping you feel and perform at your very best.

Life Priority, established in 1994, offers supplements that are scientifically-formulated, results-oriented and GRAS (Generally Recognized As Safe) and are manufactured at USDA and FDA inspected facilities.

*The products and statements made about specific products on this web site have not been evaluated by the United States Food and Drug Administration (FDA) and are not intended to diagnose, treat, cure or prevent disease. All information provided on this web site or any information contained on or in any product label or packaging is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should not use the information on this web site for diagnosis or treatment of any health problem. Always consult with a healthcare professional before starting any new vitamins, supplements, diet, or exercise program, before taking any medication, or if you have or suspect you might have a health problem.

*Any testimonials on this web site are based on individual results and do not constitute a guarantee that you will achieve the same results.

LE NEWS: The Power of Arginine

The Power of Arginine
DURK PEARSON & SANDY SHAW’S®
LIFE EXTENSION NEWSLETTERTM
©1988-1991

Life Extension Newsletter, written by Life Extension scientists Pearson & Shaw, was prescient with regard to many of the biomedical ideas it first brought to the attention of the public. Unfortunately, it is no longer available and thus, with the permission of the authors, we reproduce selected portions for your enlightenment. Please note the return of another Pearson & Shaw Newsletter, Life Extension News, the current issue of which is contained in this publication. The growth hormone story picks up where Sandy breaks her leg at a gerontological conference where she is initially attended to by no less than Dr. Denham Harman, M.D., Ph.D., father of the Free Radical Theory of Aging.

ISSUE #25
ARGININE RELEASES GROWTH HORMONE
Having a broken foot is extremely inconvenient and sometimes dangerous. Just try going up or down stairs on crutches! We had been about to start arginine supplementation experiments on ourselves for immunostimulation, when Sandy’s broken foot provided us with a golden opportunity. We had read scientific reports of arginine stimulating the healing of broken bones in experimental animals, and Sandy decided to take it.

Other nutrients have been shown to cause growth hormone release, including niacin (200 mg is a mild GH releaser) (Irie, 1967,1970), tyrosine (nutrient amino acid – releases a small amount of GH in a small percentage of subjects with 40 gram intravenous doses), and methionine (nutrient amino acid – releases GH but can cause atherosclerosis under certain conditions). The nutrient amino acid arginine and ornithine (another amino acid) are both relatively strong GH releasers. Arginine and ornithine can release enough GH to equal that found in a heavily exercising teenager.At this time, Sandy was 35 years old, and far over the hill in terms of exercise-induced GH release. She took 10 grams of arginine a day in a single dose on an empty stomach. (One might be able to ingest that amount daily in a very high protein diet heavy in chicken or turkey. Sandy was also taking about 2 grams of choline and 2 grams of vitamin B5 per day.) About 45 minutes to one hour after taking the arginine, Sandy did bench presses for about 3 minutes, once daily, on her back, so there was no stress on the broken foot. After six weeks on this regimen, she had lost about 25 pounds of fat and had put on about 5 pounds of muscle! We were amazed. We thought that amount of arginine might be enough to stimulate the release of growth hormone. We knew that growth hormone increased the ratio of muscle to fat. (Christy, 1979; Murad, 1980) But we didn’t realize how dramatic the effect could be in an essentially sedentary middle-aged research scientist. Arnold Schwarzenegger in his Bodybuilding for Men said that putting on 5 pounds of muscle would be difficult for an adult man working out every day for a year!

Arginine and ornithine cause growth hormone release via your brain’s cholinergic nervous system. (Casanueva, 1984) This is the system that uses acetylcholine – made in the brain from the nutrient choline with the help of the cofactor vitamin B5 – to transmit information between the nerve cells. Without adequate amounts of acetylcholine, neither arginine nor ornithine can cause growth hormone release, though we know of no evidence that choline or vitamin B5 alone can cause GH release. This is why we recommend the use of a choline + B5 supplement in conjunction with arginine or ornithine GH releasers. Note that many antihistamines, cold pills, and the non prescription sedative diphenhydramine are anticholinergics. These drugs will block the GH releasing effects of arginine and ornithine.

Contrary to what some people believe (and some fraudulent products claim), you can’t develop winning muscle mass without exercise, even if you take a growth hormone releaser like arginine. But arginine is very effective at helping you maintain muscle mass you already have, even if you are not exercising. We are two 47 year-old research scientists and almost completely sedentary, but we regularly take arginine supplements, as described below, and maintain the well muscled bodies we had twenty years ago. You may have seen 5’3″ Sandy bend steel horseshoes on television.

In 1982, after we reported our ideas and experiences regarding the use of growth hormone releasers such as arginine in our first book, Life Extension, A Practical Scientific Approach, there was a world-wide shortage of arginine for several months, and a world-wide shortage of ornithine for about a year! Their main prior use had been as ingredients in culture media.

ARGININE SUPPLEMENTATION
We personally use arginine in either one of two different ways: we take 12-24 grams 45 minutes to one hour before exercise (to enhance the effects of the exercise) or just before bedtime (to enhance both sex and the natural pulse of growth hormone release shortly after one falls asleep). We generally recommend the following total daily quantities of arginine (free base) for healthy male adults: Weight 100 to 140 pounds, 12 grams; 140 to 200 pounds, 18 grams; over 200 pounds, 24 grams. For healthy female non-pregnant, non-lactating adults: under 120 pounds, 6 grams; 120 to 180 pounds, 12 grams; over 180 pounds, 18 grams. Women are usually more sensitive to the GH releasing effects of arginine and ornithine than men. (Merimee, 1969) Start with about 25% of your target quantity, and increase it gradually over a period of a few days to minimize the occurrence of minor side effects such as nausea. If you prefer ornithine, use half of these amounts. The dose figures given in the literature usually refer to the amount of amino acid free base used, such as arginine. Many commercial products contain an acid addition salt such as arginine hydrochloride rather than the free base arginine. Some of the product labels give the amount of the contents as the free base, other as the hydrochloride. Unless the amount of the amino acid is given as the free base (eg, 6 grams arginine), you will need to take about 20% more since the hydrochloride adds about 20% to the weight without contributing to the GH releasing activity.

Don’t assume that more is always better. It is unlikely that a 60 gram dose would cause significantly more GH release that a 24 gram dose. A 30 gram injection of arginine is used to test pituitary function: this dose has been chosen to be high enough to completely saturate this GH release mechanism. (See the Cautions at the end of this article for side effects and precautions.)

It is important not to ingest certain other amino acids, either as a supplement or in foods, at the same time or shortly before taking the arginine. Some of these other amino acids, including lysine, compete with arginine to enter the brain (where the action takes place). You can take your protein supplement or high protein low glycemic index carbohydrate meal after your workout.

Casanueva, Villanueva, Cabranes, Cabezas-Cerrato, Fernandez-Cruz, “Cholinergic Mediation of Growth Hormone Secretion Elicited by Arginine, Clonidine, and Physical Exercise In Man,” J. Clin. Endocr. Metab.59(3):526-530 (1984)
Christy, “Anterior Pituitary Function in Normal Subjects and in Patients with Systemic Diseases,” in Obese, et al, editors Cecil Textbook of Medicine, 15th ed, pp.2085-2091, Philadelphia:Saunders (1979)
Irie, et al, “Effect of Nicotinic Acid Administration on Plasma Growth Hormone Concentrations,” Proc Soc Exptl Biol Med 126:708 (1967)
Merimee, et al, “Arginine Initiated Release of Growth Hormone: Factors Modifying the Response in Normal Men,” New Eng J Med. 280(26) :1434-1435 (1969)
Murad and Haynes, “Adenohypophyseal Hormones and Related Substances,” in Gilman, Goodman, Gilman editors Goodman and Gilman’s Pharmacological Basis of Therapeutics 6th ed, pp.1369-1396, New York:MacMillan (1980)

ISSUE #25 PAGE 7
CAUTION
Arginine Side Effects: Most men and some women report increased libido with arginine supplements. There may also be increased irritability. A large release of GH can also cause nausea. Remember how Arnold Schwarzenegger used to keep a barf bucket next to his workout station when he was a teen-ager? He said that if he wasn’t working out hard enough to throw up, he wasn’t working out hard enough to win. In his twenties, this no longer happened because the exercise no longer caused such a big GH release. You are less likely to have annoying side effects if you start out with a small amount, and gradually increase your dose over a period of couple of weeks.

Ornitine Side Effects: Arginine, but not ornithine is found in ordinary food protein. Arginine has been given to medically monitored subjects at up to 60 grams per day without reports of serious problems. Much less is known about the safety of the regular use of large amounts of ornithine. Since about half of the arginine that you ingest is normally converted to ornithine in your body, it isn’t surprising that the reported side effects of ornithine are similar to those of arginine. It takes about half as much ornithine as arginine to release a given amount of GH, but ornithine costs twice as much. We generally use arginine, considering it to be more medically conservative. The immunostimulant and wound healing stimulant effects of arginine are far better established, too. Moreover, arginine but not ornithine, increases sperm count.

Choline Side Effects: Too much choline and/or vitamin B5 can cause the production of too much acetylcholine. Since acetylcholine is what makes your muscles contract, this can cause excessive muscle tone. The most common symptoms or cholinergic excess is a stiff neck, a tension headache, or gut cramps, diarrhea, or constipation. You are less likely to have annoying side effects if you start out with a small amount, and gradually increase your dose over a period of a couple of weeks. Do not use choline bitartrate; in effective doses, there is so much bitartrate in this form of choline that diarrhea is almost inevitable. Chronic diarrhea isn’t just annoying; potassium loss can be so large that it may cause heart failure by ventricular fibrillation.

Niacin Side Effects: 200 milligrams of niacin will most certainly cause transitory skin flushing and a sensation or heat, burning, or itching, though this is not dangerous. Do not take more than 800 milligrams of niacin per day without medical supervision, since the livers of some individuals cannot tolerate higher doses.

Although the growth hormone releasing effects or arginine and ornithine have been stressed in this article, we do not wish to imply that all of the anabolic, wound healing, and immunostimulant effects of arginine and ornithine are due to their GH releasing activity. Arginine and ornithine also act as precursors to polyamines such as spermine and spermidine, which are growth stimulating substances, and these two amino acids have many other uses within the body, too. Nevertheless, the anabolic, wound healing, and immunostimulant effects of growth hormone itself are so similar to those of arginine and ornithine that we did not think that an exploration of this distinction would be of much interest to body builders and athletes.

ISSUE #13 PAGE 3
STIMULATION OF THE IMMUNE SYSTEM AND OF HEALING BY ARGININE
We have previously written about immune system stimulation and increased healing rate in experimental animals and humans with oral arginine supplements. Now a new clinical study reports the benefits of large (25 g) supplements of arginine in a liquid diet for postoperative recovery of major abdominal surgery for cancer.

The purpose of the study was to try to reduce the immunosuppression and catabolic response (loss of lean body tissue) that normally occurs after such a trauma. Glycine (43 g/day) was administered to other patients (who did not receive arginine) as a test of its possible utility. Although many animal studies have demonstrated the efficacy of arginine, relatively few human studies had been done. Barbul, in his excellent review, reports some of these. (For example, Dr. Barbul administered oral arginine hydrochloride (30 g/day) for one week and noted a significant increase in peripheral blood mean lymphocyte blastogenic response to con A and PHA, measures of immune system activity.)

The mean total daily caloric intake in this experiment was not significantly different between the arginine and glycine supplemented groups. However, daily nitrogen balance became positive after day 5 in the arginine group (indicating that lean body tissue was being built up faster than it was being broken down), whereas it remained negative in the glycine group throughout the seven day study period. There were increases in immune system T-lymphocyte activation in the arginine group and a slight increase in the glycine group, the difference between the two groups being significant. Only the arginine group had an increase in the CD4 (T helper cell) activity. (T helper cells are needed to help your immune system recognize and react to infections and cancer cells. AIDS patients fall prey to many infections because the AIDS virus kills the T helper cells.) Growth hormone increased in both groups, but somatomedin C (which mediates the effects of growth hormone) was significantly increased only in the arginine group on day 7.

Daly, et al, “Immune and Metabolic Effects of Arginine in the Surgical Patient,” Ann. Surg. Vol. 208(4), pp. 512 523 (1988)

ISSUE #23 PAGE 93
ARGININE-DERIVED NITRIC OXIDE AND ITS EFFECTS
An entirely new and important effect of the amino acid arginine has recently been discovered.

In 1987, scientists suggested that endothelium-derived relaxing factor (EDRF), a substance with important functions in the vascular (circulatory) system, such as blood pressure regulation, was nitric oxide, a gas. Now, a mere two years later, a lot more is known about nitric oxide, with evidence indicating that it is about nitric oxide, with evidence indicating that it is EDRF and that it is derived from the amino acid L-arginine. A two-day symposium was just held at the Royal Society in London entitled “Nitric Oxide from L-Arginine.”

Nitric oxide (NO) has now been found to also participate in regulation of the nervous and immune systems and is produced from arginine by the liver, adrenal, and kidney. The biological roles include control of vascular resistance and of platelet function. NO can mediate a profound vasorelaxation (reducing blood pressure) and inhibit both platelet adhesion (stickiness) and aggregation (clumping) which can lead to coronary thrombosis heart attacks and occlusive strokes. It has been hypothesized that some cardiovascular disease patients do not manufacture adequate amounts of NO. A lack of NO may play a role in vasospasm, which can lead to hypoxic tissue damage, just as occurs in a coronary or an occlusive stoke. Basal NO release is central to control of blood pressure and flow. High doses of an analog-antagonist of arginine called L-NMMA causes acute hypertension which is rapidly reversed by intravenous L-arginine. Endothelium derived relaxation is impaired by atherosclerosis and inhibited by LDL. LDL, when oxidized, is an even more effective inhibitor, which depresses NO production by endothelial cells. We would like to see a double-blind placebo controlled trial of arginine and antioxidant nutrient supplements for the control of hypertension and to inhibit abnormal clot formation.

Macrophage mediated killing of tumor cells and of some bacteria seems to involve NO. Some of the effects of L-arginine on immune functions, including increased thymic lymphopoiesis (increased T-cell production), stimulation of lymphocyte proliferation, interleukin production, promotion of tumor and graft refection and of wound healing, may involve NO derived from the arginine. Both animal experiments and double-blind placebo controlled trials in humans have shown that arginine supplements are immunostimulants and wound healing accelerators.

Griffith, Randall, “Nitric Oxide Comes of Age,” The Lancet pp. 875-876, Oct. 7, 1989
Palmer, Ashton, Moncada, Nature 333: 664-666 (1988)
Feigl, “EDRF – A Protective Factor?” letter to Nature 331: 11 Feb. 1988
Jacobs, “L-Arginine is Endogenous Source Of NO,” Trends in Pharmacological Sciences, Sept. 1988
Collier and Vallance, “Second Messenger Role for NO Widens to Nervous and Immune Systems,” Trends in Pharmacological Sciences, Nov. 1989

ISSUE, #26 PAGE 13
L-ARGININE REDUCES BLOOD PRESSURE IN HUMANS
In issue #23 [above] we wrote about a newly-discovered natural function of arginine: it serves as the precursor to NO, nitric oxide, a gas which is now believed to be endothelium-derived relaxing factor (EDRF) that powerfully relaxes blood vessels. Doctors at the Keio University School of Medicine in Tokyo recently tested the effects on human blood pressure of an infusion of L-arginine. They administered a dose of 500 mg/kg over 30 minutes (that is quite a lot, for example, the dose would be 35 grams for a 154 pound man) to five healthy men aged 24 to 37 and to five patients (four male) with essential hypertension aged 30 to 65. The antihypertensive drugs the latter patients were taking were withdrawn 4-7 days before the experiment.

The infusion caused rapid onset of hypotension in both groups, reducing both systolic and diastolic blood pressure. Blood pressure returned to baseline levels by 20 minutes following the infusion. The researchers thought the effects were probably caused by EDRF induced vasodilation.

In animal studies, L-arginine alone has not caused hypotension, although it has reversed the pressure (blood pressure increasing) effects of NG-monomethyl-L-arginine, a competitive inhibitor of EDRF synthetase (the enzyme that converts L-arginine to NO).

We would like to see a double-blind placebo controlled study of 12-18 grams of oral L-arginine (a common growth hormone releaser dose) on blood pressure. A lower dose taken orally would deliver less L-arginine than would be delivered over a longer period of time.

Nakaki, et al, “L-Arginine-Induced Hypotension,” The Lancet pg. 696, Sep. 15, 1990

ISSUE #26 PAGE 12
ARGININE AND SEX
We have found some very interesting information on arginine that suggests a mechanism for sexual enhancement (our own observations and those of others) reported anecdotally by both men and women using an arginine formulation.

On pp. 93-94 of issue #23, we discussed endothelium-derived relaxing factor (EDRF), a substance that relaxes blood vessels, and, thus, is important in the regulation of blood pressure (it has other functions, too, such as inhibiting platelet adhesion and aggregation which can lead to blood clots, occlusive strokes, and coronary thrombosis). It was recently discovered that EDRF is NO, nitric oxide, a gas, and that NO is produced from arginine by the liver, adrenal, and kidney.

Penile erection results when smooth muscle of the corpus cavernosum relaxes, which is followed by venous occlusion and engorgement of the corporal sinusoids (cavities) with blood. Four scientists now report that stimulation-induced relaxation of corporal smooth muscle is markedly inhibited by an inhibitor (NG-nitro-L-arginine) of the biosynthesis of NO from arginine, as well as by other agents that interfere with the biological actions of NO. Thus, penile erection may be mediated by NO. The chart included with their report shows that addition of L-arginine to rabbit corpus cavernosum preparations containing NG-nitro-L-arginine alone.

We have also had reports of increases in libido in women who take arginine. Although women do not have penile erection during sex, there is blood engorgement of homologous tissues: perhaps this is mediated by NO.

Ignarro, Bush, Buga, Rajfer, Nature (scientific correspondence), pp. 131-132 (13 Sept. 1990)

ISSUE #22 PAGE 84
POSSIBLE IMPROVED FERTILITY WITH ARGININE
Arginine Supplements Increase Sperm Count and Sperm Motility in Men With Low Sperm Counts/Motility

L-arginine enhanced sperm motility in vitro, with response to arginine following a dose-response curve (more L-arginine causing greater motility). Other substances tested that did not enhance sperm motility included L-ornithine, d-arginine, L-lysine, and the arginine analogs L-homoarginine and L-nitroarginine.

A daily dose of 4 grams of L-arginine was used to treat 178 men with sterility because of oligospermia (low sperm count). Sperm count increased by 100% in 42 cases (23.6%) and 15 pregnancies occurred soon after in this group. In 69 patients (38.7%), there was a marked increase in the number and motility of sperm and 13 pregnancies resulted. In 21 cases (12.3%) a moderate increase occurred in sperm count (but it was still classified as oligospermic) and in half sperm motility improved. In 46 patients (25.4%), there was no improvement in either sperm count or motility: these patients had severe oligospermia. The authors note that in some studies arginine treatment of oligospermic patients was unsuccessful probably, they propose, because of insufficient doses (1 to 2 grams daily). Other studies they cite reported significant improvement in more than 30% of patients given larger doses (10 to 20 grams daily).

Schachter, Goldman, Zukerman, “Treatment of Oligospermia with the Amino Acid Arginine,” The Journal of Urology 110:311 (1973)

Re-post permission Durk Pearson and Sandy Shaw to Life Priority Inc.

Live Long and Prosper – Durk Pearson and Sandy Shaw

 

Life Priority, established in 1994, offers supplements that are scientifically-formulated, results-oriented, and GRAS (Generally Recognized As Safe) and are manufactured at USDA and FDA inspected facilities.
*The products and statements made about specific products on this web site have not been evaluated by the United States Food and Drug Administration (FDA) and are not intended to diagnose, treat, cure or prevent disease. All information provided on this web site or any information contained on or in any product label or packaging is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should not use the information on this web site for diagnosis or treatment of any health problem. Always consult with a healthcare professional before starting any new vitamins, supplements, diet, or exercise program, before taking any medication, or if you have or suspect you might have a health problem.
*Any testimonials on this web site are based on individual results and do not constitute a guarantee that you will achieve the same results.

 

Effects of Exercise and Supplementation on Mood

Guest blog from Nicole May, Personal Trainer

I remember reading a story a few years ago about a depressed housewife who, at age 44 and 100 pounds overweight, knew that she needed to change her life. She first went to her doctor, who prescribed an antidepressant, but she thought there had to be a more natural way.
She knew she did not have a “Prozac deficiency,” but more of an exercise and whole food deficiency. She threw the prescription in the trash, started walking on her treadmill, eventually started running on her treadmill and never looked back. She also changed her diet to a more clean, whole, unprocessed diet and started taking some supplements. She is cured of her depression and obesity, and is now in her late 50s. She is a fitness model, who has won several competitions; she is also an author of several books, owns a publishing company and conducts speaking engagements all over the world.
This story always inspires me because it is an example of how our society today is over-medicated, and under-active, and under-nourished. It also shows that no matter our age or our fitness level, we can make small changes. I had seen years ago with my clients, their changes in attitude when they would exercise. Some of them could only walk for a few minutes outside due to health issues, but would tell me that their attitudes would change just from a short walk!
Studies have shown time and again that exercise increases endorphins, improves sleep, increases nerve cells, and keeps our minds sharp. I have also had periods of time over my career in which I am not able to exercise due to injuries and I notice a difference in mood and attitude when I am not able to work out.
Another important factor for overall attitude and health is supplementation. I have experienced in my life, and seen in others the effects of supplements on quality of life. Supplements that I have used and love:
Omega-3 Priority
Researchers say the results suggest diets lacking in omega-3 fatty acids may cause the brain to age faster. “People with lower blood levels of omega-3 fatty acids had lower brain volumes that were equivalent to about two years of structural brain aging,” says researcher Zaldy S. Tan, MD, MPH, of the Easton Center for Alzheimer’s Disease Research and the Division of Geriatrics at the University of California, Los Angeles.
Lift, Mind and Muscle Memory
The B complex and L-Phenylalanine in Lift, the Choline in Mind, and the L-Arginine in Muscle Memory helps keep me motivated and focused to not only exercise but in all activities in my everyday life. They also help my muscles recover so I am able to exercise almost every day and keep my attitude and mood uplifted!
Joint Decision
The Glucosamine found in Joint Decision is thought to help the body sustain ligaments, tendons and cartilage. I can say that with my “Retired Gymnast Body” my knees had gotten very sore as I got older, however I have been taking Joint Decision and can say for a fact that my knees are now virtually PAIN FREE!!
Life Priority, established in 1994, offers supplements that are scientifically-formulated, results-oriented, and GRAS (Generally Recognized As Safe) and are manufactured at USDA and FDA inspected facilities.
*The products and statements made about specific products on this web site have not been evaluated by the United States Food and Drug Administration (FDA) and are not intended to diagnose, treat, cure or prevent disease. All information provided on this web site or any information contained on or in any product label or packaging is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should not use the information on this web site for diagnosis or treatment of any health problem. Always consult with a healthcare professional before starting any new vitamins, supplements, diet, or exercise program, before taking any medication, or if you have or suspect you might have a health problem.
*Any testimonials on this web site are based on individual results and do not constitute a guarantee that you will achieve the same results.

Arginine and Muscle Memory- The “Fountain of Youth?” (Interview with Life Extension Scientists: Durk Pearson & Sandy Shaw)

Life Priority Presents— Durk Pearson and Sandy Shaw’s   MUSCLE MEMORY

Dear Customer:

One of the most valuable products offered by Life   Priority, Muscle Memory, has been described as “Youth in a Bottle”   by the formulators, Durk Pearson and Sandy Shaw. When you use it consistently   before workouts or at bedtime (on an empty stomach), you will experience why   this could be your personal fountain of youth.

The enclosed interview will describe the value of using   Muscle Memory. In 1991, I began using this formula to increase my strength   and endurance, speed up my recovery time, and have less soreness after   exercise. The use of Muscle Memory allows you to get the most from your   exercise.

For optimum results, use 1-3 servings of Muscle Memory 1   hour before exercise on an empty stomach (avoid eating protein 2-3 hours   before work outs) or 1 hour before bedtime. Read label instructions before   using Muscle Memory.

Here’s to the Retention of the Youth that is still in   you!

Greg Pryor, President Life Priority

____________________________________________________________________

Interview on Muscle Memory with scientists   Durk Pearson and Sandy Shaw–

Greg: Durk and Sandy, our customers   want to know about the Muscle Memory. Would you explain the formula to our customers   and the reasons why you created it? What is growth hormone and how important   is it to keep our bodies supplied with nutrients that increase the release of   gro

wth hormone?

Durk: Sure Greg, our interest in growth   hormone and it’s history goes back a long, long way, to the early ’70s, when   we realized that not everything associated with aging was necessarily caused   by free radicals and that corrective treatments could go beyond controlling   free radicals. Sandy and I became concerned about changes in the neuroendocrine   system that occurred with aging. For example, as a woman gets older, one of   the obvious changes is menopause. In males, there is a reduction in   testosterone. Some of these changes are in response to internal   “clocks”; others may be due to random damage, possibly related to   free radicals, possibly related to something else, such as receptor loss or   down-regulation. One of the most striking changes we noticed was the loss of   immune system function with age. A person at age 70 is lucky to have 20% of   their T-cell function left compared with when they were a young adult. That’s   why pneumonia used to be called “the old man’s friend.” That is,   pneumonia would kill you over a period of a few days; whereas something like   cancer would kill you over a period of a year, much more miserably.

Sandy: A case of viral pneumonia might   not even stop an otherwise healthy young person from going to work- just make   them miserable for a while- and certainly would never put them in the   hospital. The same virus could easily kill somebody in their 70’s.

Durk: We also noted that as you get   older you start putting on more and more body fat and it becomes harder and   harder to put on lean body mass. A potentially disastrous occurrence is the   fact that it takes longer and longer for wounds to heal. A wound that would   have healed in 5 weeks when you were in your teens or early 20’s might not   heal for 5 months when you’re in your 70’s.

Sandy: What we figured out is that all of   these changes were consistent with a reduction in the release of human growth   hormone.

Durk: Growth hormone (GH) doesn’t make   a person grow any taller after they’ve gone through puberty. You just don’t   grow any taller after that. However, during our mid-20’s to 30 or so, there’s   a big drop in GH output. And that’s when a person begins to find it much more   difficult to put on lean body mass by exercising. For example, if a person in   their teens or early 20’s does heavy exercise, they will release a relatively   large amount of GH from their pituitary. Or if they’re injured, they’ll also   release GH. By the time they’re in their 40’s, it takes a heck of an injury   to get a good GH release, and exercise will rarely do it anymore.

Sandy: It is possible to improve the   response of the GH-releasing system through the use of nutrients, and that’s   something that we became interested in during the 1970’s.

Durk: About 1976 we came to the   conclusion that it was quite possible that a reduction in GH was responsible   for many of the problems of aging, and we got a private grant to do   literature research on this. In fact, the private granting foundation asked   the person who won the Nobel Prize for sequencing human growth hormone   whether he thought our idea had any merit. He said, “Yes, this sounds   interesting. Let’s hope they follow up on it.”

So, as we proceeded to read more about   it, the more interesting it looked. Our thoughts turned to how you get GH   released, because actual human GH was very difficult to come by. Since then,   recombinant human GH has made the hormone much more available, although it’s   still very expensive.

Sandy: So what we did then was to look for   various substances that would cause release of endogenous GH, and we found   out that there were quite a few. For example, some of the opiates will do it,   but for obvious reasons that wasn’t really a suitable source.

Durk: We found out that there were   certain drugs that would do it, for example, L-dopa. But it’s highly   experimental for those who don’t have Parkinson’s disease to take L-dopa   every day for the rest of their lives. What we finally found is that amino   acids release GH, and some do it much better than others. In particular,   different amino acids had different ratios of insulin release to GH release.   Our goal was to find one that would maximize GH release and minimize insulin   release. Arginine and ornithine both fit that criterion.

We decided to use arginine for two   reasons. (Although ornithine was twice as powerful as arginine on a   gram-for-gram basis, it costs twice as much.) The first reason was that you   have a minute amount of ornithine in your diet, whereas you have substantial   amounts of arginine.

Sandy: Ornithine isn’t used to make   proteins.

Durk: You make proteins that contain   arginine. And as a result, we thought the choice of arginine would be more   conservative with respect to what human metabolism is adapted to. Also, we   found out that 20 grams of arginine is normally used intravenously as a   provocative test for GH release to see if a person’s pituitary is responding   normally. We wanted to find out whether oral doses were also capable of doing   that.

It turned out that oral arginine was   particularly effective at releasing GH when you add a couple of additional   factors to it, choline and vitamin B5 (pantothenate). That’s because GH   release involves the cholinergic nervous system.

Arginine along with choline and B5   works just fine when taken orally as long as you don’t have a lot of other   proteins in your stomach breaking down into amino acids that compete with   arginine’s entry into the brain. It worked even better than we had expected.

Sandy was the first experimental subject   matter for this treatment. We were at a Gordon research conference on the   biology of aging back in 1979. And Sandy   jumped up to try to get something off a shelf in our room, and when she came   back down she didn’t come down on her foot straight and there was this   horrible cracking sound.

Sandy: I noticed that my foot was swelling   up, and it was very tender and I couldn’t walk on it very well. I had to   hobble around.

Durk: In fact, it was Dr. Denham   Harman, the father of the free-radical theory of aging, who diagnosed her as   having a probable broken foot and suggested she get it X-rayed.

Sandy: Which I did, and it was broken. We   were aware of studies on animals with broken bones that healed faster with an   arginine supplement. And so we thought, “Well, we’ve done enough   literature search on this; time to start taking it.” The arginine growth   hormone release should help to speed up the healing.

Durk: Because she wasn’t moving around   nearly as much, she thought she ought to do some exercise, so she did some   bench presses lying on her back, which didn’t put any load on her foot. I   knew how much weight she was lifting, and I measured how far she lifted it   and counted the number of times she did it- she spent about 3 minutes a day   on it- and, by golly, in 5 weeks she lost about 20 pounds of fat and put on   about 5 pounds of lean body mass. Arnold Schwarzenegger in “The   Education of a Bodybuilder” said it would be difficult for a dedicated   male bodybuilder to accomplish that much gain in a year.

Also, the foot seemed to be completely   healed up a lot sooner than we expected. The doctor said it would be 2 or 3   months before she was really able to walk around on it. Yet in 5 weeks she   felt fine, had it X-rayed, and it was okay. I mean, it wasn’t broken anymore;   not only that, in the X-ray it didn’t look like it had ever been broken.

Another very interesting story involves   a friend of ours, a plump, sedentary, gourmet, 72 years old, who fell down on   an icy sidewalk several years ago and broke his arm. This guy is very   sedentary. His idea of exercise is taking the elevator from his condominium   down to the underground parking garage, underneath his law office and taking   the elevator up to his office.

His doctor told him that in about 5   months he would probably have to do bone grafts because he didn’t think it   would heal, given our friend’s age and condition. Well, our friend called us   up and said “Didn’t you once tell me something about accelerated wound   healing?” He asked the doctor about that and the doctor was very   dogmatic. “No, it’s not possible to speed up wound healing, there’s   nothing that can be done about it.” So he called us back and we told him   about Muscle Memory our formulation of arginine, choline, and B5, and sent   him some samples. He started taking three servings when he went to bed at   night. Five weeks later he felt so good, he went back to the doctor and said,   “I want you to take the cast off.” The doctor got a real snicker out   of that.

Sandy: He thought it was simply ridiculous.   But the patient asked for it, so he took another X-ray.

Durk: The doctor was absolutely   dumbfounded when he looked at the X-ray. It looked as though the bone had   never been broken, there was not shadow on it indicating a fracture and the   bone was a full density.

If a 12 year-old breaks an arm, you can   take the cast off at 5 weeks. But if you X-ray it, the bone is not going to   be at full density. Here, you have a guy who’s 72 years old with full density   at 5 weeks! In fact, the doctor said that if he hadn’t personally taken the   original X-ray, personally taken the second X-ray, and personally set that   arm and put it in a cast, he’d call it some type of insurance scam, because   what he saw was “completely impossible.”

We’ve heard of this sort of thing   happening to a lot of people using our arginine, choline and B5 combination,   like bodybuilders and Olympic athletes and so forth, who have also found out   how useful this is. It really helps a lot in maintaining the ability to gain   strength from peak output exercise. It also seems to help improve skin   elasticity. A lot of people who’ve been taking it for a year or so notice   that their skin, particularly on their face and neck, stays nice and tight.   And that’s because GH causes the liver to release IGF-1, which in turn   up-regulates production of elastin in the skin and also, I might add, in the   arteries. Elastin’s the molecule that makes tissue all nice and springy and   elastic. Anybody who has seen the skin pinch test done on the back of my own   hands can see that it’s really much more elastic than you would expect for   someone who’s 54 years old. We’ve been taking this formulation since 1979 now   -18 years – which is a pretty significant fraction of our adult lifetimes.

Durk: Remember, there are various   things that can limit your life span and also your quality of life. One thing   is simply muscular strength. A lot of elderly people end up falling down,   breaking their hips and then dying within the next year, because they never   really recover. Such falls have been traced in some cases to the loss of   equilibrium due to damage to the inner ear. But in most cases it’s thought to   be due to lack of muscular strength. A person who stumbles can usually right   himself but if you don’t have enough muscular strength, down you go. This   seems to be a major problem. The average woman over 65, I believe, cannot   lift 10 pounds.

Sandy: That’s right. It’s pretty shocking.

Durk: When you consider that a gallon   just of milk weighs about 9 pounds, you realize what a big limitation that   is. Another thing GH does is help maintain the function of T-cells in the   immune system. The heart of that is the thymus, where T-cells are produced,   selected, and educated or programmed. Maintaining GH levels can help retain   thymus function and thymus mass.

Maintaining elasticity goes beyond the   production of elastin. One very important thing about arginine is that it is   a very powerful sacrificial target for cross-linkers. If nothing else gets   you, you’re going to end up having to go on kidney dialysis at the age of 90   or 100 or 120, because, throughout your lifetime, cross-linking reactions are   taking place in the collagen in the basement membrane of your kidneys.

Sandy: As a result of glycosylation, this   causes the kidney’s basement membranes to thicken throughout life, and   eventually it becomes thick enough that it is not filtering the serum well at   all. In people who have diabetes, the process is accelerated. Diabetics   usually die of kidney failure. There was a very exciting study in diabetic   mice that were given arginine to what would be – scaled up to a human dose –   about 3 gm of arginine a day. They found that the mice that received the   arginine had normal kidneys when they became old as compared with controls.   The diabetic mice that did not receive arginine were dying of kidney failure.   They had thickened basement membranes in their kidneys.

Durk: In fact, what they found was that   there was no increase in thickness after about 6 months in the basement   membranes of those mice that got the arginine. It entirely abolished that   age-related increase in basement membrane thickness and cross-linkage.

Sandy: It’s interesting to note, too, that   the tests also have a basement membrane that thickens throughout life.

Durk: In some cases GH can block the   effects of insulin. And a person who has type II diabetes is already insulin   resistant. You don’t want to make them anymore insulin resistant. In fact, we   have found that in a small percentage of type II diabetics, the blood sugar   will go sky high if they take Muscle Memory. With most others, that doesn’t   happen. In fact, gradually increasing the doses of Muscle Memory may result   in an increased insulin sensitivity and a decrease in blood sugar levels.   However, this is something that has to be done under a doctor’s supervision,   where they’re actually measuring your blood sugar response as you go from   perhaps half of one serving of the nutrients to start and gradually work your   way up.

Sandy: That’s why we recommend on the label   that diabetics not use the product.

Durk: Let me also mention another   precaution: Arginine can increase the rate of growth of all tissues and that   includes, potentially, cancerous tissues. If cancer already exists, it might   accelerate its growth.

Sandy: I was reading in one paper about   breast cancer and GH. The authors found an improvement in the immune response   to the tumor in those patients taking GH, but, at the same time, the tumor   was getting assistance in growing, because growth factors – any growth   factors – do exactly that: improve growth.

Durk: Right. If a person has cancer,   they do not want to take this. If they’ve had cancer, and their doctor says,   “We got it all, there’s none left,” then there’s no reason that   they shouldn’t be able to take it.

Sandy: But caution is always the byword. I   think that by now your customers know that the two of us are extremely   conservative. We try to take as few risks as we possibly can and hope that   will contribute to our being able to live a very long time.

Durk: Another interesting thing I’ve   discovered: I’m pretty doggone sedentary; I spend most of my time lying on my   waterbed or a lounge chair reading scientific journals. But sometimes I go   out and do some very vigorous things like digging post holes or carting   concrete sacks around or branding cattle or digging out a hot spring. Believe   me, shoveling mud is a very, very backbreaking task. I find that if I don’t   take Muscle Memory before I do that, I will have aches and pains starting the   next day that’ll be really bad and will last several days.

Sandy: How achy were you after the cattle   branding?

Durk: Not at all because I was sopping   up Muscle Memory all day; over the day I took about three servings of Muscle   Memory spread out over the day. I just mixed it up in a drink and put it in   the cooler.

Durk: For GH release, you need to take   it all at once: two servings for a woman or three for a man, preferably at   bedtime, because about an hour and a half after you go to sleep is your   biggest GH release if you’re past, say, your mid 20’s. Or, alternatively,   about 3/4 of an hour before you engage in heavy peak-output exercise. But in   the cases of branding or digging out a hot spring, I’m usually at it all day   long. So I take about three servings, put it in some ice water, and stick it   in the cooler. I usually mix it with a couple of servings of Lift as well. I   just drink that throughout the day. No aches and pains that day. No aches and   pains the next day or the day after.

Durk: Basically what you want is to   mimic, as far as possible, the natural pulsatile release. What you don’t want   to do is to have elevated levels of GH all the time.

Sandy: Which is what you get with GH   infusions or even subcutaneous injections of GH that they’re giving elderly   people. These are not like the physiological releases of growth hormone.

Durk: GH is supposed to be released in   pulses, like insulin, and a continuous high level results in a resistance to   GH and all sorts of problems downstream from that. Now when you’re sipping   three servings over a period of maybe 6 hours of heavy work throughout the   day, you’re not going to get any GH release effect, but you will get the   beneficial effects of the arginine-derived nitric oxide.

Sandy: There have been a number of studies   of arginine with respect to atherosclerosis, particularly in animal models   like rabbits. The first sign you see before you see any fatty streaks or any   other visible evidence of atherosclerosis is that the arteries fail to dilate   in response to acetylcholine. That can be reversed by infusing arginine.

Durk: Instantly reversed! Twenty   seconds after you bathe the rabbits artery with the arginine, you’ve reversed   that resistance and normalized the response of the arteries so they dilate.

We know of one case where that happened   in a human. Our 72-year-old friend, after his arm healed up so fast, called   up and said, “Would it hurt me to continue taking this stuff? It really   makes me feel good, and it sure healed me up. I think this is doing a lot of good   for me.” He wasn’t a diabetic, so we said, “Well, we’ve been taking   it for 10 years now, go right ahead and do it.”

Sandy: So he started doing that. About a   year and a half later, he had a fast-synchronized MRI scan of his brain,   which gives very fine pictures of the cerebral arteries. He said that the   doctor that did this, a different doctor from the one who fixed his arm, was   absolutely astounded because, of his three major cerebral arteries, two of   them were completely clear, and one of them had about a 20% obstruction,   which is about the bottom end of the ability of this technique to measure at   that time. The doctor asked him what sort of diet he was on – was he a   vegetarian? Was he on a Pritikin diet, or what? And he said, “Well, my   diet was bacon and eggs every breakfast.” And that’s just about true;   those are the sort of things he eats. He’d be better off if he ate a lot more   veggies, but that isn’t what he eats.

Sandy: We don’t know what his arteries   looked like before he started using the arginine supplement, but the end   result is certainly consistent with what the experimental studies have shown   with arginine.

Arginine has also been studied for its   effects on blood pressure. Part of the blood pressure regulation process is   the arteries being able to dilate under the control of the cholinergic   nervous system.

Durk: And this is mediated by nitric   oxide. The scientist who figured that out won the Nobel Prize for it.

Sandy: A lot of people who have high blood   pressure, especially associated with atherosclerosis, have a failure of their   nitric oxide artery dilation system, and arginine often can help reverse   that.

Durk: We’ve been told that, under a   physician’s supervision, some people have been able to reduce their doses of   anti-hypertensive medication by taking Muscle Memory throughout the day. Some   people have even been able to discontinue the drugs entirely, particularly if   they add potassium and magnesium along with an arginine, choline and B5   supplement throughout the day. But this should be done only under a   physician’s supervision.

Sandy: One other thing to keep in mind is   that using nutrients to get GH release is a very different thing from using   the hormone itself, from the point of view of the feedback controls that   regulate the release of hormones in the pituitary and elsewhere. When you   take growth hormone itself, you bypass the normal regulatory features that   control when the hormone is released and how much is released. You put GH in   there, and you just override those controls. When you take arginine and   choline and B5, you still have all of those regulatory mechanisms in place to   control how much is released and when its released.

Durk: Another thing that we definitely   don’t want to forget is that the mechanism that causes erections in male   mammals is, in fact, nitric oxide. That’s what causes the vasodilation that   results in the corpus cavernosa engorgement with blood producing an erection.   If you take Muscle Memory 30-45 minutes before sex, you’re likely to notice   the difference. There’s similar erectile tissue in women inside the lining of   the vagina.

Sandy: Just like the arteries that we talked   about earlier in the development of artherosclerosis, the cholinergic   mechanisms are also involved in the dilation of the blood vessels to the penis.

Durk: I’m not at all surprised that   occurs.

Durk: I think that Muscle Memory does a   lot to make your neuroendocrine system look younger. In fact, the mixture was   used in a double-blind, placebo-controlled study at a private fertility   clinic. They took women who were not ovulating and put them on pergodile,   which is a dopaminergic agonist, FDA-approved for fertility purposes (as well   as for treating Parkinson’s patients). Most of them ovulated after they’d   been on Pergodile for a while. The ones that had failed to ovulate after 6   months were put on two servings of the arginine-choline-B5 mixture at bedtime   every night in addition to Pergodile.

The doctor said that the results were   absolutely amazing: 80% of the women ovulated within days of going on the   mixture. He said it was like turning on a light switch. I might add that one   woman was about 1 and a half years postmenopausal; another one was about 2   and a half years postmenopausal. So, in a lot of ways, Muscle Memory makes   your endocrine system look like that of a younger person.

Durk: Yes, in fact, it can. We reported   that over a decade ago in one of our Life Extension books. A few hundred   milligrams of buffered niacin can indeed do that; that’s what I take at   bedtime along with my Muscle Memory. About 200 mg of niacin will give you   double or triple the GH level compared with backgrounds. This is significant,   but it’s nowhere near as big a pulse as you would likely get with the   arginine-choline-B5 in Muscle Memory.

Durk: You would typically get one   several times as big as with the niacin alone.

Durk: I use it myself whenever I have   to learn some sort of new motor type-task. Also, we have had some interesting   comments from various people. We know a retired professional golfer in his   sixties who, over a period of about 5 weeks, took five strokes off his game.   Normally at his age – he’d been playing at least a few times a week for 20   years – you’re not going to get better; you’re just going to get worse with   the passage of time. And that’s what he said; his game had gradually been   getting worse over the years. Taking five strokes off in 5 weeks is not   something that normally happens. But it’s been found that nitric oxide   release is absolutely essential for motor learning in the cerebellum, and it   also appears to be necessary for long-term potentiation in the brain, which   is the mechanism that’s involved in long-term memory. And I think that   explains his success.

Durk: When you go over it all, it   really sounds like too much of a panacea to be real. As the years have gone   on we’ve found more and more delightful things about arginine.

Durk: I’ll tell you this; if you’re   full of anabolic steroids to the point where you’ve down-regulated your   anabolic steroid receptors, the dietary supplement might conceivably not   work. Another possibility is that people who abuse GH by injecting it,   subcutaneously or intramuscularly, are definitely going to develop resistance   to it because it’s not being given in the pulsatile manner. Moreover the   doses of many GH releasers are inadequate, and most formulations lack   adequate choline and B5.

Sandy: Another thing is that, people who are   restricting their calorie intake significantly are going to be less likely to   release growth hormone because, under the conditions of fasting or caloric   restriction, animals go into a state where they do not grow. They reserve the   energy that they’re getting for more important things, like maintenance.   Growth is not a priority when you’re getting a restricted amount of energy   intake. So, for people who are on a diet that’s low enough, they may not get   a growth hormone release.

Durk: Also, if a person takes a big   slug of protein supplement, like 50 gm of protein, along with their Muscle   Memory, not much of that arginine is going to get to the brain compared with   taking it on an empty stomach. I’m afraid that a lot of body-builders may be   taking a protein supplement along with Muscle Memory before exercising. What   they should do is take the Muscle Memory before the exercise and take the   protein afterwards.

Muscle MemoryTM was designed by Life Extension scientists Durk Pearson   & Sandy Shaw for their own use.

Durk Pearson and Sandy Shaw were among the first scientists, beginning more   that 15 years ago, to recommend that people take arginine supplements
(along with choline and B-5) to boost their natural GH release and thereby   achieve a variety of life-extending benefits, including building lean muscle   mass
(in preference to fat), accelerating wound healing, strengthening bones,   improving immunity, and enhancing skin flexibility.

Muscle MemoryTM has been a Life Priority classic since 1994, for more   than a decade for:

  • People who recognize that the ingredients in        Muscle MemoryTM help accelerate physical fitness.
  • Those interested in the role of nutrition in        biological aging.       Muscle MemoryTM helps trigger your own internal biochemical        resources of mental and physical power for enhanced vitality and        youthfulness.
  • Store in a cool, dry, dark place.

SUGGESTED USE: Read the directions on the bottle   before consuming.
Use 1-3 tablespoons 45 minutes before work-outs (on an empty   stomach) or take 1-3 tablespoons of 1 hour before bedtime.

Order Muscle MemoryTM now!

 

www.lifepriority.com.

© Copyright LIFE PRIORITY

Life Priority, established in 1994, offers supplements that are scientifically-formulated, results-oriented, and GRAS (Generally Recognized As Safe) and are manufactured at USDA and FDA inspected facilities.
*The products and statements made about specific products on this web site have not been evaluated by the United States Food and Drug Administration (FDA) and are not intended to diagnose, treat, cure or prevent disease. All information provided on this web site or any information contained on or in any product label or packaging is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should not use the information on this web site for diagnosis or treatment of any health problem. Always consult with a healthcare professional before starting any new vitamins, supplements, diet, or exercise program, before taking any medication, or if you have or suspect you might have a health problem.
*Any testimonials on this web site are based on individual results and do not constitute a guarantee that you will achieve the same results.

In the News: Women’s Dementia Worsens Faster Than Men’s

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 18 No. 4 • August 2015

In the News: Women’s Dementia Worsens Faster Than Men’s

So says a headline in the July 22, 2015 The Wall Street Journal. According to the study (398 subjects who participated in the Alzheimer’s Disease Neuroimaging Initiative), women’s cognitive decline took place about twice as fast as men’s. The good news is that it is very likely, based on scientific studies showing that women need more choline than men do (Fischer, 2007), and that, as choline has been identified as a nutrient important to cognition (Poly, 2011) a deficiency of choline is one cause of this vulnerability to dementia in women. Not only does estrogen play an important role in the cholinergic nervous system (Fischer, 2007, Craig, 2010)—estrogen that declines rapidly following menopause—but it is known that in older people, choline is taken up less effectively into the brain (Cohen, 1995). In addition, women are much more susceptible to autoimmune diseases than men are and the cholinergic nervous system is a major antiinflammatory system (Tracey, 2007).

Add it all up and the evidence points to a need for additional choline in older women. The amount of choline recommended by the Institute of Medicine (IOM) for non-pregnant women, 425 mg a day, is (in our judgment) too low to supply adequate amounts of choline to older women when you consider the reduced ability to transport choline into the brain, the loss of estrogen, and also the variation (dietary composition (van Wijk, 2012), choline consumption, genetic and epigenetic differences in the ability to absorb choline from the diet, get it into the brain, and then convert it to phospatidylcholine via biochemical pathways) between individuals suggests that the amount that may be adequate for much of the population per the IOM recommendation may not be adequate for YOU.

In short, choline is a major nutrient for keeping your cognitive function in good condition as you get older. We ourselves take 2 grams a day of choline in the form of choline dihydrogen citrate.

References

  • Fischer, daCosta, Kwock, et al. Sex and menopausal status influence human dietary requirements for the nutrient choline. Am J Clin Nutr.85(5):1275-85 (2007).
  • Poly, Massaro, Seshadri, 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).
  • Craig, Brammer, Maki, et al. The interactive effect of acute ovarian suppression and the cholinergic system on visuospatial working memory in young women.35:987-1000 (2010).
  • Cohen, Renshaw, Stoll, et al. Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study. 274(11):902-7 (1995).
  • Physiology and immunology of the cholinergic antiinflammatory pathway.J Clin Invest.117(2):289-96 (2007).
  • van Wijk, Watkins, Bohlke, et al. Plasma choline concentration varies with different dietary levels of vitamins B6, B12and folic acid in rats maintained on choline-adequate diets. Br J Nutr. 107:1408-12 (2012).

 

Life Priority, established in 1994, offers supplements that are scientifically-formulated, results-oriented, and GRAS (Generally Recognized As Safe) and are manufactured at USDA and FDA inspected facilities.
*The products and statements made about specific products on this web site have not been evaluated by the United States Food and Drug Administration (FDA) and are not intended to diagnose, treat, cure or prevent disease. All information provided on this web site or any information contained on or in any product label or packaging is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should not use the information on this web site for diagnosis or treatment of any health problem. Always consult with a healthcare professional before starting any new vitamins, supplements, diet, or exercise program, before taking any medication, or if you have or suspect you might have a health problem.
*Any testimonials on this web site are based on individual results and do not constitute a guarantee that you will achieve the same results.

Why the Niacin Flush May Be Surprisingly Beneficial to Your Health – Sandy Shaw

Why the Niacin Flush May
Be Surprisingly
Beneficial to Your Health 

Why We Think It May Reduce the Risk of ALZHEIMER’S
DISEASE and Other Inflammatory Diseases,
Including Atherosclerosis, Type 2 Diabetes,
Ulcerative Colitis, Even Male Pattern Baldness

Sandy Shaw

WITHOUT PRIOR REVIEW BY DURK

It has not been read or reviewed by Durk Pearson, due to considerations that include, importantly, that time has run out and Shaw insisted on getting the paper into print without waiting. Shaw and Pearson have extensively discussed the elements of the paper so that the word “we” can be understood as the result of these discussions, but not based upon a reading of the Shaw paper by Pearson. Other than this disclaimer, everything remains as it is in the paper, with an expectation that more will be written on this subject to appear in future Durk & Sandy newsletters.

Here we explain why we think that the niacin flush (see description of flush just below this paragraph) may be a key part of the cardioprotective effect of high dose immediate-release (flushing) niacin’s highly protective effects on lipid metabolism, such as potent reductions of LDL and VLDL and triglycerides, while increasing HDL and, moreover, why the niacin flush may play an important role in reducing the risk of Alzheimer’s disease, atherosclerosis, type 2 diabetes, and other inflammatory diseases.

NOTE TO OUR READERS: This paper has become both much longer and included much more complex data and mechanistic detail to evaluate than the author (Sandy Shaw) originally anticipated. As a result, we have included in this first section of the paper the basic elements of how we believe the protective mechanism works and data on some diseases that we believe supports that interpretation. The next issue of our newsletter and subsequent issues will include the remaining parts of our analysis, with data from other diseases that we believe also appear to have significant risk reduction by the same mechanism, including detailed analysis of atherosclerosis, type 2 diabetes, and other diseases that show up in our literature searches. Sandy conceived the idea of examining the literature on the subject, read the papers discussed, and analyzed the data presented in the papers. Durk has read the analysis in detail and is in agreement with it.

WHAT IS THE FLUSH? Though we have heard it described as a transient skin reddening (from increased blood flow) accompanied by a sensation of heat associated with itching, we have come to realize that not everybody is feeling the same thing when they say “niacin flush.” The reason is that while both of us find the niacin flush AS WE EXPERIENCE IT to be pleasant, many people find it intolerable. Thus we think that what people who hate the flush mean when they say “niacin flush” is not a pleasant hot with mild itch but a hot with very unpleasant biting and burning sensations (as if being bitten by an insect or stabbed with tiny knives). In studying the mechanisms involved in the niacin flush to the extent they are now understood, we have an idea why many people are having this unpleasant flush. After we have discussed how we understand some of what causes the niacin flush, we will explain what we think may be making it intolerable for many. See below in section on “What Is Intolerable About the Niacin Flush?”

We understand, then, that some people can’t tolerate the niacin flush (caused by acute release of the prostaglandin PGD2) and, as a result, won’t use high dose plain niacin. It may be possible to reduce the flush to a tolerable level and, if so, it might be a much more sensible strategy (so you would end up with a flush like what we experience) than eliminating the flush if you want to get niacin’s lipid-lowering benefits. What has happened to niacin research, however, as a result of this crash program by certain drug companies to get rid of the flush, is that data on plain niacin and the effects of the acute release of prostaglandin D2 (which induces the flush) have to a considerable extent disappeared as more and more research focuses on the “extended release” or other non-flushing versions of niacin, which are not the same as plain niacin. “Extended release” niacin is not the same as plain niacin, for which extensive literature exists showing its potent lipid benefits. You do not see very much in the literature on head to head comparisons of “non-flushing niacin” (ersatz niacin) to plain (flushing) niacin in humans to identify what it is that the flush is doing.

THE KEY TO UNDERSTANDING THE EFFECTS OF THE PGD2-CAUSED NIACIN FLUSH IS TO REALIZE THAT IN ITS ACUTE RELEASE, PGD2 ACTS IN MANY MODEL SYSTEMS AS AN ANTI-INFLAMMATORY. IN ITS CHRONIC RELEASE, PGD2 APPEARS TO BE USUALLY PRO-INFLAMMATORY, but depending on the rate at which PGD2 is released, the amount released, and the state of inflammation in the tissue where it is released, you can get a pro-inflammatory or an anti-inflammatory effect. As the old saying goes, the devil is in the details and it is the rush to avoid considering the details so as to rapidly develop a non-flushing niacin that is leading to the rash abandonment by some drug companies and health practitioners of flushing (immediate-release or plain) niacin.

It has long been known that the prostaglandins PGD2 and PGE2 are responsible for inflammation induction (Haworth, 2007). Later in the biosynthetic pathways of these prostaglandins, anti-inflammatory circuits are induced (Haworth, 2007). Here is where we believe is the source of a major misunderstanding concerning the pro-inflammatory or anti-inflammatory effects of PGD2, the prostaglandin that causes the niacin flush: A CHRONICALLY HIGH LEVEL OF A SIGNALING MOLECULE, SUCH AS PGD2 (generally pro-inflammatory when at a chronically high level) CAN INTERFERE WITH SIGNALS BY ACUTELY RELEASED (PULSATILE) AMOUNTS OF THAT SIGNALING MOLECULE (generally anti-inflammatory) BY THE ACUTE SIGNAL SIMPLY BEING “LOST” IN THE NOISE OF THE CHRONICALLY HIGH LEVEL OF THAT MOLECULE. Hence, we think that chronically high levels of PGD2 are likely to prevent or reduce the effect of acute signals of PGD2 that would otherwise be anti-inflammatory. See sections on Alzheimer’s disease (AD) below, where chronically high PGD2 signaling is thought to be a major cause of the neurodegenerative features characteristic of AD (Maesaka, 2013).

  • Haworth and Buckley. Resolving the problem of persistence in the switch from acute to chronic inflammation. Proc Natl Acad Sci U S A. 104(52):20647-8 (2007).
  • Maesaka, Sodam, Palaia, et al. Prostaglandin D2 synthase: apoptotic factor in Alzheimer plasma, inducer of reactive oxygen species, inflammatory cytokines, and dialysis dementia. J Nephropathol. 2(3):166-80 (2013).

In this section, we look at PGD2 release in model systems:

DATA ON ACUTE AND CHRONIC RELEASE OF PGD2

Prostaglandin D2 in the Resolution of Inflammation
Ulcerative Colitis

There is considerable difficulty in interpreting the huge amount of scientific literature on prostaglandins when you read that a certain tissue level is associated with a certain stage of an inflammatory disease. Most of the literature that we’ve seen is bogged down with difficulties in interpreting the role of the prostaglandin in the inflammatory process because of not knowing whether the tissue level measured is part of a pulsatile release or a chronic release.

A very interesting recent paper (Vong, 2010) was published by scientists who believe that the increased expression of prostaglandin D2 synthesis and its EP1 receptor that they detected in individuals in long-term remission from ulcerative colitis suggest that the release of PGD2 in response to acute releases of inflammatory stimuli could be important antiinflammatory protection to maintain colonic mucosal homeostasis.

To study this phenomenon in human patients, the scientists took rectal biopsies from patients with active ulcerative colitis, which have elevated levels of PGE2, PGI2, and PGF2alpha. “Several studies of experimental colitis suggest important roles for PGD2 in promoting the resolution of inflammation and long-term alterations in colonocyte and barrier function …” They examined PGD2 levels in biopsies for ulcerative colitis patients, comparing them with those of healthy individuals who had no prior history of UC or those from healthy individuals who had experienced a prior bout of UC but had been in remission without medication for >4 years. “We observed a pronounced elevation of PGD2 synthesis and DPI receptor expression only in healthy individuals with a prior history of UC. In these individuals, as has been observed in animal studies, the elevated mucosal PGD2 may contribute to the maintenance of colonic tissue homeostasis and possibly, also to an increased risk of colorectal cancer.”

One difficulty here is that the biopsy represents a snapshot of PGD2 levels at one point. Was the PGD2 being released as an acute pulse at that point or was it being measured at a chronic level? The authors are hot to track down the cause of this association (the apparent anti-inflammatory effect of PGD2 in maintaining remission in UC) and say, “we believe that PGD2 plays an important role in the initial maintenance of mucosal homeostasis.” We might as well add our own hypothesis to the mix. On the basis of other data on anti-inflammatory effects of pulsatile release of PGD2, we would expect the most protective effects of PGD2 release in this model to occur at an optimal level of a pulse of PGD2 released over a limited time period in response to pro-inflammatory stimuli, but not too little to prevent inflammation so as to maintain remission, or too much to increase PGD2 to levels that would potentiate inflammation and, perhaps, be part of an increased risk of colorectal cancer the scientists here mention as a possibility.

For example, the scientists note that their results are “consistent with studies of rodents in which prolonged elevations of PGD2 synthesis were observed after resolution of colitis.” This prolonged elevation contributed not only to resolution of inflammation but also to “long term alterations in epithelial function, some of which may have contributed to an increased susceptibility to colon cancer.” This suggests that the protective response of the immune system in some animals and humans of increasing PGD2 release in response to inflammation to modulate that inflammation may go too far and result in long-term adverse effects such as increased risk of colon cancer. It appears to us that pulsatile PGD2 release a few times a day with immediate release niacin supplementation may offer better protection against a variety of inflammatory diseases.

  • Vong, Ferraz, Panaccione, et al. A pro-resolution mediator, prostaglandin D(2), is specifically up-regulated in individuals in long-term remission from ulcerative colitis. Proc Natl Acad Sci U S A.107(26):12023-7 (2010).

MALE PATTERN BALDNESS (Nieves, 2014)

The hair follicle in male pattern baldness balding areas (but not in normal hair of balding men) have chronically high levels of prostaglandin D2 accompanied by lower levels of prostaglandin E2. One way that minoxidil has been found to work is by increasing prostaglandin E2, which in this model “normalizes” the PGD2/PGE2 ratio. However, PGE2 is an inflammatory molecule, so you wouldn’t want to increase it very much, and that is undoubtedly the “secret” of minoxidil, to NORMALIZE the ratio of PGD2/PGE2 so as to eliminate a chronically high PGD2 level.

One of the signals of the catagen phase of hair growth, where hair growth ceases for a time and some hair follicles die, is the release of very large amounts (7 fold higher than baseline) of PGD2 (Nieves, 2014). For that reason, there is interest in blocking PGD2 as a “treatment” for balding. But once again, there is a risk that blocking PGD2’s unwanted effects will also block important beneficial effects of PGD2. This, not surprisingly, is a major problem in medicine, that the change you want in a certain tissue at a certain time and by a certain amount may cause harm elsewhere where you do not want that change.

  • Nieves and Garza. Does prostaglandin D2 hold the cure to male pattern baldness? Exp Dermatol. 23(4):224-7 (2014).

ANTI-INFLAMMATORY ROLE OF PGD2 IN ACUTE
LUNG INFLAMMATION (Murata, 2012)

The authors of this paper (Murata, 2012) studied the role of PGD2 signaling in acute lung injury (ALI). Administering endotoxin (lipopolysaccharide (LPS), a potent bacterial inflammatory factor) increased edema and neutrophil infiltration into the wild type mouse lung, typical effects seen in inflammation. “Treatment with either an agonist to the PGD2 receptor, DP, or a degradation product of PGD2, 15-deoxy-delta12,14-PGJ2, exerted a therapeutic action against ALI.” The effect of LPS inhalation by the wild type mice peaked on day 1, hence this was an acute effect. The authors found, however, that whether PGD2 had an anti-inflammatory effect or a pro-inflammatory effect depended upon the stage at which the PGD2 was administered, with PGD2 at later stages of ALI being anti-inflammatory (reducing the invasiveness of neutrophils).

  • Murata, Aritake, Tsubosaka, et al. Anti-inflammatory role of PGD2 in acute lung inflammation and therapeutic application of its signal enhancement. Proc Natl Acad Sci. 110(13):5205-10 (2013).

ALZHEIMER’S DISEASE: MICROGLIAL PGE2
(PROSTAGLANDIN E2) SIGNALING VIA EP4
RECEPTOR SUPPRESSES ALZHEIMER
ASSOCIATED INFLAMMATION

A signaling system is reported here (Woodling, 2014) that the authors found to regulate an important protective anti-inflammatory mechanism in the early stages of Alzheimer pathology that decreases significantly (along with its protective effect) as the disease progresses. This is a signal from the prostaglandin PGE2 to its EP4 receptor. See section below on the PGE2 receptor system (EP1, 2, 3, and 4) and new findings suggesting that it is a key to some of the antiinflammatory properties of DHA (docosahexaenoic acid, an omega 3 fatty acid found in fish oils) and possibly that of curcumin.

As reported in a 2012 paper (Ruan, 2012), the EP1 receptor for PGE2 appears to be the key target for DHA and fish oils. There they showed that, in cultured stromal cells, the IC50 for fish oil (that is, the amount that inhibited 50% of the PGE2 activity) was 18 mg/L or 54 μM. The authors calculated that, for a 150 pound human containing 4-5 liters of blood, “consuming 100 mg. fish oil should yield IC50 results.” (This depends, of course, on how the DHA partitions in the blood and tissues, but the calculation provides a crude estimate.) The authors then indicate that they would recommend taking 500-1000 mg fish oil daily on the basis of their findings.

It is interesting to note the opposing effects of PGD2 (the prostaglandin that induces the niacin flush) and PGE2 in the balding model (above), where chronically high PGD2 resulted in suppression of PGE2. A pulsatile release of PGD2 (an ACUTE release) as in the niacin flush would be anti-inflammatory, not pro-inflammatory as with chronically high PGD2. Hence, you could see an INCREASE in PGE2 by suppressing chronically high PGD2. The balding model, in fact, shows hair growth and the cessation of hair follicle death resulting from slight modulation in the ratio of PGD2/PGE2, in which PGE2 is increased, while chronically high PGD2 levels are reduced to “normalize” the ratio. The niacin flush causes pulsatile, not chronic, release of PGD2. It is relevant to note that another paper (see just below) describes CHRONICALLY high PGD2 signalling in full-blown Alzheimer’s. We predict, in fact, that high dose niacin in the immediate-release flushable form will REDUCE the risk of Alzheimer’s, and that getting rid of the flush would probably eliminate this protective effect. If you could get rid of the flush and still retain all the protective benefits of the flush, then fine, go ahead and get rid of it. But so far, the focus seems to be on suppressing the flush without adequately understanding what the flush has to do with the protective effects of immediate release niacin.

Also, note in the urate crystal inflammation model (below) that a 5.2 fold pulsatile (acute) increase in PGD2 was anti-inflammatory, decreasing inflammatory signaling by PGE2. The opposing effects of certain dose and time-dependent releases of PGD2 and PGE2 would appear to be a system to examine closely in relation to Alzheimer’s.

  • Woodling, Wang, Priyam, et al. Suppression of Alzheimer-associated inflammation by microglial prostaglandin-E2 EP4 receptor signaling. J Neurosci.34(17):5882-94 (2014).
  • Ruan and So. Screening and identification of dietary oils and unsaturated fatty acids in inhibiting inflammatory prostaglandin E. BMC Complement Altern Med.12:143 (2012).

ALZHEIMER’S DISEASE:
INCREASED LEVELS OF A FORM OF
PGD2 SYNTHASE

In a very complex analysis (Maesaka, 2013), researchers found that a form of PGD2 synthase, L-PGDS, can in a chain of biochemical reactions, convert arachidonic acid to 15deoxyPGdelta12,14 J2(15dPGJ2), the primary ligand for peroxisome proliferator activator receptor gamma (PPARgamma), and that 15dPGJ2 has been reported to induce apoptosis in human astrocytes and cortical neurons, which could be prevented by inhibitors of L-PGDS, such as IGF, insulin, and erythropoeiten as well as PGE1, PGE2, and COX2 and caspase inhibitors. The authors identified L-PGDS “as a dominant inducer of apoptosis in AD plasma,” presumably by increasing PGD2 signalling to a chronically high level.

  • Maesaka, Sodam, Palaia, et al. Prostaglandin D2 synthase: apoptotic factor in Alzheimer plasma, inducer of reactive oxygen species, inflammatory cytokines, and dialysis dementia. J Nephropathol. 2(3):166-180 (2013).

Interestingly, another paper (Ryan, 2008) reports that 15dPGJ2 (that as noted just above induces apoptosis in brain astrocytes and cortical neurons) impairs phosphatidylcholine synthesis by promoting cysteine cross-linking in the enzyme cytidyltransferase alpha. This cross-linking could be reduced by N-acetylcysteine (Ryan, 2008).

The sleep impairments observed in Alzheimer patients may be, at least to some extent, linked to chronically high PGD2 signaling, as PGD2 is an important sleep-inducing molecule (Urade 1999). The signal of a transient pulse of a substance is lost in the noise of a continuously high background level of that substance.

  • Ryan, Chen, Vennalaganti, et al. 15-deoxy-delta12,14-prostaglandin J2 impairs phosphatidylcholine synthesis and induces nuclear accumulation of thiol-modified cytidyltransferase. J Biol Chem.283(36):24628-40 (2008).
  • Urade and Hayaishi. Prostaglandin D2 and sleep regulation. Biochim Biophys Acta. 1436:606-15 (1999).

REDUCTION OF URATE CRYSTAL INFLAMMATION
BY ACUTELY ELEVATED PGD2

After struggling through the analysis of prostaglandin D2 synthase’s link to apoptosis in Alzheimer’s disease (just above this paragraph), if you did, you may be hoping for something a little simpler. This one is.

Here, researchers found (Jung, 2007) that in mice fed root extracts of traditional oriental medicinal plants,* inflammation elicited by injecting 2 mg of monosodium urate crystals into the pouch resulted in a rapid and dramatic decrease in the measured inflammatory parameters, including neutrophil density, IL-6 and TNFalpha mRNA. Leukocyte count, IL-6, prostaglandin E2, along with prostaglandin D2 were examined in the pouch exudate. Remarkably, the concentration of the potentially anti-inflammatory Prostaglandin D2 rose 5.2 fold. The authors of this 2007 paper were very excited about these results and thought this could point to a novel way to treat inflammation, the cause of the intense pain of uric acid crystals in gout. They seem to have been right, but nothing appears to have come of this.

* Dried roots of Acanthopanax senticosus, Angelica sinensis, and Scuttelaria baicalensis.

  • Jung, Schumacher, Kim, et al. Reduction of urate crystal-induced inflammation by root extracts from traditional oriental medicinal plants: elevation of prostaglandin D2 levels. Arthritis Res Ther.9:R64 (2007).

PGD2 IN THE SKIN

A recent paper (Shimura, 2010) reports on the role of PDG2 in allergic responses in the skin, focusing on mast cells expressing the hematopoeitic PGD synthase found in dendritic cells. They discussed rapid excretion of PDG2 in response to various allergens, including an irritant compound. “A possible anti-pruritic [anti-itch] potential of PGD2 in the scratching behavior of mice was recently proposed.” [It was AFTER Sandy performed the experiment on her itchy skin described just below that she read about this finding. Serendipity!] When released rapidly in response to allergens, PGD2 can act as an anti-inflammatory, while when released in excess quantities it exacerbates the allergic response (Shimura, 2010).

  • Shimura, Satoh, Igawa, et al. Dendritic cells express hematopoietic prostaglandin D synthase and function as a source of prostaglandin D2 in the skin. Am J Pathol.176:227-37 (2010).

SANDY’S ITCHY SKIN—DISCOVERING THE EFFECT OF
ELIMINATING THE NIACIN FLUSH THE HARD WAY

Sandy had developed an itchy skin condition (probably a result of severe hypothyroidism) and had, as a result, discontinued high dose niacin about a month ago because of increased itchiness and of stabbing sensations (see description of the niacin flush above) during the flush. The itchiness got worse until it became such a serious problem that she had to take two prescription drugs to keep the itchiness under control. Hydrocortisone cream didn’t help at all, which is consistent with the reported effect of chronically elevated PGD2 in blunting the antiinflammatory effect of corticosteroids (Barnes, 2009). This doesn’t PROVE that it was chronically high PGD2 in her skin that made the hydrocortisone salve ineffective, but is consistent with data showing that effect. As a matter of fact, Sandy has a mild case of COPD, which is reported to exhibit resistance to the antiinflammatory effects of corticosteroids, suggesting the possibility that she has chronically elevated PGD2 in her lungs. The fact that it hasn’t gotten progressively worse over the years, as COPD typically does, MAY be due to her ingestion of high dose immediate-release niacin which could be reducing the inflammatory activity by discharging the release of PGD2 via pulses, thereby preventing chronic PGD2 release as a sort of constant dribble rather than as pulses. This is our hypothesis. There might be another way to explain all this, and we certainly can’t prove there isn’t (given that it is impossible to disprove a negative), but we think our explanation is quite plausible and consistent with all the data we’ve seen.

It is interesting to note that curcumin restores corticosteroid sensitivity in monocytes exposed to oxidants by maintaining HDAC-2 (histone deacetylase 2) levels (Gonzalez, 2012); HDAC-2 levels are known to be reduced in COPD. Could this be another example of a natural substance that reduces chronically high levels of PGD2? It is certainly consistent with a large amount of the literature on COPD, PGD2, and HDAC-2.

  • Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol.71:451-64 (2009).
  • Gonzalez, Ballester, Lopez-Posadas, et al. Effects of flavonoids and other polyphenols on inflammation. Crit Rev Food Sci Nutr. 51(4):331-62 (2011).

EXPERIMENT: When I (Sandy) realized that it might be the loss of the flush that was causing my monster skin itch, I took 400 mg of niacin on an empty stomach to induce the flush. After that, the flush ensued and went on for the normal period of time it usually does after I take niacin, during which the itching was intensified, the itching then subsiding to a very low level. Plus, a little bonus, my painful knee osteoarthritis had become much less painful when I went out to the supermarket a few minutes later. It had become worse during the month I was off high-dose niacin. NOTE: I still took Personal Radical Shield during this period and so was getting between 250 and 500 mg/day of niacin, but my regular dose of niacin was around 2 grams a day in addition to that.

For a relationship between osteoarthritis and prostaglandin D2, see:

  • Zayed, Li, Chabane, et al. Increased expression of lipocalin-type prostaglandin D2 synthase in osteoarthritic cartilage. Arthritis Res Ther. 2008, 10(6):R146 doi:10.1186/ar2581 (2008).

Mitigation of Inflammation with Foods

A 2012 paper (Wu, 2012) reported that polyphenols and other compounds found in foods such as fruits, berries, vegetables, nuts, whole grains, and foods of marine origin contain components can “play an important role in attenuating and mitigating chronic pro-inflammatory processes associated with chronic diseases,” such as atherosclerosis, ischemic heart disease, cancer, obesity, inflammatory bowel disease, Crohn’s disease, diabetes and autoimmnune diseases. Surprisingly few papers on the mitigation of inflammation discuss prostaglandins explicitly, revealing that there is an immense area here where increased knowledge could promote improvements in controlling the chronic inflammatory diseases associated with aging.

When you control a biochemical pathway to regulate processes taking place far downstream, it is usually best to think of ways to regulate closer to the downstream site that is a problem because regulation at the upper end of the chemical pathway will affect many processes that have nothing to do with your problem and may produce unwanted off-target effects. THAT, in fact, is one of the major problems with statins … that their effects are taking place far upstream in the process of synthesizing cholesterol (Cederberg, 2015) and there are frequent undesired effects such as myopathy and an alarmingly high increased risk of developing type 2 diabetes.

  • Wu and Schauss. Mitigation of inflammation with foods.J Agric Food Chem.60:6703-17 (2012). Cederberg, Stancakova, Yaluri, et al. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. 58:1109-17 (2015).

STATINS IN COMBINATION WITH NIACIN

As we note in the paragraph above, statins have been found to reduce insulin sensitivity, and this is associated with a large increase in the risk of developing type 2 diabetes. The combination of statins with niacin also have a significant effect in reducing the beneficial effects of increased HDL cholesterol that is seen with immediate release niacin (Keene, 2014). The mechanism that causes statins to increase the risk of type 2 diabetes are, we think, a likely place to look for what causes this adverse effect of statins on the protective effect of niacin on reduced risk of non-fatal heart attacks, the most common kind of heart attack.

Most Heart Attacks Are Non-Fatal, So the Reported
Highly Protective Effect of Niacin Against the
Incidence of Non-Fatal Heart Attacks Is Important

In a paper (Keene, 2014) providing a meta-analysis of 117,411 patients, very interesting differences between the effects of niacin taken by patients NOT RECEIVING STATINS (BEFORE THE STATIN ERA) and those who, later, were taking niacin and statins emerged. Very statistically significant results showed that in those patients NOT taking statins, niacin was associated with a significant reduction in non-fatal heart attacks (myocardial infarction) (odds ratio was 0.69, 0.56 to 0.85, p=0.0004). However, in studies where statins were already being taken, niacin showed no significant effect on the incidence of non-fatal heart attacks. The researchers say, “In the current era of widespread use of statins in dyslipidaemia, substantial trials of these three agents [niacin, fibrates, or CETP inhibitors, all of which increase HDL levels] do not support this concept [that increasing HDL would generally reduce cardiovascular events].” Statins interfere with an important protective effect of niacin. It is important to note that NON-FATAL MYOCARDIAL INFARCTIONS are the most COMMON type of heart attack, so reduction of these heart attacks is not at all unimportant, though the word FATAL may be somewhat distracting from the significance of these results.

Studies with statins HAVE repeatedly shown that reductions in LDL cholesterol with statins “has repeatedly been found to reduce cardiac events and all cause mortality in the setting of both secondary and primary prevention.” However, the increased protection against cardiovascular events expected by increased HDL has not been seen. See paragraph above. Hence, something in the interaction of statins with niacin and fibrates, where niacin and fibrates increase HDL cholesterol and which (when taken WITHOUT CONCURRENT INGESTION OF STATINS), reduces the risk of non-fatal myocardial infarctions, results in a loss of that protective effect of niacin or fibrates.

The studies with niacin were confounded by the fact that some of the patients were given aspirin or laropriprant to inhibit flushing. Laroopriprant is thought to interfere with prostaglandin pathways which, as you will see below in our discussion of prostaglandins, could be very important, and the authors of this paper (Keene, 2014) suggest that this effect “could confound the effect of niacin.”

  • Keene, Price, Shun-Shin, and Francis. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. 349:g4379 (2014) doi: 10.1136/bmj.g4379 (18 July 2014).

2012 REVIEW PAPER ON PGD SYNTHASE AND PGD2
IN IMMUNE RESPONSE (Joo, 2012)

A good recent review of PGD synthase and PGD2 described a variety of model systems in which PGD2 exhibited a proinflammatory or antiinflammatory effect. For example, a paper is cited in which a human model of an acute inflammatory response induced by the administration of LPS provides data “strongly” supporting anti-inflammatory effects of PGD2. PGD2 and its cyclopentenone prostaglandin derivatives are reported by the review’s authors to have antiinflammatory properties with functions in the resolution of inflammation, and “there is considerable interest in the importance of PGD2 and its distal products in the mediation and resolution of inflammation.” (Joo, 2012). Other models show pro-inflammatory effects. The devil is in the details of the amounts released, the time course over which the release takes place, and the inflammatory milieu of the tissue involved (as we have noted above, an acute signal of a molecule released into an environment with a high chronic level of that molecule may not convey the acute signal very well or at all).

  • Joo and Sadikot. PGD synthase and PGD2 in immune response. Mediators Inflamm. 2012:503128. doi: 10.1155/2012/503128 (2012).

Interestingly, in sleeping sickness, PGD2 is increased and the microorganism responsible for the disease has been shown to induce the production of PGD2 in culture. PGD2 is a well-known sleep promoting prostaglandin. The review authors (Joo, 2012) published a paper earlier in which they showed that PGD2 inhibits a “key proinflammatory immunoglobulin cell surface receptor TREM-1 in vitro in macrophages.” In another of the authors’ papers, they showed that the administration of PGD2 in a mouse model of P. aeruginosa lung infection resulted in enhanced clearance of P. aeruginosa from the lungs. Moreover, their study showed that mice that had COX-2 inhibited (via knockout) had enhanced clearance of the bacterium and that this effect was related to a decrease in PGE2. There we see the interaction and apparent opposing effects between PGD2 and PGE2 that has appeared in other studies.

This paper is useful for presenting an analysis of several models of inflammation and the effects of various forms of PGD2-synthase and PGD2.

PGE2 RECEPTOR SYSTEM

The inducible and inflammatory COX-2 pathway synthesizes the release of inflammatory amounts of PGE2 (Ruan, 2012). There are three different PGE2 synthases, enzymes that manufacture PGE2 from arachidonic acid. The PGE2 produced is then received by one of four PGE2 receptors, EP1, 2, 3, and 4), which is associated with pain, vascular diseases, and cancer cell growth (Ruan, 2012). DHA’s anti-inflammatory effects are mediated, at least in part, by its action at the EP1 receptor of PGE2 (Ruan, 2012) while the antiinflammatory action of curcumin is reported to be via the reduction of IL-1 beta-stimulated microsomal PGES. PGES enzymes convert the prostaglandin PGH2 to PGE2 (Kats, 2013).

  • Ruan and So. Screening and identification of dietary oils and unsaturated fatty acids in inhibiting inflammatory prostaglandin E. BMC Complement Altern Med.12:143 (2012).
  • Kats, Bage, Georgsson, et al. Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo. FASEB J.27:2328-41 (2013).

YIN-YANG BALANCE BETWEEN
PROINFLAMMATORY AND ANTI-INFLAMMATORY
PROSTAGLANDINS

This is what some researchers refer to as a “yin yang” system, where you have (for example) prostaglandins PGE2 and PGD2 working a balance of pro-inflammatory and anti-inflammatory effects depending on how much is released, the time course of the release, and the inflammatory milieu of the tissue where they are released. Acute inflammation onset and resolution have also been identified in a paper (Rajakariar, 2007) as being regulated by the balance of PGD2 and 15d-PGJ2.

  • Rajakariar, Hilliar, Lawrence, et al. Hematopoietic prostaglandin D2 synthase controls the onset and resolution of acute inflammation through PGD2 and 15-deoxy-delta12,14 PGJ2. Proc Natl Acad Sci U S A. 104(52):20979-84 (2007).

“The devil may be in the details,
But so are the angels.”

—Sandy Shaw

It would appear that all of the most important chronic diseases of man, including cardiovascular disease, cancer, and Alzheimer’s disease are critically regulated by this sort of balancing act. The devil may be in the details, but so are the angels. Another way of putting it is that you shouldn’t be in too great a rush to throw out the devils until you understand whether, by doing so, you are throwing out some or all of the angels.

What Is Intolerable About the Niacin Flush?

The niacin flush appears to be the devil in the details that most disturbs people who would use niacin but can’t stand the flush. There are many interacting biochemical pathways regulating pro-inflammatory and anti-inflammatory effects in the skin, but it would be helpful to isolate some particularly important players in the niacin flush. First, of course, is PGD2, the acute release of which is closely associated with the strength and timing of the flush in relation to when you took the niacin. Preventing the acute release of PGD2 comes close to getting rid of the flush, but doesn’t eliminate it entirely, pointing to other regulatory factors being involved (Kamanna, 2009).

But there are a number of different prostaglandins that have interactions with each other and can counter-regulate each other, and so on. Importantly, as we describe above, PGE2 seems to be in a balancing act with PGD2 in some models of inflammation, so that the nastiness of the niacin flush MAY be linked to the release of PGE2 (our supposition). A prediction of this hypothesis would be that inhibitors of the release of PGE2 would reduce how much of the nasty burning and sensations of insects biting would occur during the flush. A recent paper (Gonzalez, 2012) reported that a study of the inhibitory effects of flavonoids on the release of PGE2 in peritoneal macrophages found that some flavonoids were as effective as aspirin in this inhibitory activity, including quercetin, resveratrol, apigenin, genistein, or kaempferol, but the authors were surprised that luteolin, fisetin, or morin did NOT inhibit the PGE2 release in the peritoneal macrophages.

Here, again, we have another remarkable little clue on the psychodynamics of the niacin flush: a paper (Papaliodis, 2008) that reports that luteolin suppresses the niacin flush!! Another piece for the puzzle of what the niacin flush is all about. Moreover, to add a little additional spice to this, it has been reported (Ren, 2009) that some flavonoids produce a little skin flush of their own. The paper (Gonzalez, 2012) also mentioned that flavonols appear to exert the highest activity (in papers on anti-inflammatory effects via inhibition of lipoxygenases). Cocoa is an excellent source for flavonols. We are currently taking a flavonol-enriched supplement (expensive, however) called Cocoa-Via® as a source of these flavonols.

  • Kamanna, Ganji, Kashyap. The mechanism and mitigation of niacin-induced flushing. Int J Clin Pract.63(9):1369-77 (2009).
  • González, Ballester, López-Posadas, et al. Effects of flavonoids and other polyphenols on inflammation. Crit Rev Food Sci Nutr. 51(4):331-62 (2011).
  • Papaliodis, Boucher, Kempuraj, and Theoharides. The flavonoid luteolin inhibits niacin-induced flush. Br J Pharmacol. 153:1382-7 (2008).
  • Ren, Kaplan, Hernandez, et al. Phenolic acids suppress adipocyte lipolysis via activation of the nicotinic acid receptor GPR109A (HM74a/PUMA-G). J Lipid Res. 50:908-14 (2009).

REDUCING THE NIACIN FLUSH

A recent paper (Jacobson, 2010) that discussed in amazing detail how to reduce the niacin flush begins by noting that “[n]iacin is the most effective lipid modifying agent for raising high density lipoprotein [HDL] cholesterol …” The author explains that in clinical trials, over 60% of niacin users experienced mild or moderate flushing, with 5% to 20% of patients discontinuing niacin therapy because of the flush.

The author (Jacobson, 2010) goes on to explain various ways to reduce the flush, including taking niacin with meals or at bedtime with a low-fat snack and avoiding exacerbating factors such as alcohol or hot beverages. He also indicates that taking 325 mg of aspirin along with niacin suppresses the flush. However, aspirin has many effects on prostaglandin chemistry and as prostaglandins appear to play an important role in the beneficial cardioprotective effects of niacin, we do not recommend taking aspirin along with niacin to reduce the flush.

  • A “hot” topic in dyslipidemia management—“How to Beat a Flush:” optimizing niacin tolerability to promote long-term treatment adherence and coronary disease prevention. Mayo Clinic Proc. 85(4):365-79 (2010).

IN THE BEGINNING,
THERE WAS IMMEDIATE RELEASE NIACIN

To get some feel for the data on clinical effects of immediate release niacin over its first fifty years of use, a paper published in 2005 in the Journal of Internal Medicine (Carlson, 2005) provides an informative review. At this point, the switchover to the non- flushing niacin had not occurred to a great extent, as Niaspan had just become available. Hence, the review focused largely on immediate release niacin that caused a strong flush. Indeed, the author of this review (Carlson, 2005) had been doing pioneering work on niacin for over 40 years.

It was discovered early (some of the early data were published by the author of this review with a coauthor (see Carlson, 1962) that nicotinic acid (niacin) lowers free fatty acids by inhibiting the mobilization of free fatty acids from adipose tissue, a process called lipolysis; the antilipolytic effect of niacin is now considered a major source of the benefits of niacin. The early researchers found that the inhibition of mobilization of free fatty acids by niacin did not change the overall energy metabolism in the heart but “switched its oxidative metabolism from lipids to carbohydrates.” This is a major effect of niacin in its protective cardiovascular role. The inhibitory effect of niacin on the rise of free fatty acids and triglycerides that occurs during emotional stress was reported in a 1962 paper (Carlson, 1962) on experiments in humans.

As of the date of this review, the author stated, “[i]t is now generally accepted that nicotinic acid is the most powerful drug for raising the concentration of HDL, in particular the subspecies HDL2.” He cites data from a study that found HDL cholesterol to rise by 50% in hyperlipidemic patients, but the subfraction of HDL2, the large HDL particles, increased by almost 100%.

Interestingly, the author referred to data showing that at that time researchers had already identified the niacin flush as being due to the release of prostaglandins (by experiments using the prostaglandin synthesis [cyclooxygenase] inhibitor indomethacin) and found that indomethacin markedly reduced the flush. Other studies published before the Carlson 1962 review suggested that PGD2 might be the prostaglandin responsible for the flush.

Carlson in that review also mentioned the discovery that niacin had fibrinolytic (clot busting) effects, having been shown to decrease the plasma levels of fibrinogen by 15% by inhibiting its synthesis by plasminogen activator inhibitor 1. The increased expression of PAI-1 was discussed by Carlson as being closely associated with hypertriglyceridemia (Carlson, 1962). A recent paper (Song, 2012) proposed that PGD2, which the authors found to be synthesized by COX-1 in platelets in both mice and humans, may “function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during [flushing] niacin therapy.”

  • Nicotinic acid: the broad-spectrum lipid drug: a 50th anniversary review.J Intern Med. 258:94-114 (2005).
  • Carlson and Oro. The effect of nicotinic acid on the plasma free fatty acids; emonstration of a metabolic type of sympathicolysis. Acta Med Scand. 172:641-5 (1962).
  • Song, Stubbe, Ricciotti, et al. Niacin and biosynthesis of PGD2 by platelet COX-1 in mice and humans. J Clin Invest. 122(4):1459-68 (2012).

CONCLUSION:

In conclusion, there is a rush to develop a way to evade the niacin flush that causes an acute release of PGD2 in the use of niacin therapy to treat hyperlipidemia. This incredible rush, that has resulted in nearly a discontinuation of research on immediate release niacin is being done almost entirely for the purpose of making a non-flushing niacin available for commerce because it could make somebody a lot of money. Because of the entwined interests of government regulatory authorities at the FDA (users’ fees are a very important part of the FDA’s budget) and certain pharmaceutical companies which could benefit by the availability of such a non-flushing niacin product, this work is not (in our opinion) properly scientifically evaluating what it means to eliminate the niacin flush and what it might cost patients using the new forms of niacin (taking into account that many such patients would never take the flushing niacin in the first place) by actually comparing the two different forms of niacin. No such evaluation seems to be taking place. Just thought we ought to mention it …

The correct question that should be asked is not whether extended-release niacin has equivalent benefits to regular niacin—it doesn’t —but what benefits does it provide to which patients and what are its risks, questions that should be asked of any medicine. The almost desperate pursuit of “equivalence” between the two resembles a morbid fear of admitting that somebody might be giving up something of value by taking extended release niacin rather than immediate release niacin and—horror of horrors—finding out exactly what that something of value really is.

HUMAN STUDIES WITH “EXTENDED RELEASE” OR
“PROLONGED RELEASE” NIACIN LEAVE LITTLE
ROOM FOR DOUBT ABOUT THE LACK OF
EQUIVALENCE WITH THE BENEFITS OF
IMMEDIATE RELEASE NIACIN

  1. A human study of extended-release niacin on lipoprotein particle size, distribution and inflammatory markers in patients with coronary artery disease (Kuvin, 2006) found that compared with subjects who received placebo, 3 months of ER niacin resulted in significantly increased though “relatively small” increases in HDL and no significant change in total LDL levels. Regular niacin provides a very significant and clinically meaningful reduction in LDL. The patients participating in this study already had well-controlled LDL (that is, by prior treatment not including any form of niacin), so this study really did not explore the differences between ER niacin and immediate release niacin on the regulation of lipids.
  • Kuvin, Dave, Sliney, et al. Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease. Am J Cardiol. 98:743-5 (2006).
  1. In another human study (Plaisance, 2008), the effects of aerobic exercise and ER niacin were examined in 15 men with the metabolic syndrome. ER niacin lowered fasting but had no effect on the postprandial triglyceride AUC (amount under the curve), while it did decrease the insulin AUC. Immediate release niacin, however, reduces fasting triglycerides by 20-50%.
  • Plaisance, Mestek, Mahurin, et al. Postprandial triglyceride responses to aerobic exercise and extended-release niacin. Am J Clin Nutr. 88:30-7 (2008).
  1. In a third human trial (Jafri, 2009), ER niacin reduced LDL particle number and increased the number of HDL particles without changing total LDL cholesterol in patients with stable coronary artery disease. But the very significant lowering of LDL is considered a major protective feature of immediate release niacin.
  • Jafri, Alsheikh-Ali, Mooney, et al. Extended-release niacin reduces LDL particle number without changing total LDL cholesterol in patients with stable CAD [coronary artery disease]. J Clin Lipidol. 3:45-50 (2009).
  1. In another human trial (Westphal, 2006) (randomized, placebo-controlled double blind, 30 men with metabolic syndrome), a short term (6 week) treatment with ER niacin increased adiponectin by 56% and leptin by 26.8% but there was no change in the levels of the proinflammatory factors TNFalpha, IL-6 and C-reactive protein, no improvement in endothelial function (as measured by FMD), and an actual deterioration in glucose and insulin parameters. Despite increased levels of adiponectin, the authors note that this “fails to improve atheroprotective functions attributed to adiponectin, such as insulin sensitivity, anti-inflammation, and endothelial function.”
  • Westphal, Borucki, Taneva, et al. Extended-release niacin raises adiponectin and leptin. 193:361-5 (2007).

A review paper (Vosper, 2009) looking at niacin’s effects on prostaglandin chemistry, came to the conclusion that “recent advances in understanding of the contribution of prostaglandin metabolism to vascular wall health suggest that some of the beneficial effects of niacin may well result from activation of the same pathways responsible for the adverse [the flush] reactions. The purpose of this review is to emphasize that the search for agonists that show higher tolerability must take into account all aspects of signaling [by prostaglandin D2] through this [the DP1] receptor.”

  • Niacin: a re-emerging pharmaceutical for the treatment of dyslipidaemia.Br J Pharmacol. 158:429-41 (2009).

In another review paper (Song, 2013), the authors conclude that while the pursuit of a more tolerable form of niacin with some benefits that might add to statins might be attractive to a commercial sponsor, “Such pragmatic reasoning may drive the progressive abandonment of niacin, a drug that has long been a mainstay of cardiovascular therapy, while we still poorly understand its many potentially relevant mechanisms of action and have an incomplete picture of its clinical utility.” (Hear, hear!)

  • Song and FitzGerald. Niacin, an old drug with a new twist. J Lipid Res.54(10):2586-94 (2013).

A further review of niacin in its various forms (McCay, 2012) notes that “[w]hether other compounds that are converted to NA [nicotinic acid] or that contains NA, nicotinamide (NM) or their releasable moieties should be referred to as ‘niacin’ depends on the biological effects that are attributed to the compound, the interpretation of the evidence for the rates of uptake and metabolism, and/or the release of the chemical components (apparent bioavailability) that produce biological effects similar to the primary forms of niacin.”

  • MacKay, Hathcock, Guarneri. Niacin: chemical forms, bioavailability, and health effects. Nutr Rev.70(6):357-66 (2012).

LIVER TOXICITY

This review (McCay, Hathcock, Guarneri, 2012) noted that in the matter of LIVER TOXICITY, “[m]any severe reactions to NA, especially liver toxicity, have involved ill-advised or uninformed switching from NA preparations to ER-NA formulations without adjusting the dose.” That is, the same dose of niacin exhibits a greater risk of liver toxicity in the ER form. We suspect that this is caused by the loss of the PGD2 acutely released by plain niacin which in the ER form is more of a chronic release of PGD2, hence reducing the flushing effect but with the differences we have described in the body of this article above from an anti-inflammatory effect of acutely released PGD2 to a pro-inflammatory effect of chronically elevated levels of PGD2. John Hathcock, a co-author of this review, was formerly a prominent extensively-published scientist at the FDA who is an expert on matters of toxicity, writing frequently on toxicity issues involving nutrients. Dr. Hathcock left the FDA to become a scientist and analyst at the Council for Responsible Nutrition.

  • (McCay, Hathcock, Guarneri 2012 reference in paragraph above)

MORE ON STUDIES OF “EXTENDED RELEASE”
AND “PROLONGED RELEASE” VS. IMMEDIATE
RELEASE NIACIN

It was a surprise to us that in their review discussed just above (McCay, Hathcock, Guarneri, 2012), the authors stated their belief that “the beneficial lipid lowering effects of both NA [nicotinic acid] and ER-NA [extended-release nicotinic acid] are well established with data showing reduction of total triglyceride levels by 20-50%, reduction of LDL-C levels by 10-25%, increases of HDL-C by 10-30% and reduction of lipoprotein a levels by 10-30% which includes preferential reduction of the more atherogenic, small dense LDL-C” as the data we have seen do not tend to support an equivalent effect on lipid levels between NA and ER-NA. As to the declaration of interest for this review, the authors simply note that McCay and Hathcock are “employed by The Council for Responsible Nutrition, a trade association representing dietary supplement manufacturers and ingredient suppliers.” Hence, we do not know why they came to this conclusion, telling us only that they did an extensive search of the literature.

In our own search, we found a number of papers reporting discrepancies between immediate or extended-release niacin with that of immediate-release niacin on lipid lowering that we found to be convincing that there was no such equivalence. For example, a study (Usman, 2014) showed that extended-release niacin could suppress post-meal triglyceride levels but unlike immediate release niacin, it had to be administered just before the fat-containing meal. NON-FATAL MYOCARDIAL INFARCTIONS, as the authors of that study (Usman, 2014) explained “[t]his disparity is relevant because extended-release niacin dominates clinical use, even though only immediate-release niacin prevented hard cardiovascular outcomes.” The authors went on to describe another study (Plaisance, 2008) in which the researchers found that bedtime dosing of <1500 mg extended-release niacin for six weeks failed to suppress postprandial (after meal) triglycerides the next day, unlike immediate-release niacin. The Plaisance et al study, however, involved repeated (that is, chronic) use of niacin over six weeks, whereas the Usman et al study was just for a single dose and the pattern of suppression of triglycerides, the Usman group suggested, depended on post-dose pharmacodynamics, referring to “disappointing cardiovascular effects of bedtime extended-release niacin …”

The paper by other authors (Vogt, 2007) showed that prolonged-release niacin (in this paper they used Niaspan) did increase HDL but not as effectively as immediate-release niacin and that only immediate-release niacin had been shown to reduce cardiovascular event rates.

  • Usman, Qamar, Gadi, et al. Extended-release niacin acutely suppresses postprandial triglyceridemia. Am J Med.125(10):1026-35 (2012).
  • Plaisance, Mestek, Mahurin, et al. Postprandial triglyceride responses to aerobic exercise and extended-release niacin. Am J Clin Nutr.88(1):30-7 (2008).
  • Vogt, Kassner, Hostalek, et al. Prolonged-release nicotinic acid for the management of dyslipidemia: an update including results from the NAUTILUS study. Vasc Health Risk Manag.3(4):467-79 (2007).

SCHIZOPHRENIA AND THE NIACIN FLUSH

It is curious to note that a blunted flushing response to niacin has been observed in most schizophrenics, and even in a significant portion of first-degree relatives of schizophrenics (Shah, 1999), “suggest[ing] that niacin subsensitivity is a genetic trait …” (Messamore, 2003). A later paper by the same lead author (Messamore 2010) on niacin sensitivity and the arachidonic acid pathway in schizophrenia reported that, in a study of 20 schizophrenic adults compared to 20 controls, “[t]he schizophrenia-associated niacin response abnormality involves both diminished sensitivity and reduced efficacy.” This supports the possibility that the niacin flush plays a significant role in the clinical effects of niacin.

  • Shah, Ramchand, Peet. The niacin skin flush test: first-degree relatives show responses intermediate between patients and controls. Schizophr Res.38:314 (1999).
  • Relationship between the niacin skin flush and essential fatty acids in schizophrenia. Prostaglandins Leukot Essent Fatty Acids. 69:413-9 (2003).
  • Messamore, Hoffman, and Yao. Niacin sensitivity and the arachidonic acid pathway in schizophrenia. Schizophr Res.122(1-3):248-56 (2010).

A HUMAN STUDY OF DIETARY NIACIN AND THE
RISK OF INCIDENT ALZHEIMER’S (Morris, 2003)

Here, it was reported that, in a group of 3718 participants of 65 years and older residents of a Chicago community, evaluated through the use of dietary data and at least two cognitive assessments to detect cognitive changes over a median 5.5 years, higher food intake of niacin was associated with a slower annual rate of cognitive decline. The authors of this study reported in two case control studies conducted by others that there were lower blood levels of a nicotinic acid metabolite among demented patients than among age and sex matched controls. The detection of such a difference in cognitive changes in individuals ingesting such small amounts of dietary niacin is really surprising, as the participants in the highest fifth of intake (with a median of 22.4 mg/day) had an 80% statistically significant reduction in risk compared with the lowest quintile (12.6 mg/day). These authors attempted to determine whether there was a difference in participants with an apoE4 allele, but could not detect any. At these levels of niacin, it is hard to imagine it would be possible to measure such a small difference.

  • Morris, Evans, Bienias, et al. Dietary niacin and the risk of incident Alzheimer’s disease and of cognitive decline. J Neurol Neurosurg Psychiatry. 75:1093-9 (2004).

Sandy Shaw Copyright 2015

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