HAPPY NEW YEAR!!!!

APPETIZERS

HOW DOES HE KNOW WHEN YOU’VE BEEN NAUGHTY OR NICE?

You’d better watch out,
You’d better not cry,
You’d better not pout,
I’m telling you why,
Santa Claus is tapping
Your phone.

So—you mustn’t assume
That you are secure,
On Christmas Eve
He’ll kick in your door,
Santa Claus is tapping
Your phone.

Our thanks to Eugene Volokh,
THE VOLOKH CONSPIRACY,
posted 9 Sept. 2013

When I played drunks I had to remain sober
Because I didn’t know how to play them
when I was drunk.

— Richard Burton

LSD is a drug that causes psychotic and aberrant behaviors in people who have not taken it.

— tyr

If that’s an army, they are too few. If it’s a diplomatic embassy, they are too many.

— Tigranes the Great of Armenia at Tigranocerta in 69 BC, surveying the 12,000 Roman soldiers who were about to tear apart his army of some 135,000 men (from The Classical Compendium by Philip Matyszak, Thames & Hudson, 2009)

Love is not altogether a delerium, yet it has many points in common therewith.

— Thomas Carlyle

Love is a great beautifier.

— Louisa May Alcott

There is pleasure in the pathless woods.

— Lord Byron

Joy is not in things; It is in us.

— Richard Wagner

Random processes produce many sequences that convince people that the process is not random after all. You can see why assuming causality could have evolutionary advantages. It is part of the general vigilance that we have inherited from our ances- tors. We are automatically on the lookout for the possibility that the environment has changed. Lions may appear on the plain at random times, but it would be safer to notice and respond to an apparent increase in the rate of appearance of prides of lions, even if it is actually due to the fluctuations of a random process.

— Daniel Kahneman, Thinking, Fast and Slow (Farrar, Straus and Giroux, 2011) (pg. 115)

(D & S Comment: The automatic vigilance is described in the book as being part of System 1, the intuitive way of thinking. So while it is certainly good to be vigilant of marauding lions even if you think their appearance is caused by the boogie man, the fly in the ointment is that the belief in an incorrect assumption of a cause can, in the world of politics, end up costing a huge amount of money if the process is random rather than caused by what people believe intuitively. And, unfortunately, as the author points out earlier in the book (pg. 91) the people who are most likely to make snap (intuitive) judgments of the competence of political candidates on the basis of whether they have a “competent” face were those that were most politically uninformed and who watched a lot of television.

Francis Crick (Nobel Prize Winner, Medicine, 1962) must have been bom- barded with mail following his receipt of the Nobel Prize. Here is a response he is reported to have sent out: Dr. Crick thanks you for your letter but regrets that he is unable to accept your kind invitation to: send an autograph/ help you in your project/ provide a photograph/ read your manu- script/ cure your disease/ deliver a lecture/ be interviewed/ attend a conference/ talk on the radio/ act as chairman/ appear on TV/ become an editor/ speak after dinner/ write a book/ give a testimonial/ accept an honorary degree.

— reported in David Frost’s The Impossible Takes Longer the 1,000 wisest things ever said by Nobel prize laureates (Walker & Co. 2003)

(D & S Comment: We think we know how he felt. After the publication of “Life Extension, a Practical Scientific Approach” and our very extensive publicity tours in 1982 and 1983, we received over 500,000 letters with nearly all of the above requests.)

To be secure, take the advice of a 19th century Boston politician, Martin Lomasney: “Never write if you can speak, never speak if you can nod, and never nod if you can wink…“

I was asked at a lecture by someone in the audience who said, why can’t I clone myself and keep the copies as spare parts? And my answer was, be careful, one of the copies might keep you for spare parts.

—Sydney Brenner, Nobel Prize for Medicine, 2002

A common principle often invoked in scientific discourse is Occam’s Razor. This principle dictates that the simplest or most parsimonious explanation should be favored. However, one shouid keep in mind that a simple explanation that does not explain the facts is to be discarded. Sydney Brenner introduced the concept of “Occam’s Broom,” which is used to sweep inconvenient truths under the rug to salvage the ‘simplest’ explanation. Recognizing when to use the razor and avoid the broom is a use- ful reflection in evaluating scientific models as the subtle Mendel and McClintock examples attest.

— pg. 11, Birchler, Mendel, Nechanism. Models, Marketing, and More in the Sept. 24, 2015 Cell

The philosopher Friedrich Hayek, who led the debate against social and economic planning in the mid-twentieth century, noted a paradox that applies today. As science advances, it tends to strengthen the idea that we should “aim at more deliberate and comprehen sive control of all human activities.” Hayek pessimistically added, “It is for this reason that those intoxicated by the advance of knowledge so often become the enemies of freedom.“

— Nico Stehr, in an oped (“Democracy is not an inconvenience”) in the 24 Sept. 2015 Nature

(D & S Comment: Scientific journals are disproportionately full of opeds propos ing regulations before, during, and after any technology not fully understood (as they all are). In the end, their agenda ends up attempting to regulate nearly all human activities, thus supporting Hayek’s pessimistic suggestion above.)

FDA “Protects” Public From Cancer Detection Blood Test

In another move toward police state medicine, the FDA has notified Pathway Genomics that it cannot market a blood test to screen for various cancers in healthy people because the company didn’t get the FDA’s permission to do so. In a 21 Sept. 2015 warning letter, the FDA declared the company’s test blood collection tubes a “medical device” and therefore, their use comes under the agency’s jurisdiction. The test, which would have allowed the public to determine whether they had cancer cells circulating in their bloodstream at a cost of $299 to $699 will probably never become available because the cost of getting FDA approval is prohibitive. Meanwhile, the FDA calls the test, which simply collects blood for analysis by their Pathway Cancer Intercept Detect service, the results to be sent to the patient’s doctor (who has to order the test), a “high risk test that has not received adequate clinical validation and may harm the public health.”

Where is the “high risk” the FDA claims exists here and how might it “harm” the public health, provided a disclaimer truthfully explains limits to the test’s ability to provide conclusive proof of having or not having cancer, a disclaimer we would be amazed if the company didn’t already provide for legal protection, if for no other reason.

The FDA is a dangerous entity backed by little more than government force that is immensely harmful to the public health. The agency pursues a vigorous agenda of extending its jurisdiction by decree (they simply proclaim authority over whatever suits their fancy), without Constitutional or statutory basis, to more and more of new medical technologies, effectively eliminating most of them from public access. In the meantime, courts regularly “defer” to the FDA and other regulatory agencies, providing little in the way of an effective check to their power-seeking. The result is the shrinking of choices available in the medical marketplace. And for THIS, we pay taxes??? We’d be better off shredding the money.

• FDA warning on cancer test reported in the 2 Oct. 2015 Science, 12

HYDROGEN ADMINISTERED IN HYDROGEN RICH SALINE IMPROVES MEMORY IN A RAT MODEL OF AMYLOID BETA INDUCED ALZHEIMER’S DISEASE

The researchers of a paper studying the above subject (Li, 2010) wanted to learn whether hydrogen could reduce inflammation and improve cognition in a rat model of Alzheimer’s disease. The 84 rats were divided into three groups: sham operated (icv injection that did not include amyloid beta1-42), amyloid beta 1-42 icv, and amyloid beta 1-42 icv plus hydrogen saline. Hydrogen saline was injected into the third group of rats for 14 days after intracerebroventricular (icv) injection of Amyloid beta1-42. They were tested for inflammatory cytokines IL-6, and TNFalpha and the lipid peroxidation product malondialdehyde (MDA), as well as testing the rats in the (uh oh) Morris Water Maze and open field trial to test for learning and memory function.

The hydrogen-enriched saline significantly improved animal performance in the Morris Water Maze and enhanced LTP (long term potentiation), an important process in learning, in the hippocampus, where LTP is blocked by amyloid beta1-42. The treatment also reduced levels of the inflammatory cytokines and the malondialdehyde, as well as reducing the hyperactive immune response to HNE and GFAP, which was induced by amyloid beta1-42.

So far, the experiments with hydrogen treatment for various medical conditions have used only hydrogen gas or hydrogen in saline or water. Why nobody is using hydrogen generated by the hydrogen producers residing in the gut microbiota for this purpose is not clear. It is possible that the reason is that a test for evaluating how much hydrogen is generated by the microbiota and which then diffuses into the tissues has not yet been developed; it is much simpler to know how much hydrogen the animals were administered when it is done by gas or by water or saline saturated with hydrogen.

Unlike hydrogen administered by gas or in water/saline, the ingestion of fermentable fibers, such as long chain fructooligosaccharide (long chain inulin), which is a particularly good fuel for the hydrogen producers in the gut, is a simple inexpensive way to get hydrogen into your system, PLUS it is not limited to the short time following the breathing of the gas or the drinking of the hydrogen containing liquid for exposure to hydrogen.

We are both enthusiastic users of our hydrogen power supplement. It is a powder that is not miscible in water, but mixes in very well when added to oatmeal, which is one way we use it. You could also add it to smoothies, casseroles, thick soups, etc. It is stable when cooked.

• Li, Wang, Zhang, et al. Hydrogen-rich saline improves memory function in a rat model of amyloid beta-induced Alzheimer’s disease by reduction of oxidative stress. Brain Res. 1328:152-61 (2010).

WHITE MATTER IN THE BRAIN MAY BE A KEY TO DEGENERATIVE CHANGES LEADING TO ALZHEIMER’S

Recently it has become a focus of much attention in Alzheimer research on the lesions in white matter that are so strongly associated with the disease. White matter is the myelinated tracts that connect neural networks of the brain that are found in gray matter, such as the visuo-spatial processing area that is severely impaired in Alzheimer’s disease. In our last newsletter, Sandy hypothesized that Alzheimer’s might not be a disease where memories are lost, but where the areas containing memories are disconnected from being accessed by other brain areas. If this is the case, then the white matter tracts that constitute these connections might be the key to Alzheimer’s via their vulnerability to damage. White matter lesions have been found in imaging studies of Alzheimer brains and are attracting scientific attention as an important factor, possibly a key factor, in the disease (Godin, 2009; den Heijer, 2006; Stebbins, 2009). Interestingly, depression in older individuals is often accompanied by white matter abnormalities. An earlier paper (Alexopoulos, 2005, cited in Alexopoulos, 2010) proposed that, “white matter abnormalities compromising frontolimbic circuitry may predispose to geriatric depression and interfere with its response to pharmacotherapy.”

One scientist who has done considerable work on the white matter changes in Alzheimer’s disease, George Bartzokis, M.D., has proposed that “white matter may be the primary origin of the complex process that comes to present as AD [Alzheimer’s disease]. That is, white matter involvement may precede, not follow, cortical degeneration. In a series of thoughtful papers, Bartzokis has presented the ‘myelin model’ as an alternative to the traditional conceptualization of the pathogenesis of AD.” “Although still theoretical, the myelin model draws support from many neuroimaging studies.” For example, individuals at familial risk of AD or late onset AD associated with the ApoE4 allele have been found to have white matter abnormalities in memory-related tracts, such as the parahippocampal white matter, cingulum, inferior occipitofrontal fasciculus and splenium of the corpus callosum. “A particularly intriguing DTI study of normal ApOE4 carriers found decreased microstructural integrity of temporal lobe tracts with normal hippocampal and entorhinal cortical volumes.” (quotes in this paragraph come from pp. 305-306 of Christopher M. Filley’s book The Behavioral Neurology of White Matter, 2nd edition, (Oxford University Press, 2012).

VITAMIN D AND THE RISK OF DEMENTIA AND ALZHEIMER’S DISEASE

A 2014 paper (Littlejohns, 2014) reports the interesting finding that severe deficiency of Vitamin D (<25nmol/L) and deficiency of Vitamin D (≥25 to <50 nmol/L) was associated with a substantially increased risk of all-cause dementia and Alzheimer disease.

Vitamin D has been shown to mitigate age-related cognitive decline, possibly by reducing inflammation and decreasing amyloid beta burden (Briones and Darwish, 2012). Another paper reported that vitamin D prevents cognitive decline and enhances synaptic function in the hippocampus in aging mice (Latimer, 2014). A recent paper (Mizwicki, 2014) reported that vitamin D3 promoted the recovery of impaired amyloid beta phagocytosis by Alzheimer’s disease macrophages. This is important because the rate of production of amyloid beta in Alzheimer’s brains has been found not to differ from that of normal brains, but the ability of the Alzheimer’s brain to clear amyloid beta is impaired compared to that of normals.

Interestingly, multiple sclerosis is also a disease where damage to myelinated white matter tracts is responsible for failure of linkages between areas of the brain that send commands to motor areas and the motor areas that are supposed to receive those messages. The damage to the white matter tracts blocks these communication pathways. Moreover, multiple sclerosis is known to be increased at higher latitudes, that is the farther north you live, the higher the risk of getting multiple sclerosis. Vitamin D deficiency is associated with that higher risk and, of course, people at higher latitudes are exposed to less sunlight and consequently get less vitamin D via its manufacture in the skin. It may be a stretch but it is still tempting to extend the vitamin D association to Alzheimer’s disease as well.

Moreover, a paper (Huebbe, 2011) has shown that the apoE4 allele, which increases the risk of Alzheimer’s disease, is associated with higher vitamin D levels in targeted replacement mice (where the human apoE4 is substituted for their apoE) and in humans. This is consistent with the fact that in Europe, the apoE4 allele distribution is positively correlated with geographic latitude, with a greater than 4-fold greater frequency in the north than in the south (e.g., 22.7% in Finland vs. 5.2% in Sardinia. The authors (Huebbe, 2011) interpret this to possibly mean that the apoE4 allele may be beneficial early in life but then have a cost in later life (beyond reproductive age). Another paper (Norberg, 2011) also found that there was a north-south difference in the cognitive impairment resulting from apoE4 in non-demented subjects, with data coming from 16 centers across Europe. The latter study showed apoE4 carrier prevalence was 62.7% for the northern region, 42.1% in the middle region and 31.5% in the southern region. “Similar to AD [Alzheimer’s disease], APOE4 status is also associated with white matter (WM) abnormalities that may contribute to age- and disease-related neurodegeneration.” (Foley, 2014).

Durk hypothesizes that taking high dose vitamin D to get into the higher concentration of vitamin D that is still safe may be a way to reduce the damaging effect of having an apoE4 allele, because the gene’s expression may be plausibly assumed to be increased when vitamin D levels are low. Taking high dose vitamin D may, therefore, decrease the expression of apoE4 and reduce its deleterious effects thereby. This is an exciting possibility and one we hope will be tested soon. In the meantime, taking vitamin D at levels up to 4000 iu per day may be reasonable for most.

References

• Littlejohns et al. Vitamin D and the risk of dementia and Alzheimer disease. 83:920-8 (2014).
• Huebbe, Nebel, Siegert, et al. ApoE4 is associated with higher vitamin D levels in targeted replacement mice and humans. FASEB J.25:3262-70 (2011).
• Latimer, Brewer, Searcy, et al. Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats. Proc Natl Acad Sci U S A.111(41):E4359-66. (Sept. 29, 2014).
• Briones and Darwish. Vitamin D mitigates age-related cognitive decline through the modulation of pro-inflammatory state and decrease in amyloid burden.J Neuroinflammation. 9:244 (2012).
• Mizwicki, Menegaz, Zhang, et al. Genomic and nongenomic signaling induced by 1 alpha,25(OH)2-vitamin D3 promotes the recovery of amyloid-beta phagocytosis by Alzheimer’s disease macrophages.J Alzheimers Dis. 29:51-62 (2014).
• Stebbins and Murphy. Diffusion tensor imaging in Alzheimer’s disease and mild cognitive impairment. Behav Neurol.21:39-49 (2009).
• Godin, Tzourio, Maillard, et al. Apolipoprotein E genotype is related to progression of white matter lesion load. 40:3186-90 (2009).
• den Heijer, Sijens, Prins, et al. MR spectroscopy of brain white matter in the prediction of dementia. 66:540-544 (2006).
• Norberg, Graff, Almkvist, et al. Regional differences in effects of apoE4 on cognitive impairment in non-demented subjects. Dement Geriatr Cogn Disord.32(2):135-42 (2011).
• Alexopoulos, Glatt, Hoptman, et al. BDNF Val66met polymorphism, white matter abnormalities and remission of geriatric depression. J Affect Disord.125(1-3):262-8 (2010).
• Depression in the elderly.Lancet. 365:1961-70 (2005).
• Foley, Salat, Stricker, et al. Interactive effects of apolipoprotein e4 and diabetes risk on later myelinating white matter regions in neurologically healthy older aged adults. Am J Alzheimer’s Dis Other Demen.29(3):222-35 (2014).

BILE ACIDS INDUCE EXPRESSION OF GENES IN BROWN FAT THAT INCREASE METABOLIC RATE (THERMOGENESIS)

The physiological functions of bile acids have been found to extend beyond that of regulating the absorption and catabolism (breakdown) of fats such as cholesterol and triglycerides. It is reportedly involved in the liver’s metabolism of fatty acid and triglyceride synthesis and VLDL (very low density lipoproteins) production mediated by sterol-regulatory-element-binding protein 1c and bile acids have been shown to inhibit high fat diet induced hyperglycemia and obesity in C57BL/6J mice (Ikemoto, 1997). Not too long ago, a paper (Watanabe, 2006) reported that bile acids increased energy expenditure in brown fat (this was in mice) and prevented obesity and insulin resistance. Remarkably, they found that cholic acid, a bile acid, induced the enzyme (D2, iodothyronine deiodinase type 2) that converts the biologically inactive thyroid hormone T4 to its active form T3. Cholic acid increased D2 activity and oxygen consumption in brown fat, preventing obesity and increasing fat oxidation (thus increasing insulin sensitivity). Incidentally, as an aside, niacin (via the pulsatile release of prostaglandin D2) also increases the oxidation of fats by signaling the conversion of cellular energy use from glucose to fats (Virtue, 2012); this appears to be one of the mechanisms by which niacin beneficially affects the metabolism of lipids.

Iodothyronine diodinase type 2 (D2) is also expressed in skeletal muscle. The researchers (Watanabe, 2006) found that skeletal muscle cells from the mice treated with cholic acid also had increased D2 activity and therefore served as a source of the active form of thyroid hormone.

D2 Is a Selenoprotein

One way to improve the function of D2 is to take adequate amounts of selenium as the enzyme is a selenoprotein (Curcio, 2001). Inadequate selenium intake is one way that people can be hypothyroid even when they secrete adequate amounts of T4 because D2 is needed to convert that T4 to its active form T3.

References

• Curcio et al. The human type 2 iodothyronine deiodinase is a selenoprotein highly expressed in a mesothelioma cell line.J Biol Chem. 276:30183-7 (2001).
• Watanabe, Houten, Mataki, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. 439:484-9 (2006).
• Ikemoto, Takahashi, Tsunoda, et al. Cholate inhibits high-fat diet-induced hyperglycemia and obesity with acyl-CoA synthetase mRNA decrease. Am J Physiol.273 (Endocrinol Metab 36): E37-E45 (1997).
• Virtue, Feldmann, Christian, et al. A new role for lipocalin prostaglandin D synthase in the regulation of brown adipose tissue substrate utilization. 61:3139-47 (2012)

NUTRITION AND THE BRAIN DIETARY
PROTECTION AGAINST AUTOIMMUNE DISEASES IN THE BRAIN
BARLEY BETA GLUCANS

Short Chain Fatty Acids (acetate, propionate, butyrate) Protection Against Autoimmunity (especially by propionate) in the Central Nervous System (in an animal model of multiple sclerosis)

Barley and oats are two excellent sources of beta glucans, a component of fiber, that has been shown to reduce cholesterol by lowering the reabsorption of bile acids, thus increasing the excretion of cholesterol (which is converted to bile acids) in the feces (Kim and White, 2010). Bile acids are described as “physiological detergents that play important roles in facilitating the absorption of dietary lipids and fat-soluble vitamins and biliary excretion and disposal of endogenous metabolites and xenobiotics.” “In the liver, bile acids inhibit both triglyceride synthesis and gluconeogenesis.” “…bile acids activate a G protein coupled receptor TGR5, which stimulates energy expenditure in brown adipocytes. TGR5 agonists have been shown to improve obesity and insulin resistance.” (last three quotes from Li, 2010). [More on the effect of bile acids on obesity in the article just following this one.]

Interestingly, the fermentation of beta glucans takes place in the large intestine (in contrast to many other more readily digested fibers that are usually fermented in the small intestine) as a result of the action of colonic microflora (Kim and White, 2010). Here, the fermentation of beta glucans results in the formation of short chain fatty acids—acetate, propionate, and butyrate—which are now known to provide protection to the gastrointestinal (GI) tract by inhibiting the growth of pathogenic bacteria, reducing cholesterol, as well as helping in the absorption of essential minerals including calcium and magnesium (Kim and White, 2010).

A very new paper (Haghikia, 2015) now reports that long chain fatty acids enhanced the formation of T helper 1 (Th1) and/or Th17 cells that are involved in autoimmune diseases (Haghikia, 2015). Short chain fatty acids, particularly propionate, were shown in the Haghikia et al paper to ameliorate experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. The mechanism involved the ability of the short chain fatty acids to beneficially influence the creation of T regulatory (Treg) cells that restrain excessive immune system activity as seen in autoimmune diseases. As the authors note, the Treg cell effector cell balance “is disturbed in MS [multiple sclerosis] patients.” They also point out the exceptional effect of propionate, “[o]f particular interest is the ability of PA [propionic acid] to beneficially influence the generation of Treg cells. Our study posits PA as a potent compound with the capacity to restrain CNS [central nervous system] autoimmunity via restoration of the altered Treg cell effector T cell balance, which is disturbed in MS patients.” Moreover, the researchers note “growing evidence for the lasting dietary effect [of propionic acid] on microbiome composition” and indicate their opinion that “a rapid translation of PA therapy from clinical studies to clinical trials in MS patients seems reasonable.”

We agree that clinical trials with propionate seem reasonable, but as propionate is an unpatentable compound, widely available and inexpensive, it is unlikely to interest pharmaceutical companies in investing millions for research and with economic conditions as bad as they are, government money is unlikely to be forthcoming for this research either.

How to Get More Propionate from Your Diet

One way to get increased amounts of propionate (which cannot be taken orally as a supplement because it will not survive passage through the liver) is to ingest digestive resistant fiber. Our hydrogen power formulation is a fructo-oligosaccharide or long chain inulin and the published literature indicates it as an extremely good source of fiber that is fermented to short chain fatty acids, with especially large amounts of propionate as compared to other fibers (Kim and White, 2010). Of course, the hydrogen power formulation is specifically intended to be used as a fuel by hydrogen producing gut microbes in the lower digestive tract, where the hydrogen diffuses throughout the body, passes through the blood-brain barrier and into mitochondria, and provides protection against hydroxyl radicals, the most dangerous biological radical, and peroxynitrite (Ichihara, 2015). Our barley nuggets, flour, and flakes are from a special barley strain that is very high in beta glucans. Our resistant starch is also a good precursor to propionate.)

Interestingly, there may be autoimmune components to Alzheimer’s disease (AD) (as indicated by a literature search we did on October 20, 2015; also see Bartzokis, 2011) and, thus, there is the possibility that a fiber that is fermented to propionate and other short chain fatty acids might also help prevent or mitigate the autoimmune involvement in AD. We have not seen a paper specifically testing this hypothesis.

References

• Kim and White. In vitro bile-acid binding and fermentation of high, medium, and low molecular weight beta-glucan.J Agric Food Chem. 58:628-34 (2010).
• Haghikia, JIorg, Duscha, et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. 43:817-29 (2015).
• Li, Chanda, et al. Glucose stimulates cholesterol 7 alpha-hydroxylase gene transcription in human hepatocytes. J Lipid Res.51:832-42 (2010).
• Ichihara, Sobue, Mikako Ito, et al. Beneficial biological effects and the underlying mechanisms of molecular hydrogen—comprehensive review of 321 original articles. Med Gas Res.5:12 (2015), 21 pp.
• Alzheimer’s disease as homeostatic responses to age-related myelin breakdown. Neurobiol Aging. 32(8):1341-71 (2011).

PROSTAGLANDINS AS MAJOR FACTORS IN INFLAMMATION, BOTH AS PRO-INFLAMMATORY AND ANTI-INFLAMMATORY

Sandy Studies the Niacin Flush and Learns a Lot About the Regulation of Inflammation by Prostaglandins

When Sandy wrote her paper on the niacin flush (see the July, August, and September issues of the Durk & Sandy newsletter at the Life Enhancement website (www.life-enhancement.com), her purpose was to find out whether it was a good idea to eliminate the niacin flush in order to make niacin supplementation more pleasant for those who didn’t like the flush. It was not self-evident whether the flush played a part in the protective effects of niacin (the immediate release form that causes flushing) or whether it could be suppressed without reducing the very powerful beneficial effects of niacin in protecting against non-fatal heart attacks (the most common kind) and reducing the risk of a variety of diseases associated with dyslipidemia and inflammation, such as diabetes, cardiovascular disease, non-alcoholic fatty liver disease, and many others.

In the course of writing the paper, she learned a lot about how the niacin flush works (a major effect is the pulsatile release of prostaglandin D2, which suppresses the inflammatory prostaglandin E2, which appears to be a factor in every inflammatory disease. She also learned that finding out what was known at any particular time was very difficult, requiring many extensive literature searches, due to the disseminated understanding of a particular aspect of science, the “balkanization” of science (where many areas of science are not very well connected to other areas), and the level of understanding differing from one scientist to another. Sometimes it seemed that a particular fact that had been discovered years ago had to be rediscovered due to a sort of failure of the earlier knowledge to be kept alive in ongoing discussions. This is why the disclaimer “we are the first to discover what we report in this paper, to the best of our knowledge” has become ubiquitous, because you can never be entirely sure.

A good example of the last point, that you can find work that predates new research and anticipates its findings is the following: Sandy just found a 1998 paper (Prasad, 1998), a review that proposed that “PG [prostaglandin] induced elevation of Abeta [amyloid beta] may lead to an increased binding of Abeta…” and they report their prior work in which they show that “prostaglandins (PG), which are [] released during inflammatory reactions, cause rapid degenerative changes in differentiated murine neuroblastoma (NB) cells in culture.”

Sandy became very interested in prostaglandins D2 and E2 and their apparent ubiquitous appearance in inflammatory diseases. It seemed that the papers she read did not distinguish between the PULSATILE release of PGD2, which appeared to be an important anti-inflammatory signal, as compared to CHRONIC release of PGD2, which was pro-inflammatory, as she learned was the case in Alzheimer’s disease. Even now, this distinction does not seem to be mentioned in papers.

A recent paper (Das, 2011) describes inflammation and its resolution as follows: “During the early phase of inflammation, COX-2 derived PGs [prostaglandins] and TXs [thromboxanes] and lipoxygenase-derived LTs [leukotrienes] initiate exudate formation and inflammatory cell influx. TNF-alpha causes an immediate influx of neutrophils concomitant with PGE2 [prostaglandin E2] and LTB4 [leukotriene B4] production, whereas during the phase of resolution of inflammation, an increase in LXA4 [lipoxin A4, a pro-resolution molecule derived from arachidonic acid], PGD2 [prostaglandin D2] and its product 15deoxydelta12-14PGJ2 formation occurs that induces resolution of inflammation with a simultaneous decrease in PGE2 synthesis that stops neutrophil influx and enhances phagocytosis of debris.”

References

• A defect in the activities of delta6 and delta5 desaturases and pro-resolution bioactive lipids in the pathobiology of non-alcoholic fatty liver disease. World J Diabetes. 2(11):176-88 (2011).
• Prasad, Hovland, La Rosa, et al. Prostaglandins as putative neurotoxins in Alzheimer’s disease. Proc Soc Exp Biol Med.219:120-5 (1998).

AGE-ASSOCIATED DECREASE IN ARACHIDONIC ACID AND EPA, DHA

A paper (Das, 2011) reviews changes with age that result in reduced levels of arachidonic acid and the long chain omega 3 fatty acids (found in fish oils) EPA and DHA and, consequently, low-grade systemic inflammation due to a reduced level of the important antiinflammatory, inflammation resolving molecules that are derived from them, lipoxins, resolvins, and protectins, respectively. It may surprise you to learn that arachidonic acid, which is the source of highly inflammatory prostaglandins, can also be converted to lipoxins, that have antiinflammatory effects. The chemical pathways are described in Das, 2011: “TNFalpha [tumor necrosis factor alpha, a major inflammatory cytokine] causes an immediate influx [to the inflamed tissues] of neutrophils concomitant with PGE2 [prostaglandin E2, a powerful inflammatory prostaglandin] and LTB4 [leukotriene B4] production, whereas during the phase of resolution of inflammation, an increase in LXA4, PGD2 [prostaglandin D2, which can function as an important antiinflammatory molecule via pulsatile release, as in the niacin flush] and its product 15 deoxydelta 12-14PGJ2 formation occurs that induces resolution of inflammation with a simultaneous decrease in PGE2 synthesis that stops neutrophil influx and enhances phagocytosis of debris.” The authors explain that this is a process in which there are two waves of release of arachidonic acid, one in which it and its metabolites are involved in inflammation and one in which they are involved in the resolution of inflammation. They note that high fat diets, trans-fat, and cholesterol block the action of the enzymes (delta5 and delta6 desaturases) that are required to produce GLA (gamma linolenic acid), DGLA (dihomogammalinolenic acid), AA (arachidonic acid) EPA, and DHA, thus exacerbating inflammatory conditions.

DECREASE IN MEMBRANE ARACHIDONIC ACID IN HIPPOCAMPUS WITH AGE SHOWN TO IMPAIR COGNITION

Another paper (McGahon, 1997) described how the age-associated decrease in membrane arachidonic acid (AA) observed in the dentate gyrus of the hippocampus of rats resulted in impaired long-term potentiation, an important process in learning and memory. Giving the aged animals a diet supplemented with arachidonic acid and its precursor, gamma-linolenic acid, resulted in reversal of the decreased membrane AA and sustained long term potentiation “indistinguishable from four month controls.”

We both take supplemental gamma linolenic acid.

References

• A defect in the activities of delta6 and delta5 desaturases and pro-resolution bioactive lipids in the pathobiology of non-alcoholic fatty liver disease. World J Diabetes. 2(11):176-88 (2011).
• McGahon et al. The ability of aged rats to sustain long-term potentiation is restored when the age-related decrease in membrane arachidonic acid concentration is reversed. 81(1):9-16 (1997).

PHENOLIC ACIDS IN PLANTS SUPPRESS LIPOLYSIS IN ADIPOCYTES (FAT CELLS) VIA ACTIVATION OF THE NIACIN RECEPTOR GRP109A (ALSO CALLED HM74A/PUMA-G)

The phenolic acids (including the important polyphenols you get in your diet and probably also take in supplement form), found ubiquitously in the plant kingdom, have been reported in a recent paper (Ren, 2009) to suppress lipolysis via activation of the same receptor by which niacin also suppresses lipolysis, one of the major protective effects of niacin against cardiovascular disease.

The phenolic acids tested and reported (Ren, 2009) to inhibit adipocyte lipolysis were shown in Table 1 and included (showing the dose that inhibits lipolysis by 50%, the IC50): niacin (nicotinic acid) at 0.2, caffeic acid at 14, gallic acid at 30 and others less well known, such as protocatechulc acid at 20. Note that niacin is much more effective at inhibiting lipolysis, but keep in mind that the dose of niacin being reported here is the pharmacological dose used in conventional therapy for reducing LDL cholesterol and increasing HDL cholesterol and is far higher than the physiological amount of niacin found in a good diet. The other compounds are presumably reported at doses closer to the physiological amounts one can get in a diet.

The authors explained how they became interested in the possible activity of phenolic acids at the niacin receptor: “ …both phenolic acids and nicotinic acid are small carboxylic acids with close structural similarity. We also note that application of certain phenolic acids, such as benzoic acid, also induces a flushing response and prostaglandin D2 release in a manner similar to that of nicotinic acid treatment. We thus asked whether phenolic acids could act as GPR109A agonists [activators].”

The authors conclude in their paper’s abstract: “Activation of GPR109A by phenolic acids may thus contribute to a cardiovascular benefit of these plant-derived products.” They also note in the text of the paper that, “while considered on an individual basis, the amount of a given phenolic acid may be low, and a combined phenolic acid content could be quite high.” They give as an example of combining different phenolic acids, “…addition of 80 mm of trans-cinnamic acid, p-coumaric acid, or benzoic acid alone led to a suppression of lipolysis by 17, 26, and 3%, respectively. However, when the same concentrations of these three compounds were combined, a suppression of 53% was observed.”

References

• Ren, Kaplan, Hernandez, Cheng, 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).

LIPOLYSIS MAY MEDIATE THE PROINFLAMMATORY EFFECTS OF VERY LOW DENSITY LIPOPROTEIN (VLDL)

In a 2006 paper (Saraswathi and Hasty, 2006), researchers studied the effect of incubating mouse peritoneal macrophages with 100 μg/ml VLDL for six hours, finding that it resulted in 2.8 to 3.7 fold increases in intracellular triglycerides and free fatty acids, respectively, via intracellular hydrolysis (lipolysis). There were significant increases of at least two fold in inflammatory proteins as well, including TNFalpha, IL-1beta, MCP-1 (monocyte chemoattractant protein-1, intercellular adhesion molecule 1, matrix metalloproteinase 3 (MMP3), and macrophage inflammatory protein 1alpha. The authors suggest that these changes point to a direct proatherogenic effect of VLDL. The increases in triglycerides and free fatty acids was eliminated by Orlistat, an OTC weight-loss drug.

Interestingly, VLDL is known to be the lipoprotein carrier for apoE4. “ApoE3 binds preferentially to HDL and apoE4 to VLDL.” (Tetali, 2010). The fact that the ApoE4 gene is being carried by a potentially proinflammatory lipoprotein suggests the possibility of an interplay that may increase the adverse effects of apoE4. Suggestion: keep your VLDL level down. Niacin is very effective at this, as is fish oils.

References

• Saraswathi and Hasty. The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritonial macrophages.J Lipid Res. 47:1406-16 (2006).
• Tetali, Budamagunta, Simion, et al. VLDL lipolysis products increase VLDL fluidity and convert apolipoprotein E4 into a more expanded conformation. J Lipid Res.51:1273-83 (2010).

RESTLESS LEGS: OTHER POSSIBLE REMEDIES

Quinine Might Work for Some

Quinine in the form of tonic water, a very popular mixer with spirit alcohol, has been found to have the very interesting effect (Talavera, 2008) of inhibiting the TRPM5 channel-dependent response of taste receptors to sweet taste. This is part of a recently discovered facility of bitter compounds to frequently inhibit the sweet taste transduction pathway.

Dr. xxxx, the new editor/author of the “Nutrition & Healing” newsletter, formerly written by Jonathan V. Wright, M.D., suggests that 2-4 ounces of tonic water with quinine may be able to stop ongoing restless legs in some. I’ve tried it. Sometimes it helps. But don’t drink too much of it. Though there is no warning on a bottle of tonic water, there is about 75 mg of quinine in a bottle (1 liter) and some people have been reported to be sensitive to as little as 30 mg. (See “Wikipedia” article on quinine.) Those sensitive to it can end up having a kind of hangover that includes lower blood pressure (even to the point of fainting), lightheadedness, and difficult in walking (as if you were drunk on alcohol). This may possibly be due to the decreased response of the taste receptors to sucrose, which is supposed to release insulin that then releases noradrenaline. Reduced noradrenaline can lower blood pressure and might lead to lightheadedness, fainting, memory problems, and motor clumsiness.

Scaring Away Restless Legs

A possibility (per an experience of Sandy’s) is that a scary incident can frighten away restless legs, just as hiccups can also be eliminated that way. (You may have to be totally unprepared for the surprise fright.) This suggests (but doesn’t prove) that a bolus release of (probably) noradrenaline/adrenaline might be what counteracted the restless legs in this case. On the other hand, a chronic release (as compared to a bolus release) of noradrenaline/adrenaline might make restless legs worse so don’t take a long-acting adrenergic agonist and necessarily expect it to give you longtime relief.

Sandy has found agonists of the adrenergic alpha2 receptor to be usually effective at suppressing restless legs. Such agonists include the anti-hypertensive/sedative drug clonidine and dopamine (with L-dopa as its precursor). Alpha 2 adrenergic agonists suppress noradrenergic neurons in the locus coeruleus; these neurons “fire during waking, fire less during sleep and their activity increases just before waking, suggesting they promote wakefulness.” (Zhang, 2015). The scientists who produced that paper (Zhang, 2015) found that a drug with alpha 2 adrenergic receptor agonism produced sedation that resembled closely recovery sleep following loss of sleep.

References

• Talavera, Yasumatsu, et al. The taste transduction channel TRPM5 is a locus for bitter-sweet taste interactions. FASEB J. 22:1343-55 (2008).
• Zhang, Ferretti, Guntan, et al. Neuronal ensembles sufficient for recovery sleep and t he sedative actions of alpha2 adrenergic agonists. Nat Neurosci.18(4):553-61 (2015).

ALPHA2 ADRENERGIC AGONISTS MAY MIMIC RECOVERY SLEEP

After not getting enough sleep, recovery sleep is an induced state that helps restore normal waking feeling and behavior. A paper (Zhang, 2015) reports that, “…recovery sleep and alpha 2 adrenergic receptor-induced sedation were not only similar behavioral states, but were both induced by activating similar neuronal populations in the PO [preoptic] hypothalamus.” The researchers found that GABAergic neurons in the LPO (preoptic hypothalamus) were required for the onset of dexmedetomidine-induced sedation. Desmedetomidine is an alpha2 adrenergic agonist used in clinical practice as an anesthetic.

This might be useful for people who have lost sleep and want to try using an alpha2 adrenergic receptor agonist to help them recover. Clonidine is such an agonist, a prescription drug that has been widely used as a sedative and is safe for most normal people at usual dosage prescribed. It will put you to sleep, so don’t take it when you plan to be working or driving. This drug may help relieve restless legs, but in Sandy’s experience it helped only when taken at night before bedtime. Natural products that act as agonists at alpha 2 adrenergic receptors are arginine and possibly agmatine (decarboxylated arginine found naturally in human serum) (Joshi, 2007). Clonidine potently lowers blood pressure, so be very cautious about dizziness-induced falls.

Interestingly, the authors (Zhang, 2015) note that, “candidate homeostat molecules, which accumulate proportionally to the amount of sleep deprivation and act locally in the preoptic area, include PGD2 [prostaglandin D2] and adenosine.” PGD2 is released in a pulse by immediate release niacin at doses of 50 mg or more, depending on individual sensitivity. We have found niacin to have a calming, sometimes nap-inducing effect.

References

• Zhang, Ferretti, Guntan, et al. Neuronal ensembles sufficient for recovery sleep and the sedative action of alpha2 adrenergic agonists. Nat Neurosci.18(4):553-61 (2015).
• Joshi, Ferguson, Johnson, et al. Receptor-mediated activation of nitric oxide synthesis by arginine in endothelial cells. Proc Natl Acad Sci U S A. 104(24):9982-7 (2007).

APPETIZERS

AI theorist Eliezer Yudkowsky coined Moore’s Law of Mad Science: Every eighteen months, the minimum IQ necessary to destroy the world drops by one point.

The task is … not so much to see what no one has yet seen; but to think what nobody has yet thought, about that which everybody sees.

—Erwin Schrodinger

The important thing in science is not so much to obtain new facts as to discover new ways of thinking about them.

—Sir William Lawrence Bragg

When everything is connected to everything else, then anything can be explained in terms of any single piece that is a part of that everything.

—Sandy Shaw

(Sandy’s comment: Do you ever wonder why some scientists, having discovered an important biological fact that connects other things in biology that had hitherto not been connected to it, begin to try to explain everything in terms of that newly discovered connection. It is because everything in biology is connected to everything else in biology at a certain level, so you really CAN explain everything in terms of any one factor in that whole. Of course, the same is true for physics or chemistry as well.)

The mind is its own place, and in itself 
Can make a heaven of hell.

—John Milton, Paradise Lost

“Nasrudin went into a bank with a cheque to cash. “Can you identify yourself?” asked the clerk. Nasrudin took out a mirror and peered into it. “Yes, that’s me all right,” he said.”

—Idries Shah, The Subtlties

OF THE INIMITABLE MULLA NASRUDIN... the “me“ who is responsible and whom society recognizes as responsible resides in the ability to control the diverse systems within [the mind]. Something has to command the wheeling in and out of one or the other small minds. In [one] view, the separate minds clamor and fight for control and the strongest wins, with no directing force.

—Multimind by Robert Ornstein, pg. 179, said to be “A New Way of Looking at Human Behavior” (Major Books, 2003). See below for recent scientific publication that supports this prescient view of how “pieces” of the mind “clamor and fight for control and the strongest wins.” The science of the mind of man meets science fiction. ‘Tis amazing.

Finally, we have this fascinating quote from Adam Smith in his The Theory of Moral Sentiments (1759):

When I endeavor to examine my own conduct… I divide myself as it were into two persons, and that I, the examiner and judge, represent a different character from the other I, the person whose conduct is examined into and judged of. The first is the spectator… The second is the agent, the person whom I properly call myself, and of whose conduct, under the character of a spectator, I was endeavoring to form some opinion.

AUTOPHAGY AGAINST TYPE II DIABETES

Pancreatic Beta Cells Protected By Autophagy Against Amyloidogenic Degradation That Induces the Onset of Type II Diabetes

Aggregates of Amyloid Involved in Type II Diabetes Very Similar to the Aggregates of Neurotoxic Amyloid in Alzheimer’s Disease

TREHALOSE, An Inducer of Autophagy, May Be a Possible Protectant Against Amyloid Aggregation

VITAMIN D3 Induces Autophagy, Protects Against Inflammation and Infection

Following a trail of damaging mechanisms that cause type II diabetes, we find that an important source of protection is the process of autophagy.¹ A new paper¹ reports on how the loss of autophagy along with beta cell expression of IAPP (amyloid islet polypeptide, also called amylin), a 37 amino acid protein coexpressed and released by pancreatic beta cells along with insulin, results in the death (apoptosis) of beta cells. IAPP forms amyloid deposits in beta cells remarkably similar to the amyloid deposits that form in the brain during Alzheimer’s disease; these deposits are composed of aggregated, misfolded proteins that are normally cleared by the process of autophagy. In the absence of adequate autophagy, the toxic effects of IAPP deposits induces endoplasmic reticulum stress that kills beta cells and can, in that way, lead to type II diabetes.

In the paper (Rivera, 2014) the researchers report on their experiments with rodent beta cell islets, showing that when autophagy was stimulated by the autophagy-inducing drug rapamycin that (at the dose used) beta cell IAPP content was reduced by 54% ±5.5% versus untreated (no rapamycin) cells. More interestingly, since the rodent form of IAPP does not form amyloidogenic aggregated, misfolded cytotoxic deposits, the researchers duplicated their experiments using HUMAN islets and found that rapamycin decreased IAPP content by 31% ±12.4% as compared to untreated human islets.

The researchers cite a paper (one which we already had) (Zang, 2007) that listed a number of FDA-approved drugs that, like rapamycin, had also been found to have autophagy-enhancing effects. What is particularly interesting among these identified autophagy-enhancing drugs is the safe and relatively inexpensive over-the-counter drug loperamide, which is used to treat diarrhea. (Not unsurprisingly, one possible side effect of using too much is constipation. Side effects of the drug are generally mild. Though loperamide is a mu opioid agonist, it does not pass the blood-brain barrier except in those rare individuals with “leaky” blood-brain barriers.)

The researchers conclude that their paper presents “the first line of evidence” that establishes a protective effect of autophagy against human IAPP-induced toxicity in human beta cells and protects the cells from being killed, part of the process resulting in type II diabetes. They propose “the players of the autophagy pathway as key therapeutic targets for treatment and prevention of T2D [type 2 diabetes].” (Rivera, 2014).

Enhancing Autophagy With TREHALOSE or Loperamide

If you have type II diabetes and would like to try loperamide to induce autophagy to possibly improve your diabetes, we suggest you follow the label instructions. The limited amount of loperamide as given on the label is particularly aimed at avoiding constipation, but if you are under the supervision of a physician, you might ask him or her about taking up to twice that amount and simply reducing your dose if you encounter constipation.

Note that TREHALOSE, the natural osmolyte that acts as a chaperone to help proteins fold properly (found in our protein folding formulation), is also an inducer of autophagy. In a different paper on autophagy, IAPP, and the development of type II diabetes, TREHALOSE was used to induce autophagy to promote clearance of the amyloidogenic IAPP in mice fed a high fat diet (Kim, 2014).

VITAMIN D3 Is Another Natural Inducer of Autophagy

Recent research (Wu, 2011) reports that VITAMIN D3 induces autophagy in and provides protection during inflammation and infection. “Vitamin D deficiency is a critical factor in the pathology of at least 17 varieties of cancer, as well as autoimmune diseases, diabetes, osteoarthritis, periodontal disease, and more.” (Wu, 2011) “Autophagy … plays important roles in the degradation of damaged cytosolic components and misfolded proteins and in organelle turnover.” (Yuk, 2009).

References

• Cheng et al. Coffee components inhibit amyloid formation of human islet amyloid polypeptide in vitro: possible links between coffee consumption and diabetes mellitus. J Agric Food Chem.59:13147-55 (2011).
• Huxley et al. Coffee, decaffeinated coffee, and tea consumption in relation to incident type 2 diabetes mellitus. Arch Intern Med.169(22):2053-63 (2009).
• Kim, Cheon, Jeong, Quan, et al. Amyloidogenic peptide oligomer accumulation in autophagy-deficient beta cells induces diabetes. J Clin Invest.124(8):3311-24 (2014).
• Rivera et al. Autophagy defends pancreatic beta cells from human islet amyloid polypeptide-induced toxicity.J Clin Invest. 124(8):3489-3500 (2014).
• Wu and Sun. Vitamin D, vitamin D receptor, and macroautophagy in inflammation and infection. Discov Med.11(59):325-35 (2011).
• Yuk, Shin, Lee, et al. Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. Cell Host Microbe.6:231-43 (2009).
• Zhang et al. Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci U S A.I 104(48):19023-8 (2007).

COFFEE COMPONENTS INHIBIT AMYLOID FORMATION OF HUMAN IAPP IN VITRO: MAY EXPLAIN THE INVERSE RELATION BETWEEN COFFEE CONSUMPTION AND TYPE II DIABETES

Significant Inverse Association Between Tea and Type II Diabetes Incidence

Another aspect of the IAPP-type II diabetes link is found in a recent paper (Cheng, 2011) reporting that three major components of coffee, caffeine, caffeic acid, and chlorogenic acid, all inhibited the toxic aggregation of human IAPP in vitro. The protection was greatest for caffeic acid and least for chlorogenic acid. The paper also reports that in other studies EGCG (especially enriched in green tea) can inhibit the fibril formation of human IAPP (EGCG also inhibits the toxic amyloid formation in Alzheimer’s disease) as well as having protective effects on pancreatic beta cells.

A paper (Huxley, 2009) in a recent issue of Archives of Internal Medicine provided a meta-analysis of 18 studies involving00,000 people on the associations between the consumption of coffee and tea on the incidence of type II diabetes, finding an overall reduction in the risk of the disease. (Protection against the cytotoxic effects of IAPP could be one of the mechanisms responsible, but others are likely to be involved.) The beneficial effects of coffee, decaf coffee, or tea was found for those who ingested four cups a day, with the paper (Huxley, 2009) reporting that “every additional cup of coffee consumed in a day was associated with a 7% reduction in the excess risk of diabetes, 0.93 [95% confidence interval, 0.91-0.95] after adjustment for potential confounders.”

References

• Cheng et al. Coffee components inhibit amyloid formation of human islet amyloid polypeptide in vitro: possible links between coffee consumption and diabetes mellitus. J Agric Food Chem.59:13147-55 (2011).
• Huxley et al. Coffee, decaffeinated coffee, and tea consumption in relation to incident type 2 diabetes mellitus. Arch Intern Med.169(22):2053-63 (2009).
• Kim, Cheon, Jeong, Quan, et al. Amyloidogenic peptide oligomer accumulation in autophagy-deficient beta cells induces diabetes. J Clin Invest.124(8):3311-24 (2014).
• Rivera et al. Autophagy defends pancreatic beta cells from human islet amyloid polypeptide-induced toxicity.J Clin Invest. 124(8):3489-3500 (2014).
• Wu and Sun. Vitamin D, vitamin D receptor, and macroautophagy in inflammation and infection. Discov Med.11(59):325-35 (2011).
• Yuk, Shin, Lee, et al. Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. Cell Host Microbe.6:231-43 (2009).
• Zhang et al. Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci U S A.I 104(48):19023-8 (2007).

MOST HEART ATTACKS ARE NON-FATAL, SO THE REPORTED HIGHLY PROTECTIVE EFFECT OF NIACIN

AGAINST THE INCIDENCE OF NON-FATAL HEART ATTACKS IS OF MAJOR IMPORTANCE

In a paper (Keene, 2014) reports a meta-analysis of 117,411 patients, very interesting differences between the effects of niacin taken by patients NOT RECEIVING STATINS (this was before the statin era) and those who, later, were taking niacin and statins showed very statistically significant results 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 dyslipidemia, 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.

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 USE OF THE DESCRIPTOR “NON-FATAL” MAY CAUSE PEOPLE TO UNDERESTIMATE THE SIGNIFICANCE OF THESE RESULTS.

Studies with statins and cholesterol-reducing agents (niacin or fibrates) have repeatedly shown that reductions in LDL cholesterol with these in combination with statins are able “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. Laropriprant is thought to interfere with prostaglandin pathways which, as is explained in Sandy’s paper on prostaglandins and the niacin flush (Sandy Shaw, 2015), could be important and the authors of this paper(Keene, 2014) suggest that interference with prostaglandin pathways “could confound the effect of niacin.”

References

• Keene et al. 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 (published 18 July 2014).
• Sandy Shaw. Why the Niacin Flush May Be Surprisingly Beneficial to Your Health” in the July, August, and September 2015 issues of the web edition of the Life Enhancementmagazine (www.life-enhancement.com).

WHY RELIGIONS TEND TO HAVE PUNISHING GODS: PUBLIC GOODS GAMES MAY REVEAL PART OF THE REASON

BY SANDY SHAW AND DURK PEARSON

A “new” hypothesis to explain the success of the major religions posits that belief in judgmental gods that punish those who violate social norms have been a key to the cooperation needed to build and sustain large complex human societies (Wade, 2015).

The major successful religions tend to have punishing gods. Why might this be? The results of some public goods games on what humans are willing to contribute to the punishment of bad guys may help elucidate the source of this preference for punishing gods.

Some experiments have shown that a phenomenon called altruistic punishment is a form of human behavior, in which people have been shown to be willing to pay to punish bad guys (those who do not comply with social norms) by donating resources to their punishment even when it costs the donors more than they get back in benefits to themselves (e.g., their contribution acts as a public good by providing benefits to anyone whether they donate to the funding of the punishment or not). This could help to explain at least in part why people are willing to pay tithes to religions with punishing gods, even when they themselves do not benefit any more than those who do not pay such tithes. (Part of the reason for donating tithes may be a hope of getting into heaven. This reward would, if realized, be a privatized benefit rather than a public good.)

It appears that punishing bad guys is a strong motivation that supports altruistic punishment by inducing humans to pay to punish even when it costs them more than they can get back for their own individual benefit. Hence, punishing gods may be a mechanism by which humans seek to enforce cooperation with respect to social norms. The fact that religions with punishing gods have done so well indicates that they have been successful (so far) in this. However, some major religions evoke cooperation among their believers for the enforcement of social norms that differ from the social norms of other religions, leading to a sort of war of punishing gods as we see now in extreme Islam versus Christianity or Judaism.

During the fall of the ancient Grecian civilization, there was a veritable war of the gods, with polytheism where people chose sides by supporting various gods. Once again, we see a similar result from the loss of faith in central government as the instrument of punishment. Perhaps a war of punishing gods in religions is something like the war for power between different governments or even parts of governments such as we see now in the declining stages of Western governments. And notice how these different parts of government are moving more and more in the direction of punishing regimes of regulatory rules and regulations, with EPA, FDA, and NSA as particularly dangerous examples in the United States. The rapidly increasing sizes of “fines” for supposedly bad behavior is an example of where these agencies are heading.

When, in the Middle Ages, people lost the ability to believe in organized religion due to factors such as widespread corruption (with religions selling absolutions, you didn’t have to be good to get a ticket to heaven, etc.), it caused a major breakdown in civil order. You couldn’t trust God to be doing His job of punishing bad people. The disastrous result we suspect would be more violence as people looked to secular processes to do the punishing. This was finally resolved by the Reformation and Martin Luther to (some extent) restore God back to do the punishment.

The design of the American Republic with its innovative Constitution represented a form of restoration of government from an increasingly incoherent/punishing European model. Now we have an increasingly incoherent/punishing model for both European and American governments, so where this is going to end up and what will glue things back together into something coherent is impossible to predict from our current situation. John Galt isn’t going to do it; we think his imagination was too limited and nobody on the scene looks like John Galt, anyway. Donald Trump could, I suppose, be John Galt with severely limited long-term principles, but with the frank talk and honest depiction of the bad guys (other than himself) that we expect from Mr. Galt. In this new rendering, Mr. Galt’s inventive genius is applied to the benefit of Mr. Galt, while appearing to be (by Mr. Trump’s telling) on the side of everybody else, too. The occasional seizure of an old lady’s house by Mr. Trump to build a Trump superstructure has to be (suspend your disbelief) to the benefit of the overall society by adding a fabulous superstructure (a limousine parking lot for the Trump casino in Atlantic City, for example) to improve economic conditions, offer jobs, etc. It wouldn’t quite make the cut for John Galt, though. In fact, such behavior (seizing people’s houses for your own benefit) fits the pattern of a sociopath.

The very fact that people are turning to somebody like Trump indicates, as we see it, that at least some people are looking for that individual who will represent their desire for a punishing State, a really bad sign for the possible appearance of somebody like Hitler or Lenin. But the rise of Trump also suggests, we think, that people are looking for somebody who can restore a coherent punishing function of the government, when their faith in the extant government as the effective punishing agent is collapsing. A good model is the collapse of the Weimar Republic and the emergence of Naziism in Germany.

A good friend of ours suggested that this need for a punishing state is a defect in human intelligence, perhaps a fatal flaw. We have to agree. If people living in a large political entity cannot learn how to live together without having a Big Brother government forcing people to follow His rapidly increasing numbers of rules and regulations or be severely punished, what sort of future can Homo sapiens have?

One solution is to decentralize—reduce the sizes of political entities. Fifty states offer a lot more opportunity to find congenial rules and regulations than one giant superstate. That’s why the Founders designed the Constitution as they did. The passage of the 17th Amendment was a severe blow to that design as it eliminated the Senate as a body that represented the interests of the fifty states; after its passage, the entire Congress served the federal government. Federalism was given a mortal injury and we see the results today with ever increasing federal hegemony over the states. States aren’t perfect, but a choice of 50 as compared to one federal government ain’t chicken feed, either.

References

• Fehr & Gachter. Altruistic punishment in humans. 415:137-40 (2002).
• Fowler, Johnson, Smirnov. Egalitarian motive and altruistic punishment. 433:E1-E2 (2004).
• Birth of the moralizing gods. Science.349:919-22 (2015).

RESTLESS LEGS

PERSONAL OBSERVATIONS

BY SANDY SHAW

My experience with restless legs finds that, at least in my case, it can be brought on or made worse by:

1. Drinking carbonated beverages—Carbon dioxide inhalation can induce arousal by activating serotonin receptors (Richerson, 2004). Certain serotonin receptors surprisingly, induce arousal. “It is now clear that 5-HT [serotonin] actually causes arousal.” (Richerson, 2004, pg. 451) “Serotonergic neurons in the midbrain are also chemosensitive, and might mediate non-respiratory responses to increased carbon dioxide, such as arousal.” (Richerson, 2004) This arousal may be what drinkers of carbonated beverages are looking for. I find that drinking carbonated beverages increases my symptoms of restless legs. How serotonergic activation would do that I do not know. It is known that serotonin receptors can be involved in motor control (Richerson, 2004). The absorption of carbon dioxide from drinking carbonated drinks may be modulated by taking GAS-X or similar remedy to cause the carbon dioxide gas to be “burped” out, reducing the amount that is absorbed in the gastrointestinal tract. (There has to be a reason why humans go to the trouble and expense of getting carbon dioxide into so many drinks. Yes, it is pleasurable, but why? It may have a stimulating effect to increase awareness and arousal via serotonergic receptors. There may be, however, other chemoreceptors involved in the arousal response to carbon dioxide. See (Buchanan, 2010).
2. Eating foods on an empty stomach when the food contains more than about 20 grams of sugar (sucrose). This may be due to the release of insulin and subsequent release of noradrenaline (Watson, 2006). “Thus, changes in insulin levels may modulate synaptic NE [norepinephrine/noradrenaline] levels and behaviors normally associated with noradrenergic activity.” (Watson, 2006). Although noradrenaline levels decrease with aging, there is the possibility of compensatory hypersensitivity (increased reactiveness to NE). (Ah, yes, it is a delicate balancing act to get the dose of noradrenaline just right.)

Eating sugar with a meal should reduce the likelihood of stimulating restless legs because of the dilution of the sugar and the consequent slower absorption of it. Good sweeteners that avoid insulin release include erythritol (unlike other sugar alcohols, doesn’t cause diarrhea), xylitol, other sugar alcohols, palatinose (a natural sugar, found in honey and sugar cane). These slowly releases sugar for a very low glycemic index effect and little increase in insulin). Synthetic sweeteners such as saccharin, aspartame, sucralose, and others have been shown to have a detrimental effect on the gut microbiota. Stevia may also have similar detrimental effects. See below for article on the potential adverse effects of various non-sucrose sweeteners, both natural and synthetic.

3. I speculate (this is purely a speculation) that restless legs may be a symptom of temporal lobe epilepsy (Ottoson, 2015), which I have, and the symptoms of which increase in my own case concurrently in response to the same inducing factors, such as #1 and #2 above. Moreover, the drugs and nutrients I use to control temporal lobe epilepsy, such as gabapentin (with GABA receptor inducing effects), glycine, and taurine, also are effective in controlling restless legs in my case. The latter are personal observations only. I make no claim of cause and effect or generalizability.
4. Drinking very cold drinks can bring it on in my case, perhaps due to adrenergic stimulation. (Rossato, 2014) “In vivo cold sensation is detected by specific sensors for cold temperature expressed on peripheral cutaneous nerve endings leading to adrenergic stimulation.” (Rossato, 2014) (There has to be a reason why humans prefer very cold drinks and throughout history have gone to great lengths and expense to get what is necessary (refrigeration, ice, deep storage in the earth, etc.) to get their drinks cold. One has to presume that there is a preferred psychopharmacological state. I think it may be, in this case, adrenergic activation (Rossato, 2014) —and/or possibly cholinergic activation—by very cold-detecting sensors in the mouth or gastrointestinal tract. People like the effects of being stimulated.)

“The effect of adrenoceptors agonists on the production of other important mediators involved in inflammation have also been investigated. Prostaglandins are produced via the metabolism of AA [arachidonic acid] by a cyclooxygenase (COX) and subsequently by prostaglandin synthases.” “Our laboratory has also demonstrated that NE [norepinephrine, noradrenaline] is able to increase COX-2 expression in LPS-stimulated microglia.” (Schlachetzki, 2010). LPS is lipopolysaccharide, a bacterial cell wall component that activates the immune system and its inflammatory effects. However, noradrenaline levels decline with aging, a detrimental effect on cognition (Schlachetzki, 2010). Clinical trials treating patients with dementia or cognitive impairments with beta adrenergic receptor blockers has resulted in both beneficial results and detrimental results. In other studies, increasing noradrenaline by treatment with insulin resulted in improvement cognition in demented patients but in another study increased the level of inflammatory markers in the CSF (cerebral spinal fluid). The data are conflicting at this point (or as of 2010).

References

• Buchanan, Richerson. Central serotonin neurons are required for arousal to CO2. Proc Natl Acad Sci U S A. 107(37):16354-9 (2010).
• Ottosson, Wu, Nolting, et al. Resin-acid derivatives as potent electrostatic openers of voltage gated K channels and suppressors of neuronal excitability. Sci Rep.5:13278 (2015). “Many diseases that affect a large number of people, such as epilepsy, cardiac arrhythmia, and chronic pain, depend on increased electrical excitability.” Restless legs is a disorder that clearly involves increased electrical excitability.
• Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nat Rev Neurosci.Jun;5(6):449-61 (2004).
• Rossato, Granzotto, Macchi, et al. Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production. Mol Cell Endocrinol. 183:137-46 (2014).
• Schlachetzki et al. Function of norepinephrine in neuroinflammation and chronic neurodegenerative diseases. In Biochemistry and Histocytochemistry …  1. Edited by Fuchs and Auer. Hauppauge NY: Nova Science Publishers, Inc. 2010.
• Watson, Bernhardt, Reger, et al. Insulin effects on CSF norepinephrine and cognition in Alzheimer’s disease. Neurobiol Aging.27:38-41 (2006).

SAFETY ISSUES IN THE USE OF SWEETENERS AS ALTERNATIVES TO SUCROSE

ERYTHRITOL —A recent paper (Chung, 2013) reported that, using the Ames test and a test for the formation of micronuclei in the bone marrow cells of male ICR mice, erythritol was not mutagenic to bacterial cells and did not cause chromosomal damage in mammalian cells either in vitro or in vivo.

STEVIA, SACCHARIN —The OAT (organic anion transporter) is involved in the elimination by the kidneys of certain drugs (Schiffman, 2012). Competition with this transporter can have serious effects if drug elimination is reduced. An example given in Schiffman, 2012 is the interaction at OATs between non-steroidal-anti-inflammatory drugs and methotrexate that can result in severe methotrexate toxicity. When SACCHARIN coexists in the plasma with drugs that are substrates of OATs, it is said to potentially compete for transport and modulate the drug’s pharmacokinetics (Schiffman, 2012). STEVIOL, the metabolite of steviol glycosides (stevioside and rebaudioside) are also excreted with the involvement of OATs. It is not known what the clinical significance is of the interaction of saccharin or steviol with OATs (Schiffman, 2012). Interestingly, the Schiffman paper notes that steviol is sold commercially (Sigma Aldrich, 2012) as an OAT inhibitor. Stevioside was also associated with DNA aberrations in the liver, spleen, and brain as detected by comet assays, though the effects were possibly due to steviol, a metabolite of stevioside.

The Schiffman paper also notes that studies in rodents have found that sucralose (Splenda^®), acesulfame-K, and saccharin were shown to increase the expression of the Na+-glucose cotransporter SGLT1 and the glucose transporter GLUT2 via interaction with sweet taste receptors in the gastrointestinal tract. Schiffman reports that interaction of these same sweeteners with sweet taste receptors in pancreatic beta cells has been shown to induce insulin secretion. These and other effects discussed in the Schiffman paper indicate, the author says, that more research needs to be done on these sweeteners. For example, he notes, it was not known at that time (2012) whether these sweeteners passed the blood-brain barrier.

Another thing reported in the Schiffman paper was that neuroimaging studies had shown in a 2011 paper that routine use of artificial sweeteners altered responses to sucrose in the amygdala and insula as measured by fMRI scanning.

Another paper (Schiffman and Rother, 2013) provided a very lengthy (52 pages) discussion of the various effects of sucralose, including its alteration in the composition of the gut microbiota.

The safest sweeteners appear to be sugar in small amounts and sugar alcohols (such as erythritol, xylitol). In the case of sugar alcohols, it is useful to know that erythritol is by far the least likely of the sugar alcohols to cause diarrhea in excessive amounts and has almost no calories, being excreted largely unchanged in the urine. Another possibility for a safe sweetener is Palatinose™ (isomaltulose, a disaccharide composed of glucose and fructose linked by an alpha-1,6-glycosidic bond), a natural sugar found in honey and sugar cane extract that is digested only very slowly, has a low glycemic index, and increases insulin levels very little. Palatinose is also easy on teeth, as it is not usable by oral bacteria. (See “Isomaltulose” in Wikipedia.)

References

• Abou-Donia, El-Masry, Abdel-Rahman, McLendon, Schiffman. Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats. J Toxicol Environ Health A. 71(21):1415-29 (2008).
• Chung and Lee. Genotoxicity assessment of erythritol by using short-term assay. Toxicol Res. 29(4):249-55 (2013).
• Rationale for further medical and health research on high-potency sweeteners. Chem Senses. 37:671-9 (2012).
• Schiffman and Rother. Sucralose, a synthetic organochlorine sweetener: overview of biological issues.J Toxicol Environ Health B Crit Rev. 16:399-451 (2013).

A SCIENTIST COMPLAINS OF THE DIFFICULTY OF GETTING FUNDING FOR UNUSUAL PHENOMENA FOR WHICH THERE IS NO HYPOTHESIS

BY SANDY SHAW & DURK PEARSON

An article by Steven McKnight, the President of the American Society for Biochemistry and Molecular Biology (which publishes The Journal Of Biological Chemistry and The Journal of Lipid Chemistry) in the June/July 2015 issue of ASBMB TODAY (Vol. 14 No. 6, pp. 2-3) deplores the difficulty in getting funding to study very interesting scientific puzzles for which there is no hypothesis. (Such research may be an important way of developing data to suggest hypotheses.)

He pointed to a particular puzzle as an example. He noted that “[d]uring hibernation, the core body temperature of ground squirrels goes from 37 degrees C down to 4-5 degrees C. Perplexingly, with robust periodicity, hibernating ground squirrels warm back up to 37degrees C around once every 10 days [reference provided]. These brief periods of warming are called interbout arousals. What is the utility to the hibernating ground squirrel to periodically warm up for about a day?”

Sandy has a suggestion for a possible reason for the warming. She suggests that it is to activate neurons (possibly of the serotonergic, cholinergic, and adrenergic nervous systems) that are known to die if not activated for a certain period of time. Durk suggests that one way to test this is to see if hibernating bears also have interbout arousals about every 10 days, similarly to the squirrels. Another question is whether the neurons die in ten days or less if they remain inactivated.

Durk suggests that the warming (the arousal from hibernation) may be needed for effective immune system function. He notes that snakes seek greater heat when ill, and will become infected with pathogens if this increased warmth is unavailable.

Incidentally, we agree with Dr. McKnight that it is a shame that more far reaching research that looks for hypotheses rather than investigates hypotheses you already have is hard to get funding for. But this is perhaps a more risky way of spending government money than when you have already advanced to having a hypothesis based on available data. Bureaucracies do not tend to engage in risk when it is so much safer to put money into research that is more fully developed. Look to entrepreneurs in the private sector for investment in risky new science and technology.

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 declines rapidly following menopause—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 phosphatidylcholine (via biochemical pathways) varies between individuals suggesting that the amount that may be adequate for much of the population per the IOM recommendation may not be adequate for YOU. Note that human nutrition experiments are usually performed on young healthy college students, not on elderly people.

In short, choline is a major nutrient for keeping your cognitive function in good condition, as you get older. Durk takes 2 grams a day of choline in the form of choline dihydrogen citrate. Sandy is now taking CDP-choline, a form of choline that is a step closer in the synthesis of phosphatidylcholine (Carter, 2008) (a defect in this synthesis is now believed to be a major cause of Alzheimer’s disease) and has recently been identified as being epigenetically tagged by the cytidine diphosphate and, hence, may have some benefits over choline alone in the complex use of choline in the function of the cholinergic nervous system. She also takes 1 gram of choline a day as choline dihydrogen citrate in our sugar-free choline formulation.

References

• Carter, Demizieux, Campenot, et al. Phosphatidylcholine biosynthesis via CTP:phosphocholine cytidylyltransferase beta2 facilitates neurite outgrowth and branching.J Biol Chem. 283(1):202-12 (2008).
• 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).
• Craig, Brammer, et al. The interactive effect of acute ovarian suppression and the cholinergic system on visuospatial working memory in young women. 35:987-1000 (2010).
• Fischer 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, 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).
• Physiology and immunology of the cholinergic antiinflammatory pathway.J Clin Invest. 117(2):289-96 (2007).
• van Wijk, Watkins, et al. Plasma choline concentration varies with different dietary levels of vitamins B6, B12 and folic acid in rats maintained on choline-adequate diets. Br J Nutr. 107:1408-12 (2012).

CHOLINE REQUIREMENT ASSOCIATED WITH GENETIC POLYMORPHISMS

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, and muscle damage. In this new paper (da Costa, 2104), 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 could 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.

Add to the genetic variation the decreasing ability of older persons to transport choline into the brain (Cohen, 1995) 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.

It as also been reported that choline acetyltransferase, the enzyme needed to convert choline to acetylcholine, is inhibited by exposure to excitatory amino acids (Louzada, 2004). 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.

How Something That Looks More Complicated Can Actually Be a Simplification

As you connect more and more of the dots in a regulatory pathway, you actually “simplify” the overall understanding of how the pathway works. The increased connections between the dots improve the explanatory power of the overall picture because you reduce the number of independent elements in the analysis. It is like what happens when you increase the number of data points in a statistical analysis to where the statistical “power” of the analysis allows it to explain more than it otherwise could.

References

• Cohen, Renshaw, Stoll, et al. Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study.”JAMA. 274(11):902-7 (1995).
• 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).
• 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).

UR-INE CONTROL 
WHEN IT DOESN’T PAY TO PEE ON SOMEBODY ELSE’S WALL

A clever new way to deter people from urinating on your walls, doors, etc. was reported in the Sept. 28, 2015 Chemical & Engineering News, Newscripts, pg. 56.

We hope this will find a positive reception from those under attack by people who find it convenient to pee on your doorstep. Even if they don’t have anyplace to use a toilet, they could still pee into a bush or against a telephone pole rather than on somebody’s wall. It seems to us pretty likely that there is a certain malicious intent involved in doing it on somebody’s door or wall of their house. Reminds us of how cats will do that sometimes to show humans that they can do what they like whether you like it or not.

The city of San Francisco is said to be testing a superhydrophobic coating sprayed onto walls that is so water repellant that it causes any urine hitting them to bounce back onto the culprit who emitted the pee, hitting them on their shoes or even on their pants. The city’s director of public works is calling it “pee-back” for bad behavior. The coating is manufactured by UltraTech International in Jacksonville, Florida and named Ultra-Ever Dry.^® “It is sprayed onto a surface in two coats. The base coat contains xylene and tert-butyl acetate, while the primary substance in the top coat is acetone.” It is said to create a nanoscale surface texture with geometric shapes that have peaks that repel water-based liquids.

It is interesting that San Francisco, home of politicians and bureaucrats wildly averse to “chemicals” and with a tendency to see deadly effects from any “chemicals,” that they have considered the use of this stuff. They must be desperate. Or perhaps they are becoming reasonable about the risk/benefits of the use of chemical substances —but, Nah, that seems unlikely.

Originally Published in Our Newsletter of June 2015 (Vol. 18 No. 2):

REVOLUTIONARY NEW VIEW OF CONSCIOUSNESS:
SCIENCE FICTION MERGES WITH REALITY
THE BRAIN AS A COMMUNITY OF INTERACTING PIECES

We were amazed to see that, in the May 2015 Nature Neuroscience, a paper was published (X. Wan et al. Neural encoding of opposing strategy values in anterior and posterior cingulate cortex,” pp. 752-759; commentary on pp. 616-617) that goes a very long way in supporting the notion that the brain is made up of discrete areas that, in decision-making, come to a decision by a consensus process, with competition between the differing areas as to what the areas would prefer as a decision. In other words, the idea that our personalities are not homogeneous, there really may be different characters inside our heads, and there is a continuous process of negotiation going on between these characters to produce a single decision that includes “everybody” in the decision-making process. What was nuts yesterday could be scientifically respectable today!

The way the authors of the commentary put it: “This result speaks to the idea that decisions may be realized via a distributed consensus, a viewpoint that argues that no single brain area is critical in decision-making, but that decisions instead emerge via competitions occurring in many brain regions.”

The process called “automatic writing,” which, since William James’ (Koutstaal, 1992) early writings on the subject (1885-1899), was used to describe how an author of fiction could write a story and just let the words flow—it seems as if the text writes itself—without consciously interceding in the process would be entirely consistent with this viewpoint of distributed consciousness. The flow is where you allow the different brain areas to interact, watching them while they do this rather than directing them via central control. You might have to be a fiction writer to have had the experience of writing this way, with characters seeming to emerge spontaneously from the subconscious.

Reference

• Skirting the abyss: a history of experimental explorations of automatic writing in psychology. J Hist Behav Sci. 28:5-27 (1992).

This dissociation of the consciousness into mutually exclusive parts is evidently a phenomenon destined, whenunderstood, to cast a light into the abysses of Psychology.

—William James (Koutstaal, 1992)

Getting to the actual experiments described in Nature Neuroscience (Kolling, 2015): The researchers used a Japanese game called shogi in which the players make decisions concerning moves that have either an offensive or a defensive purpose. The game is well suited to this, it is said, because the moves are so clear as to whether they are defensive or offensive. So while the players are making these decisions/moves, they are followed by fMRI to identify which parts of the brain are interacting. The result was that they found very specific areas worked together when you made a defensive decision and very specific other areas worked together when you made an offensive decision. Posterior cingulate cortex reflected the subjective value of offensive strategies, while rostral anterior cingulate cortex activated as a function of the subjective value of the defensive strategy. These two regions interacted with the dorsolateral prefrontal cortex, which is said to be implicated in cognitive control. The commentary’s authors (Wan, 2015) put it this way: “… the functional connectivity results of Wan et al suggest that, in addition to distributed competition, changes in connectivity could be crucial for understanding how flexible choices could be implemented.”

This is a revolutionary view of human consciousness that appears now to have emerged from science fiction to reach a highly reputable scientific journal.

References

• Kolling and Hunt. Divide and conquer: strategic decision areas. Nat Neurosci.18(5):616-7 (2015).
• Wan, Cheng, Tanaka. Neural encoding of opposing strategy values in anterior and posterior cingulate cortex. Nat Neurosci.18(5):752-9 (2015).

FAMOUS PHYSICIST, DR. FREEMAN DYSON, SAYS CLIMATE MODELS USED TO PREDICT WARMING ARE GETTING WORSE, NOT BETTER

Freeman Dyson, 91 years old, has made a public statement* deploring the fact that President Obama, who Dr. Dyson says he likes and also says “I’m 100 percent Democrat myself,” has chosen the “wrong side” on the climate change issue. Dyson speculates that the issue is only partly explained by following the money (billions of government grant money on “climate change”), but also reflects (he thinks) a kind of collective yearning for apocalyptic doom.

Dr. Dyson was quoted as saying that the current scientific obsession with climate change is “not a scientific mystery but a human mystery. How does it happen that a whole generation of scientific experts is blind to the obvious facts?” It may have something to do with the recently noted (in Science and Nature) phenomenon of scientists having biases in favor of particular interpretations of data that support their political orientations. This is causing some concern among scientists who see this as something that could undermine public trust in science. (See, for example, the lead editorial in the 8 Oct. 2015 Science. Let’s think about cognitive bias.” A couple of quotes from the editorial: “One enemy of robust science is our humanity—our appetite for being right, and our tendency to find patterns in noise, to see supporting evidence for what we already believe is true, and to ignore the facts that do not fit.” “Another common fallacy in research is the Texas sharp-shooter effect—firing off a few rounds and then drawing a bull’s eye around the bullet holes.”)

* In an interview with Andrew Orlowski of THE REGISTER (a British rag). Reported in http://www.breitbart.com/big.government/2015/10/13/top-physicist…

Because of the need to prepare our income taxes, this may be the shortest issue of the year. You can thank Uncle Assam for the loss of content. Back next month with a regular issue, assuming Uncle Assam doesn’t have something new and time-consuming for us (a big “if” these days). Just think of all the extra work piled onto doctors these days at the point of Uncle Assam’s guns and you can’t help but wonder that anyone wants to be a doctor anymore. The people making all this extra work are dangerous and are a direct threat to our health and longevity. Don’t elect new “better” people who want to do those jobs, get rid of those jobs! OK to elect people who truly want to get rid of those jobs, but watch out, lying is almost ubiquitous among the political class. Example: Gov. Sandoval of Nevada lied and lied about reducing taxes and is pushing for more and more of them. We believe that this man is a true SOCIOPATH. He doesn’t care what it costs to innocent bystanders for him to pursue what politically benefits himself. Something seems horribly amiss, when your political class is populated (mostly) by sociopaths.

APPETIZERS

Men ought to know that from the brain, and from the brain only, arise our pleasures, joys, laughters, and jests, as well as our sorrows, pains, griefs, and tears… These things that we suffer all come from the brain…Madness comes from its moistness.

—Hippocrates(*)

The brain has to model everything it encounters, including itself. …In that sense, the self is just a representation maintained in the brain, just like any other representation that we have of objects in the world.

—Jacob Mohwy, Monash University, Melbourne, Australia (from an interview by Anil Ananthaswamy, author of The Man Who Wasn’t There, Dutton, 2015)

To open a shop is easy, to keep it open an art.

—a proverb from the far East (probably China), no date given

(Comment: You have to wonder where it was and when that opening a shop was easy. It sure isn’t easy most places in the USA of 2015. On the way up, one supposes, as in the rise of the U.S. and the Roman Republic, it was easy to open a shop, but not on the way down in the U.S. and the Roman Empire after they passed the Republic phase. Julius Caesar ended the Roman Republic by declaring himself the Dictator, while in the U.S. it happened more quietly because no one was honest enough to declare the Republic kaput. According to the World Bank, the USA is now down to #40 in the ease of starting a new business. There are now more small businesses dying than being born.)

If I return to earth in another life, I hope it’s not during a Republican administration.

—Timothy Leary

[Dr. Leary never met Barack Hussein Obama.]

If we wanted to regain freedom, we were forced to strike. We told the Soviets that you can enter with your tanks if you wish. Then, we will put flowers in the guns of those tanks and your soldiers will sooner or later be forced to open the tanks and get out and get some air. When they are out, our girls will kiss them to death. However. we are not going to work for you anymore.

—Lech Walesa, PEACE 1983

[Ah, it’s the bonobo strategy of peace, trading sex for aggression. It works for the bonobos and it appears to have worked for Poland.]

EGCG AND CAPSAICIN SHOWN TO HAVE POWERFUL ANTICANCER EFFECTS

Catechin (EGCG) and activators of the TRPV1 receptor have been recently shown to have, in combination, very powerful anticancer effects in cell culture and in a mouse model of metastasis and ought to be tested for pain. The combination was 10-100 times as effective against cancer as either agent alone.(Morre & Morre, 2006)

• Morré, Morré . Catechin-vanilloid synergies with potential clinical applications in cancer. Rejuvenation Res.9(1):45-54 (2006).

TAURINE INCREASES HIPPOCAMPAL NEUROGENESIS INCREASING STEM AND PROGENITOR CELL PROLIFERATION AND INCREASING THE SURVIVAL OF NEWBORN NEURONS

Neurogenesis, the process of creating new neurons from stem cells, includes the maturation of the new neurons in which the neurons compete with one another for survival. Incredibly, a new paper (Bian, 2015) has now reported the discovery of some details of this competition.

They studied dendritic spines (the structures that provide important biochemical and electrical compartmentalization within neurons). Neurogenesis includes rapid spinogenesis. Here, the authors explain a hypothesis that new spines (mostly thin) underlie memory acquisition, while mature spines (mostly mushroom shaped and stubby) contribute to memory consolidation and storage. The authors found through their experiments that the small proportion of new neurons that were enriched in beta catenin were the ones that survived the pruning process that follows neurogenesis, while the ones with less beta catenin died by apoptosis. Interestingly, the neurons surrounding the beta catenin-enriched survivors were most likely to die. The authors ascribe this to “local competition for limited resources.”

Environmental enrichment, known to increase neurogenesis, also (according to the authors) accelerates spine pruning. “In the PFC [prefrontal cortex] and hippocampus…new memories are constantly formed and unconsolidated ones removed throughout life, a few synapses at a time, resulting in individualized spine dynamics and sustained circuit plasticity.” The authors also explain how enhanced or reduced expression of genes for spinogenesis can result in neurological disorders, including autism and schizophrenia. In fact, in another paper by different scientists (Yi, 2015), an autism-linked mutation was discovered (inherited maternally) that causes excessive dendritic spine development in the brain. It is interesting to note that one of the autism spectrum disorders, Asperger’s syndrome, actually shows some evidence for beneficial effects in some individuals. Though there may be deficiencies in recognizing faces, for example, there seem to be countervailing advantages such as enhanced sensory abilities (for example, the ability to recognize different colors) and possibly increased creativity. (A guy we know who has the syndrome suggests that the best game “trackers” would be Asperger’s because of superior ability to pick out the bent blades of grass and faint footmarks that you have to be able to track.) If so, this may explain why this gene hasn’t disappeared into the trash bin of evolutionarily dumped genes but has remained around, benefitting some and being a disaster for others, particularly for those who inherit two alleles for the trait rather than just one. Interestingly, Nobel Prize winners in mathematics and chess grandmasters disproportionally have the Aspberger form of autism.

But, getting back to neurogenesis, there are a number of nutrients that are known to increase neurogenesis, including resveratrol (found in red wine, cocoa, green tea), EGCG (particularly enriched in green tea), curcumin (found in turmeric root), and taurine, among many many others. Taurine, for example, has been found to increase hippocampal neurogenesis in aging mice (Gebara, 2015). “We found that taurine increased cell proliferation in the dentate gyrus through the activation of quiescent stem cells, resulting in increased number of stem cells and intermediate neural progenitors.” “Furthermore, taurine increased the survival of newborn neurons, resulting in a net increase in adult neurogenesis.” This is a very impressive benefit from ingesting adequate amounts of taurine, which is a sulfur-containing amino acid not incorporated into proteins; it is found in large amounts in the brain, but also in the liver and kidney. Its concentration in the brain decreases with aging. The fact that taurine increases the stem cell pool is particularly exciting, as the renewal of the stem cell pool is limited in adults.

• Gebera, Udry, et al. Taurine increases hippocampal neurogenesis in aging mice. Stem Cell Res.14:369-79 (2015).
• Bian, Miao, et al. Coordinated spine pruning and maturation mediated by inter-spine competition for cadherin/catenin complexes. 162:808-22 (2015).
• Yi, Berrios, Newbern, et al. An autism-linked mutation disables phosphorylation control of UBE3A. 162:795-807 (2015).

NEW SCIENTIFIC DISCOVERY: PREDATOR V. PREY POWER LAW MIGHT PREDICT WHAT HAPPENS TO LARGE POLITICAL ECOSYSTEMS SUCH AS THE UNITED STATES

Sometime very soon: You enter your library stacks and put American History next to “The Road to Serfdom” and file it under “The Ashheap of History.” Have you just entered “the Twilight Zone” or is the United States, a large ecosystem, governed by the same rules of the predator vs. prey Power Law shown to apply to all large ecosystems and which predicts that the biomass pyramid becomes increasingly bottom heavy (more prey, fewer predators) at higher biomass. See our analysis in next issue of this newsletter. REF: Hatton, McCann, Fryxell, et al. The predator-prey power law: biomass scaling across terrestrial and aquatic biomes. Science. 349(6252) (4 Sept. 2015).

INCOHERENCE IN GOVERNMENT ADMINISTRATIVE REGULATIONS—THEN AND NOW A PROPHECY FROM THE PAST MIGHT POINT TO THE OUTCOME OF OUR NEXT ELECTION

In a recent online post (Sept. 1, 2015) entitled “Government Decoherence and Its Discontents” by Philip A. Wallach, Mr. Wallach discusses his view that decoherence (we think the proper word is incoherence) is a natural outcome of tendencies in liberal, pluralist democracy. He notes that this was the prophecy of Carl Schmitt, who was a political scientist/economist during the Weimar Republic of Germany. Schmitt’s book Legality and Legitimacy, “diagnosed legislature-dominated liberal orders as utterly incapable of meeting the demands of crises, and perhaps even the tasks of economic management for which they were taking responsibility” at the time he wrote this. “Lack of legislative dexterity would lead liberal societies to embrace what Schmitt called an ‘administrator’ form of government based on ad hoc decrees designed to respond to the needs of the moment.” This incoherence of policy would lead to an erosion in citizens’ belief in the congruence between “law and statute, justice and legality, substance and process,” with a loss of legitimacy. “In Schmitt’s oracular telling, this will lead to total dissolution of the state or the rise of some more viable alternatives rooted in a single leader’s plebiscitary connection with the people.” Indeed, Adolf Hitler proved to be that single leader prophesied by Schmitt. We know how that ended ….

We do not currently appear to have a Hitler on the horizon, but interestingly there is a candidate for President who proposes policies designed to meet the needs of the moment and who speaks a language of frankness that attracts people looking for somebody who is not afraid to say it like it is, even in an uncouth manner disrespectful of the political class. That might not end well, either…

YOUR PRIVACY IS TOTALLY OBLITERATED IN THE NEXT VERSION OF WINDOWS

SORRY. THIS IS NOT A JOKE.

PLEASE PAY ATTENTION IF YOU PLAN TO USE THE NEXT VERSION OF WINDOWS, WINDOWS 10

We regret to inform you of the following. If you use the next version of WINDOWS, you will notice in the Microsoft Privacy Statement (updated July 2015), this statement under “REASONS WE SHARE PERSONAL DATA,” third paragraph under “Full text,:” “…we will access, disclose and preserve personal data, including your content (such as the content of your emails, other private communications or files in private folders), when we have good belief that doing so is necessary.” After this incredible statement, Microsoft gives four possible reasons for believing (in good faith!) it to be necessary, number one being: “1. comply with applicable law or respond to valid legal process, including law enforcement or other government agencies.”

Draw your own conclusions about (1) why Microsoft included this statement in their “privacy” statement, (2) what “government agencies” might want access to data such as what is in your private emails, and (3) is there any privacy left in relation to the government? You use the next version of WINDOWS at your own risk.

https://github.com/WindowsLies/BlockWindows

Worse yet, Microsoft is pushing spyware updates into Windows 7 and 8 installations. See also other comments in the above thread. Look especially at the comments entered at the following times by these parties:

Understanding Squid Self-Healing Teeth

September 9, 2015 5:54 AM by Curious

September 4, 2015 6:36 PM by Peanuts

September 4, 2015 12:05 AM by Peanuts on History of the L0pht:

http://www.theregister.co.uk/2015/09/01/microsoft_backports_data_slurp_
to_windows_78_via_patches/

Alien Jerky • September 2, 2015 10:01 AM (on schneier.com)

Peanuts • September 3, 2015 12:47 AM (on schneier.com)

Thomas_H • September 3, 2015 2:56 AM (on schneier.com)

We suspect that these spyware additions to Windows happened following an offer from the US government that Bill Gates couldn’t refuse… There will undoubtedly be more 4th Amendment trashing to come. Great source of security info:

https://www.schneier.com/

But on to life enhancing and fun stuff…

RECIPE FOR A PEACEFUL CIVILIZATION? COULD THIS KNOWLEDGE SAVE THE WORLD?

We interrupt this tax preparation waste of productive effort for a flash from the scientific literature on what may be an excellent recipe for the peaceful, productive society we all want. This paper (Rilling, 2012) presents what the authors claim is the first ever [we’ve certainly never seen anything like this before] comparison of chimpanzee and bonobo brains using diffusion tensor imaging, supplemented with a voxel-wise analysis of T3-weighted images to specifically compare neural circuitry implicated in social cognition. As you know, the bonobos have largely substituted sex and play for aggressive violence in social interactions, while chimps are more like humans, with plenty of aggressive violence in social interactions.

Here it is: “We find that bonobos have more gray matter in brain regions involved in perceiving distress in both oneself and others, including the right dorsal amygdala and right anterior insula. Bonobos also have a larger pathway linking the amygdala with the ventral anterior cingulate cortex, a pathway implicated in both top-down control of aggressive impulses as well as bottom-up biases against harming others. We suggest that this neural system not only supports increased empathic sensitivity in bonobos, but also behaviors like sex and play that serve to dissipate tension, thereby limiting distress and anxiety to levels conducive with prosocial behavior.” (Rilling, 2012)

WOW! You’d think that findings such as this would receive a lot of attention, but have you seen this anywhere in the press??? This could be a formula to save the world because human aggression, particularly the coercive type, is wrecking havoc.

Imagine having the opportunity to find out how the brains of your potential mates or potential business associates look as compared to the bonobo brain? We’d definitely choose people with those traits over what you usually get. People are dangerous and, in business, the difficulty of distinguishing liars, sociopaths, and criminals from the others is such that you make mistakes and may have to pay a high cost for those mistakes. We’ve had plenty of experience with that. It has cost us a lot.

Our thanks to the authors, whose names we give in full as the heroes that they are:

James K. Rilling, Jan Scholz, Todd M. Preuss, Matthew F. Glasser, Bhargav K. Errangi, and Timothy E. Behrens. Differences between chimpanzees and bonobos in neural systems supporting social cognition. Soc Cogn Affect Neurosci. 7:369-79 (2012).

Correspondence should be addressed to: James K. Rilling, Ph.D., Associate Professor, Dept. of Anthropology, Dept. of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322 E-mail: jrillin@emory.edu [email as given in the paper; don’t know why the “g” was dropped from jrillin.]

Negative and Competitive Social Interactions Are Related to Heightened Proinflammatory Cytokine Activity

We may have reported this before, but it is so relevant to the matter of bonobo vs. chimp style social relationships, that we mention it again here. A recent study (Chiang, 2012) found that, among 120 healthy young adults who kept daily diaries for 8 days that noted positive, negative, and competitive social interactions, the negative social interactions and those involving hostile competition (not ordinary leisure time competitive activities) led to significantly higher inflammatory cytokine levels. (The volunteers were tested within 4 days of completing the daily diaries, but the effect of social interactions that took place in the intervening period could not be determined.) It would be interesting to measure the level of proinflammatory cytokines in bonobos as compared to chimpanzees.

• 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).

(*) Comment on Hippocrates’ Notion of the Brain Circa 400 BC (see quote above)

It is stunning how much had been figured out so long ago by the most learned. “Moistness” in Hippocrates’ quote probably refers to the cholinergic nervous system, which when overactive, causes profuse sweating and oodles of saliva (don’t know whether the brain itself is “moist”). This visible moistness is associated with conditions such as epilepsy, dissociative disorders, schizophrenia, and other states that could be thought of as madness. Interestingly, compensatory hypersensitivity to the cholinergic nervous system (Scinto, 2008) under conditions where cholinergic signaling is deficient speculates Sandy and Durk may be involved in the development of brain disorders such as Alzheimer’s and Parkinson’s diseases, both of which can be accompanied by dementia, with AD being the most severe, of course. Thus, the cholinergic system may play a complex role in the development of Alzheimer’s and Parkinson’s, as the following reports on the negative impact of anticholinergic drugs and the beneficial effects of cholinergic agonists in a model of cholinergic denervation show.

• Pupillary cholinergic hypersensitivity predicts cognitive decline in community dwelling elders. Neurobiol Aging.29:222-30 (2008).

A HYPOTHESIS ABOUT ALZHEIMER’S DISEASE, ITS CAUSE AND A POSSIBLE METHOD OF TREATMENT, AND EXPERIMENTAL SUPPORT FOR THE HYPOTHESIS

by Sandy Shaw

One hypothesis shared by me and probably some others about AD is that it is the ultimate dissociative disorder, with the connections between various areas of the brain being destroyed, leaving behind the originally connected material (memories, stored data, etc.), in a state where it cannot be accessed by other brain areas (some scientists including myself wonder whether it might theoretically be possible to reconstruct the connections and retrieve this material. If that is possible, it is likely, I think, to be limited to a certain critical period of time as neurons die when they are not active.)

If the hypothesis is correct, then one prediction is that the restoration of connections in a model of cholinergic denervation might be a reasonable model for Alzheimer’s disease and a possible correction. Thus, a 2010 paper (Kampen and Eckman, 2010) is right on point. Here, the researchers studied the use of cholinergic agonists to restore hippocampal neurogenesis and improve cognition in a model of cholinergic denervation (the very connections the hypothesis would suggest are missing or damaged). The authors report “the effects of various cholinergic compounds on indices of hippocampal neurogenesis, demonstrating a significant induction following pharmacological activation of [cholinergic] muscarinic M1 receptors, located on hippocampal progenitors in the adult brain [of female Sprague-Dawley rats].” The chemicals studied included nicotine (which is an agonist, that is, it activates, nicotinic-cholinergic receptors and the cholinesterase inhibitor physostigmine, the nonselective cholinergic agonist carbachol, the muscarinic agonist oxotremorine, or their vehicle.

Results showed that the maximal induction was observed following the highest dose of oxotremorine, the muscarinic agonist. Only lower doses of carbachol elevated cell proliferation in the dentate gyrus (an area of neurogenesis), and the CHOLINESTERASE INHIBITOR physostigmine triggered a modest, but significant, elevation in the production of new neurons from progenitors. As the authors explain, “…we have shown that selective activation of muscarinic receptors is capable of triggering an induction of cell proliferation not only in the DG [dentate gyrus], but also the CA1 region of the hippocampus, an area of severe neuronal loss in AD [Alzheimer’s disease].” “…oxotremorine-induced increases in BrdU-positive cell counts [neurogenic cells] are likely to reflect an effect on cell proliferation rather than an indirect effect on cell survival.” “…impairments in cell proliferation, in a model of basal forebrain cholinergic cell loss are counteracted by chronic muscarinic activation. This restoration of cell proliferation is accompanied by a time dependent increase in the number of newly generated cells expressing neuronal markers and by a reversal of cognitive deficits characteristic of this model.”

• Kampen, Eckman. Agonist-induced restoration of hippocampal neurogenesis and cognitive improvement in a model of cholinergic denervation. 58:921-9 (2010).

THE MEXICAN SIESTA:GOOD FOR YOUR HEALTH, NOT JUST FOR A NAP AFTER LUNCH

HYPOTHESIS: Sandy thinks that the Mexican siesta, where people sleep for a while following a heavy lunch, is linked to the pulsatile release of prostaglandin D2 (also released by the niacin flush as a pulse. See Sandy’s paper on that subject if interested in technical discussion, available in three parts at the Life Enhancement magazine for July, August, and September, www.life-enhancement.com). The Mexican foods found in a lunch are generally high in hot chili peppers that contain capsaicin, which activates the TRPV1 receptor (Lee, 2015). That receptor does a number of interesting things, such as reducing the risk of obesity and diabetes (Lee, 2015), reducing pain (Origoni, 2014), reducing inflammation (Zhao, 2013) generally, as well as being a major sleep-inducing signal (hence the siesta).

A major part of the pathway by which TRPV1 accomplishes these effects is via the pulsatile release of the prostaglandin PGD2, which suppresses the chronic release of PGD2 that has proinflammatory effects in diseases such as Alzheimer’s disease and also reduces the release of PGE2, an inflammatory prostaglandin associated with hyperalgesia (severe pain). (Ndengele, 2008) (Also see Sandy Shaw’s paper on the niacin flush in the section on Alzheimer’s disease that appeared in the August issue of the LIFE ENHANCEMENT magazine online at www.life-enhancement.com.)

• Lee, Jung, Kim, et al. Transient receptor potential vanilloid type-1 channel regulates diet-induced obesity, insulin resistance, and leptin resistance. FASEB J.29:3182-92 (2015).
• Origoni, Maggiore, et al. Neurobiological mechanisms of pelvic pain. Biomed Res Int. 2014:903848. doi: 10.1155/2014/903848. Epub 2014 Jul 8 (2014).
• Zhao, Ching, Kou, et al. Activation of TRPV1 prevents OxLDL-induced lipid accumulation and TNF-alpha-induced inflammation in macrophages: role of liver X receptor alpha. Mediators Inflamm. 2013:925171. doi: 10.1155/2013/925171. Epub 2013 Jun 26 (2013).
• Ndengele, Cuzzocrea, et al. Cyclooxygenases 1 and 2 contribute to peroxynitrite-mediated inflammatory pain hypersensitivity. FASEB J. 22:3154-64 (2008).

RELIEF FROM INTRACTABLE PAIN BY ENHANCING THE EFFECTS OF OPIATES WITH NATURAL PRODUCTS

People who are having intolerable pain, such as those with far advanced cancer, have the problem both of getting opiates to treat their pain and of the fact that opiates have limits in their effectiveness in really severe pain. Here are a couple of suggestions for what can be done with simple easily available totally legal no prescription needed supplements that have been shown to enhance the effectiveness of morphine.

CHOLINE ENHANCES THE EFFECT OF MORPHINE

Choline and acetylcholine agonists have been shown in animal studies to have antinociceptive (to decrease pain) effects. (Rowley, 2010) (Serrano, 1994) (Yong-Ping, 2011). As described in Rowley, 2010, choline provided (in mice) “moderately effective analgesic via activation of alpha7 nicotinic acetylcholine receptors.” Cholinesterase inhibitors (such as galantamine, which is active at the alpha7 nicotinic acetylcholine receptor) are known to have analgesic activity (Rowley, 2010) Importantly, the administration of choline (2 mg/kg) with morphine (0.165 mg/kg) significantly increased the pain-killing efficacy of morphine in the late phase but not in the early phase (Wang, 2005).

Moreover, the combination of cholinergic agonists and aspirin provided significantly enhanced relief of pain in a model where mice received painful acetic acid intraventricular injections. (Yong-Ping, 2011) The same effect would be expected with the combination of cholinergic agonists and other NSAIDS.

In addition, another report (Serrano, 1994) showed in rats and mice subjected to painful acetic acid and to the tail flick test (where the animal removes its tail from a hot plate when it gets painful), that the antipain effects of taurine required peripheral cholinergic mechanisms. In studies done before (Serrano, 1994), the authors note, taurine prevented the development of tolerance to a centrally administered enkephalin analog (enkephalin is an endogenous opioid).

There is some evidence that cholinergic agonists and TRPV1 (vanilloid) receptors have antinociceptive effects (Origoni, 2013), and the combination is synergistic. (ref vanished) The TRPV1 (vanilloid) receptor is sometimes called the capsaicin receptor because hot peppers containing capsaicin activate that receptor, manifested by sweating and skin flushing. It is also activated by vanillin, the major constituent of vanilla. Incidentally, you can get vanillin by buying “synthetic vanilla” at the supermarket; as the major constituent of vanilla, it tastes a lot like vanilla but has to be labeled as “synthetic vanilla.” It has recently been discovered that niacin activates the TRPV1 receptor, explaining at least in part the flush you get from hot peppers (Ma, 2014). This suggests (but we have not seen a test of this) that niacin might act to increase the antipain effects of TRPV1 agonists and combinations of cholinergic and TRPV1 agonists.

REDUCING PAIN BY INHIBITING TRPV1, THE CAPSAICIN RECEPTOR, WITH OTC DRUG

TRPV1 is a pain detecting receptor, but desensitizing it, by for example eating a lot of hot chili, is a way to reduce pain. It has been discovered that the TRPV1 receptor can be downregulated (desensitized) by mu opioid drugs. Mu opioid drugs includes morphine and fentanyl, but interestingly there is an OTC drug that activates the mu opioid receptor that will do the same thing to the TRPV1 receptor. We refer to loperamide, a PERIPHERAL mu opioid receptor agonist that does not pass the blood brain barrier and, hence, cannot cause addiction, respiratory depression, itching, and other side effects of central mu opiate activity. Loperamide is used to treat diarrhea, firming up feces, and unsurprisingly a side effect of taking too much is constipation. Use according to label instructions.

A paper (Butelman, 2004) reports that rhesus monkeys exposed to capsaicin to induce pain (assessed by a tail withdrawal assay), “loperamide (0.1-1 mg. /kg sc) acting as a peripherally selective mu-agonist after sc [subcutaneous] administration, produced a prevention of topical capsaicin-induced allodynia [pain induced stress].” However, loperamide did not prevent pain induced by heat, presumed to be a centrally mediated effect of mu agonist. Fentanyl, a mu agonist centrally active opioid, was more effective than loperamide at REVERSING pain induced by capsaicin and could PREVENT pain induced by both capsaicin and heat. Peripheral mu receptor agonists (such as loperamide) are reported to be particularly effective in decreasing pain due to inflammatory hypersensitivity (Endres-Becker, 2007)

• Butelman, et al. Antiallodynic effects of loperamide and fentanyl against topical capsaicin-induced allodynia in unanesthetized primates.J Pharmacol Exp Ther.311:155-63 (2004).
• Endres-Becker, et al. Mu opioid receptor activation modulates transient receptor potential vanilloid 1 (TRPV1) currents in sensory neurons in a model of inflammatory pain. Mol Pharmacol.71:12-8 (2007).
• Kumar, Priyadarsini, et al. Inhibition of peroxynitrite-mediated reactions by vanillin. J Agric Food Chem.52:139-45 (2004).
• Origoni, Maggiore, et al. Neurobiological mechanisms of pelvic pain. Biomed Res Int. 2014:903848. doi: 10.1155/2014/903848. Epub 2014 Jul 8. (2014).
• Ying-Pong et al. Pharmacological action of choline and aspirin coadministration on acute inflammatory pain. Eur J Pain.15:858- 65 (2011).
• Rowley, et al. Antinociceptive and anti-inflammatory effects of choline in a mouse model of postoperative pain. Br J Anaesth.105(2):201-7 (2010).
• Ma, Lee, Mao, et al. Nicotinic acid activates the capsaicin receptor TRPV1—a potential mechanism for cutaneous flushing. Arterioscler Thromb Vasc Biol. 14(6):1272-80 (2014).

CAUSE OF CHRONIC ITCH IDENTIFIED CHRONICALLY HIGH PROSTAGLANDIN D2 LEVELS MAY BE INVOLVED AND SUGGEST POTENTIAL TREATMENTS

Lipocalin-2 was shown to be upregulated by astrocytic STAT 3 and to be crucial for chronic itch (Shiratori-Hayashi, 2015). In experiments in mice with atopic dermatitis, “…conditional disruption of astrocytic STAT 3 suppressed chronic itch, and pharmacological inhibition of spinal STAT 3 ameliorated the fully developed chronic itch.” As lipocalin-type prostaglandin D2 and prostaglandin E1 are isoprostanes involved with inflammation (acting either as a proinflammatory mediator or, if released in a pulse, as an antiinflammatory mediator), they may be involved in this process, Sandy hypothesizes. The researchers found that the reactive astrocytes might be maintained in lesioned skin (such as skin that has been scratched repeatedly) by TRPV1 receptors (the pain receptors that are activated by capsaicin, but can be desensitized by chronic activation by capsaicin). See discussion of TRPV1 receptors below, which indicate that pulsatile prostaglandin D2 is indeed involved in the process by which capsaicin can be used to reduce itching and pain.

• Shiratori-Hayashi, Koga, et al. STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch. Nat Med.21(8):927-31 (2015).

NATURAL PRODUCT INHIBITORS OF STAT3

There are a number of them. Most likely, a combination will work better than just one if you want to suppress a nasty itch. They include curcumin, resveratrol, piceatannol (an analog of resveratrol), caffeic acid, capsaicin (possibly make it worse at first), betulinic acid, ursolic acid, oleanolic acid, gamma tocotrienol, and many others (Miklossy, 2013)≥

• Miklossy et al. Therapeutic modulators of STAT signalling for human diseases. Nat Rev Drug Discov. 12(8):611-29 (2013).

SEXUAL EXPERIENCE PROMOTES ADULT NEUROGENESIS

Environmental enrichment and exercise, as well as a large number of natural products can increase neurogenesis. SEX is another way to get it. A study with sexually experienced adult male rats were exposed to an acute dose of sex by having access to a receptive female for one occasion or were exposed to a chronic dose by having access to a receptive female once daily for 14 days. (Over the 14 days, the males were generally given a new female each time but because there were only a limited number of females, occasionally they got one they’d had before, but the researchers say that it made no difference in sexual behavior.) Videos were analyzed for mounts, intromissions, and ejaculations.

The results showed that circulating corticosterone levels were elevated in male rats after sexual experience compared to naive controls (did not engage in sex, but were left undisturbed in their cages), although these levels were no longer increased following chronic sexual exposures. Whereas most stresses that increase corticosterone levels increase anxiety and decrease neurogenesis, neither of these took place in the sexually experienced rats, which were less anxious than naive controls and had increased neurogenesis and the growth of dendritic spines. It was the difference between aversive stressors and rewarding ones that produced the alteration in the outcomes of anxiety and neurogenesis. The authors point to exercise as a similar positive stress that increases corticosterone levels but reduces anxiety and enhances neurogenesis.

The researchers also point out that “neuromodulators altered with sexual experience and known to influence adult neurogenesis, like opiates or dopamine, seem plausible [as possible mediators of the beneficial effects of sexual experience], as does oxytocin, a neuropeptide that buffers the brain and body against some of the adverse consequences of stress hormones.”

• Leuner, Glasper, Gould. Sexual experience promotes adult neurogenesis in the hippocampus despite an initial elevation in stress hormones. PLoS One.2010 Jul 14;5(7):e11597. doi: 10.1371/journal.pone.0011597. (2010).

THE FLUSH CAUSED BY ACTIVATION OF TRPV1 BY AGONISTS LIKE CAPSAICIN APPEARS TO BE PART OF THE NIACIN FLUSH!

A speculation: While TRPV1 receptors are pain receptors that are activated by capsaicin, they can be desensitized by chronic treatment with capsaicin. This desensitization may involve, Sandy speculates by pulsatile release of PGD2, prostaglandin D2, which seems to be involved as a stop signal for inflammation in a large variety of inflammatory diseases. (See Sandy Shaw’s paper on the niacin flush (actually it is on prostaglandins and their role in inflammatory diseases) in the July, Aug., Sept. 2015 issues of Life Enhancement on the web at www.life-enhancement.com.

One thing that makes me suspicious that a pulse of prostaglandin D2 (PGD2) might be involved here is that, when you eat a meal with hot spices, you sweat and feel hot for a short period, a cutaneous flush much like the niacin flush, which is caused by a pulsatile release of PGD2.

Serendipity Strikes Again!

The above two paragraphs (in the exact words as originally written) was typed into this newsletter on 8-30-2015. Later that very same day, Sandy found a paper in a search she requested that was conducted by Durk for her that reports (Ma, 2014) that nicotinic acid (niacin) activates the capsaicin receptor TRPV1 (in a slightly different way than capsaicin) and that the flush that results is part of the niacin flush. The rest is due to the release of a pulse of prostaglandin D2 produced by niacin’s HCA2 activation in Langerhans cells and keratinocytes of the skin. (Ma, 2014) However, I did not see anything in the Ma et al paper that rules out the release of pulsatile prostaglandin D2 by activation of the TRPV1 receptor. In fact, a search Durk did at my request on TRPV1 and PGD2 suggests that it is in fact a pulse of PGD2 that occurs as a result of TRPV1 activation that is responsible for the flush produced by TRPV1 agonists such as capsaicin. The “niacin flush” strikes again!!

Hence, it is not only the niacin flush that results from the pulse of prostaglandin D2, but the TRPV1 “hot spices” flush that (in part) results from it, revealing the importance of the antiinflammatory PGD2 pulse and its potential application to a large variety of inflammatory diseases.

• Ma, Lee, Mao, et al. Nicotinic acid activates the capsaicin receptor TRPV1—a potential mechanism for cutaneous flushing. Arterioscler Thromb Vasc Biol.34(6):1272-80 (2014).

APPETIZERS

I don’t want to just mess with your head. I want to mess with your life. I want you to miss appointments, burn dinner, skip your homework. I want you to tell your wife to take that moonlight stroll on the beach at Waikiki with the resort tennis pro while you read a few more chapters.

—Stephen King

If you have always believed that everyone should play by the same rules and be judged by the same standards, that would have gotten you labeled a radical 50 years ago, a liberal 25 years ago, and a racist today.

—Thomas Sowell

Quemadmoeum gladis nemeinum occidit, occidentis telum est. (A sword is never a killer, it’s a tool in the killer’s hands.)

—Lucius Annaeus Seneca “the younger”
(ca. 4BC – 65AD)

The American Republic will endure, until politicians realize they can bribe the people with their own “money.”

—Alexis de Tocqueville

(D & S comment: The above is a fine epitaph for the former American Republic, now the American administrative state.)

You can’t possibly hear the last movement of Beethoven’s Seventh and go slow.

—Oscar Levant, explaining his
way out of a speeding ticket

The censors wouldn’t even let me sit on a guy’s lap, and I’ve been on more laps than a table napkin.

—Mae West

THE CHOLINERGIC NERVOUS SYSTEM IN THE BRAIN

Memory and Learning, Sexual Desire (LIBIDO), Reduction of Pain

Galantamine Enhances Cognitive Performance in Aged Ovariectomized Rats

One of the best ways to protect your aging brain is to get adequate amounts of choline, either through the diet (eggs, liver) or via supplements. As we have pointed out before, some 92% of Americans do not get even the minimal amount of choline recommended by the U. S. Institute of Medicine in their diet. Moreover, older women (past menopause, hence, with lower levels of estrogen in their system) require even more choline than premenopausal women. (Fischer, 2010) A food industry trade publication called this “Choline: The Silent Deficiency” and pointed to an opportunity for food companies to find ways to fortify their food products with choline. (See the January 2015 issue of “Prepared Foods.”)

As we have also reported before, cholinergic nervous system activity in the brain is vitally important for, among other things, cognitive performance. In women, it has been found that estrogen enhances the effects of cholinergic activity in the brain involved in learning and memory. With age in humans, the ability of the brain to take up choline declines. (Cohen, 1995)

Galantamine is a cholinesterase inhibitor, a class of compounds (in the case of galantamine, this is a natural substance despite being offered in a prescription form) that increases the length of time that the signal for cholinergic nervous system activation remains turned on in the neuronal synapse. Mounting evidence indicates that estrogen enhances brain function in women by increasing cholinergic nervous system activation. For example, a recent paper (Dohanich, 1989; reviewed in our last newsletter) showed that in rodents androgen-inhibited estrogen induced sexual receptiveness (LIBIDO) was prevented by choline, indicating that estrogen acted via a cholinergic mechanism to prevent androgen inhibition of libido or, another way of putting it, androgens had an anticholinergic effect in the female brain thus inhibiting libido induced by estrogens.

A recent paper (Gibbs, 2011) shows that galantamine plus estradiol enhanced cognitive performance in aged female rats with reduced levels of estrogens (as compared to young female rats). (This paper was previously reviewed by Will Block in the Dec. 2012 issue of Life Enhancement.) Especially interesting here was the fact that galantamine was able to enhance the effects of estradiol in the acquisition of a cognitive task (called the DMP, delayed matching to position, task—see paper for details of this, for a rat, fairly complex task) even after an extended period of reduced estrogen levels following ovariectomy. The rats were ovariectomized at 16-17 months of age. At 21-22 months of age, rats received daily galantamine treatment or vehicle by subcutaneous injection, then after a week, half the rats also received estradiol subcutaneously. Interestingly, neither galantamine nor estradiol alone had any effect on the rats after this extended period following ovariectomy.

Nevertheless, the COMBINATION of galantamine and estradiol significantly improved the animals’ ability to perform the DMP task, but not a different cognitive task, the stimulus discrimination/reversal learning task. Still, this is a very impressive enhancement of cognition in female rats after an extended period of very low estrogen in the brain and systemically. The authors suggest that this might indicate that “older women who have not used hormone therapy for many years and are beginning to show signs of mild cognitive impairment” could benefit from such a regimen. This is indeed good news for older women who have previously passed on hormone replacement because of concerns about it and are reaching the point where cognitive decline is becoming noticeable.

References

• Dohanich and Cada. Reversal of androgen inhibition of estrogen-activated sexual behavior by cholinergic agents. Horm Behav.23:503-13 (1989).
• Cohen, Renshaw, Stoll, Wurtman, et al. Decreased brain choline uptake in older adults.274(11):902-7 (1995).
• Gibbs, Chipman, et al. Galanthamine plus estradiol treatment enhances cognitive performance in aged ovariectomixed rats. Horm Behav.60:607-16 (2011).
• Fischer, da Costa, et al. Dietary choline requirements of women: effects of estrogen and genetic variation. Am J Clin Nutr. 92:1113-9 (2010).

LITHIUM ENHANCES THE EFFECT OF EXOGENOUS
CHOLINE ON BRAIN ACETYLCHOLINE LEVELS

From a classic book on nutrition and the brain by three of the pioneering scientists in that field (Barbeau, 1979), we read the following on the effects of lithium on the cholinergic nervous system in the brain: “…manic behavior can be suppressed by giving physostigmine, a drug which, by inhibiting acetylcholinesterase [GALANTAMINE also inhibits acetylcholinesterase], increases intrasynaptic acetylcholine concentrations.”

The researchers (Millington, McCall, Wurtman, 1979) report in the classic book cited in the paragraph above that they investigated possible interactions of exogenous lithium and choline on choline’s entry into the brain. The researchers stated: “To our surprise we found that chronic treatment with lithium enhances the effects of exogenous choline on brain choline and acetylcholine, probably by preferentially suppressing choline’s efflux from the brain.” Although the researchers found that lithium inhibited the uptake of choline into the brain, it also suppressed the efflux of choline from the brain, the overall effect being an enhancement of choline levels in the brain. These scientists also found that lithium suppresses choline influx into erythrocytes (red blood cells). Moreover, another group found that chronic lithium treatment increases the synthesis of brain acetylcholine. The researchers commented: “The neurochemical effects of lithium and choline may thus be complementary …”

This very early finding on the effects of combining choline and lithium seems to still be somewhat little known, as is so commonly the case with unpatentable nutrients that cannot be used to make blockbuster moneymakers for market sales. Although lithium itself is sold for the treatment of manic-depressive disorder because no good substitute has yet been found for it, the combination of choline and lithium remain in limbo, with no visible presence in mainstream medicine as a way to counteract declining choline levels in the brain with age that may lead to age-associated cognitive impairment.

Reference

• Millington, McCall, Wurtman. Choline and Lecithin in Brain Disorders. In: Barbeau, Growdon, Wurtman, editors. Nutrition and the Brain.Volume 5. New York: Raven Press, 1979. P. 417-24.

SEXUAL ACTIVITY AND THE CHOLINERGIC SYSTEM

Another fascinating section of the book (reference given just above) was written by A. G. Karczmar. Entitled “Overview: Cholinergic Drugs and Behavior—What Effects May Be Expected from a ‘Cholinergic Diet’,” it contained a remarkable report on a very early (1972) paper on the effects of the cholinergic system on sexual activity. “The significance of supraspinal cholinergic mechanisms was dramatically illustrated by Heath [reference given below] when he demonstrated that intraseptal administration of ACh [acetylcholine] evoked orgastic behavior in several patients that was indistinguishable overtly, subjectively, and electroencephalographically from spontaneous coital behavior …” Note, however, that Heath also reported a similar action of norepinephrine. “Generation of hippocampal theta waves by cholinergic agonists and anti-ChEs [anticholinesterases] should be emphasized, as this pattern is a concomitant of coital behavior. It must be added that the hippocampus and other limbic sites such as the amygdala known to control sexual behavior are innervated cholinergically.” WOW!!

Reference

• Pleasure and brain activity in man. J Nerv Ment Dis.154:3-18 (1972).

PAIN AND THE CHOLINERGIC NERVOUS SYSTEM

The amazing array of subjects covered in the 1979 book referred to above includes very early data on the effect of the cholinergic system on pain. In the same section of the book in which the discussion of sexual behavior is contained, there is this fascinating material on pain and cholinergic agonists: “For almost 40 years now [the book was published in 1979] it has been apparent that cholinergic agonists (particularly muscarinic agonists) and anti-ChEs [anticholinesterases] exert analgesic actions; these compounds, initially shown to potentiate the analgesic actions of morphine and codeine, also exert antinociceptive [pain suppressive] actions of their own …” Choline, however, was reported to attenuate morphine analgesia in the rat. “Since cholinergic agonists and anti-ChEs markedly increase serotonin levels, this effect could underlie the cholinergic analgesia.” In fact, a 2012 paper (Byung-Sang Lee, 2012) supports the link between increased serotonin signaling and pain relief.

Reference

• Lee, Jun, Kim, Park. Interaction of morphine and selective serotonin receptor inhibitors in rats experiencing inflammatory pain. J Korean Med Sci. 27:430-6 (2012).

AGGRESSION AND THE CHOLINERGIC NERVOUS SYSTEM

Aggression is part of human nature, not to be considered something harmful in itself. It all depends on what the aggression is used for. A mother protecting her infant is a type of well-known aggression and can serve a beneficial effect. Active self defense in the face of attack is another type of aggression that you had better have or you’re a sitting duck. In fact, I think it’s fair to say that if people didn’t have the ability to be aggressive in their own defense, the human species (or any species, for that matter) would have died out long ago. So aggression is a type of behavior that is necessary and is under the control of a number of neurotransmitters that both promote it and inhibit it, These includes serotonin, noradrenaline, and the cholinergic nervous system, among many others. Yes, it is very complicated and it is a wonder that people are able to live in a generally peaceful way among large numbers of other people. Not as peacefully as bonobos, for example, but perhaps (I (Sandy) speculate) the cholinergic system can offer a clue in that respect since it regulates both aggression and sexual activity and might act as a switch between these to the benefit of bonobos that would rather f__k than fight.

Early recognition of the cholinergic nervous system’s connection to the regulation of aggression was discussed in the classic book we have been talking about here. This is a 36 year old book and just shows you what three genius editors could do in giving an overview of a field that it seems these many years later has hardly penetrated the consciousness of many scientists, let alone laypeople.

The author of this section of the book (same author of the material on sexual activity we have discussed here) has this to say about aggression and the cholinergic nervous system: “Whether applied to several brain structures, particularly limbic brain structures or administered systemically, cholinergic (mostly muscarinic) agonists and/or anti-ChEs [anticholinesterases] cause aggression or facilitate experimentally induced aggression, whether of affective [emotional aggression that can be induced in small rodents by footshock or isolation] or predatory type [like the mouse killing behavior of rats]. Of interest in this context is the recent investigation of aggression induced in monkeys by small intravenous doses (6.25-25 μg/kg) of physostigmine [a cholinesterase inhibitor].” Long story short, a dominant monkey and a subordinate monkey were paired together, and one of the pair received physostigmine, which enhanced the aggressive action of the animal receiving it, whether that was the subordinate or the dominant animal, though it is reported that the effect was greater in the dominant animal. When the subordinate monkey got the drug, it reversed the hierarchical status of that animal. If this sounds familiar to you, like much more recent experiments that have produced similar results in monkeys treated with serotonergic drugs, it is likely due to the fact that activation of the cholinergic system increases the release of serotonin. But the old study with cholinergic drugs has been around for decades and seems to have been pretty well forgotten.

The author concludes this section of his part of the book by saying, “…it may be predicted that when ACh [acetylcholine] accumulation results as a consequence of a cholinergic diet, facilitation or induction of aggression should follow, as in this situation ACh would act as a cholinergic agonist.” A cholinergic diet might include a lot of eggs (with the choline largely contained in the yolks as phosphatidylcholine) or liver (yech).

Indeed, there is a very large scientific literature on the influence of cholinergic agonists on aggression, though there seems to be no general awareness of what this might mean in particular instances of human aggression. For example, a 2015 paper (Chen, 2015) reports that plasma butyrylcholinesterase regulates ghrelin to control aggression. Butyrylcholinesterase is an enzyme that also hydrolyzes acetylcholine (as does acetylcholinesterase) but at a higher concentration. Male BALB/c mice that had high levels of plasma butyrylcholinesterase (and thus decreased acetylcholine) as a result of gene transfer exhibited sharply reduced plasma ghrelin and surprised the paper’s authors by fighting less, both spontaneously and in a resident/intruder provocation model. On the other hand, mice with the BChE gene deleted had increased ghrelin and had a lot more fights. There was no mention of the early studies on the cholinergic system and aggression. It is almost as if the very early studies on aggression and the cholinergic system had been lost somewhere.

Reference

• Chen, Gao, Geng, et al. Plasma butyrylcholinesterase regulates ghrelin to control aggression. PROC NATL ACAD SCI U S A.112(7):2251-6 (2015).

THE CHOLINERGIC NERVOUS SYSTEM, FISH OILS, AND ESTROGENS—EMERGING LINKS

As I indicated before, emerging links may be emerging or they may have been hiding out in the immense scientific literature waiting for you to run across them, but in any event, I am now aware of papers that provide a plausible link between the cholinergic nervous system, fish oils (EPA and DHA), and estrogens. (Don’t think this just applies to women; men have estrogens, too.)

Docosahexaenoic acid (DHA, an omega-3 fatty acid because of estrogenic effects. This may link estrogen, the cholinergic nervous system, and cognition (as reviewed above). Gilray et al. Docosahexaenoic acid concentrations are higher in women than in men because of estrogenic effects. Am J Clin Nutr. 80:1167-74 (2004) inflammation and the cholinergic system and DHA.

“The soluble form of amyloid protein (sAPP) released from neurons activates microglia [a type of immune cell in the brain] and induces excessive microglial expression of IL-1 [an inflammatory cytokine]. IL-1 increases the production and activity of the acetylchol-degrading enzyme acetylcholinesterase, which results in a decrease in brain acetylcholine levels.” Here, part of the Alzheimer’s disease process is revealed to be an increased expression of an inflammatory cytokine, which decreases brain acetylcholine levels. The cholinergic nervous system in which acetylcholine is the neurotransmitter is a major antiinflammatory regulatory system in the brain and body. DHA, on the other hand, is also an antiinflammatory molecule in the brain when converted to Neuroprotectin D1. DHA inhibits the formation of proinflammatory molecules such as the prostaglandin PGE2 (Das, 2008).

Reference

• Das, “Essential fatty acids and their metabolites could function as endogenous HMG-CoA reductase and ACE enzyme inhibitors, anti-arrhythmic, anti-hypertensive, anti-atherosclerotic, anti-inflammatory, cytoprotective, and cardioprotective molecules. Lipids Health Dis.7:37 (2008).

“Prostanoids represent another key component of neuro-inflammation. Particularly, PGE2 is highly synthesized in the brain during inflammation.” (Laye, 2003) For more on PGE2, see the two-part paper by Sandy Shaw on the niacin flush at www.life-enhancement.com.

Reference

• Laye and Dantzer. Polyunsaturated Fatty Acids and Neuro-Inflammation. In: Yehuda and Mostofsky, editors. Nutrients, Stress, and Medical Disorders.New York: Humana Press; (2005). P. 353-76.

EPIGENETIC CHANGES WITH AGING AND CANCER

DECREASED METHYLATION > INCREASED INFLAMMATION?

PROTECTION AGAINST DECREASED METHYLATION BY BETAINE

It has been reported in recent papers that there is an average decrease in methylation levels in the regulation of genetic expression, an epigenetic change that has become a very hot area of research in aging and in the occurrence of a large variety of inflammatory and other diseases. Average decrease in methylation means just that, most genetic methylation decreases but there are some areas, such as the expression of some tumor suppressors that are overmethylated and, hence, less expressed, increasing the risk of cancer.

A very new paper (Veldhoven, 2015) reports that an epigenome-wide association study found there was an average decrease in methylation levels years before breast cancer was diagnosed. The authors suggest that this is a good biomarker for very early detection of possible breast cancer.

Reference

• van Veldhoven, Polidoro, Baglietto, et al. Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis.Clin Epigenetics. 7:67 (2015).

PGE2, a powerful inflammatory prostaglandin (discussed extensively in my paper (Part I) on the cause of the niacin flush—see at www.life-enhancement.com, “Why the Niacin Flush May Be Surprisingly Beneficial to Your Health” in the August 2015 issue—may be involved here. Importantly involved in inflammatory diseases, PGE2 has recently been reported (Venza, 2012) to induce interleukin-8 derepression (restores IL-8 expression from tight regulatory suppression) in human brain astrocytoma cells, where the increased IL-8 expression recruits and activates immune and inflammatory factors, increasing the spreading and invasiveness of the deadly glioma brain tumor.

The paper (Venza, 2012) reported that the PGE2 induced derepression of PGE2 took place through coordinated DNA demethylation and histone hyperacetylation. Interestingly, there are some other inflammatory diseases, such as COPD (chronic occlusive pulmonary disorder) where histone deacetylation is decreased (that is, there is hyperacetylation of the histone) at HDAC-2, histone deacetylase 2. (NOTE: Importantly, some diseases are associated with increased levels of histone deacetylases and others with increased levels.) In the second part of my paper on how the niacin flush may benefit your health there is a section at the very end of natural substances that, like the niacin flush, reduce the activity of PGE2. That includes substances such as omega-3 fatty acids, curcumin (constituent of turmeric root), and ginger, for example.

Reference

• Venza I1, Visalli M, Fortunato, et al. PGE2 induces interleukin-8 derepression in human astrocytoma through coordinated DNA demethylatiuon and histone hyperacetylation. 7:11, 1315-30 (2012).

SEX AND ORGASM

An interesting early paper (1994) reported that the synthesis and release of prostaglandins D2 and E2 by rat uterine tissue takes place throughout the sex cycle. Pulsatile PGD2 (as occurs in the niacin flush) is antiinflammatory while chronic release of PGD2 (as occurs in Alzheimer’s disease, for example) is proinflammatory. PGE2 is generally inflammatory but can under some circumstances be antiinflammatory (perhaps depending upon dose and time course of its release). Prolactin, released during orgasm, regulates levels of PGD2 and PGE2. Somewhere in this complex stew is the magic switch that might be useful for producing orgasm and increasing its strength. Just for fun, you know. Might make a moneymaking formula, too, but the fun comes first.

Could An Orgasm At the Same Time As the Niacin Flush Result in a Stronger Orgasm?

A possible clue is an observation Durk made many years ago that having a niacin flush at the same time as having an orgasm would increase (I noticed this, too) the strength of the orgasm, which hints that pulsatile PGD2 (the cause of the niacin flush) may be part of the orgasm process. If you can tolerate the niacin flush, you might give it a try and let us know if you notice anything (write to us c/o Life Enhancement Products about this but please do not ask for medical advice. We can get into serious legal problems (prison, legal expenses that bankrupt us, etc.) doing that and we simply cannot reply to such requests.

A DELICIOUS, NUTRITIOUS RECIPE FOR DEVILED EGGS
GREAT FOR A PARTY DISH OR JUST EVERYDAY GOURMET EATING

Great source of choline (mostly from the egg yolks)
Good source of isothiocyanates from fermented cabbage
Also get isothiocyanates from horseradish

You’ll need:

One dozen hard-boiled eggs, cut lengthwise in half after cooking

Filling:

Place all ingredients in a medium bowl, the yolks removed from the eggs after hard boiling the eggs

6 tablespoons mayonnaise
1 tablespoon prepared horseradish or two tsp. powdered horseradish
1⁄4 tsp salt
1⁄2 cup finely chopped corned beef

Topping:

1⁄4 cup finely chopped corned beef
1⁄4 cup finely chopped sauerkraut, drained well

Mix all ingredients for the filling until well blended.

Spoon the filling mixture into the egg white halves.

Top each egg-half with a teaspoon of the topping. You might want to make more of the topping, as a teaspoon may not be enough!

Serve to your friends and wait for the compliments!

EPILEPSY: MAJOR INFLAMMATORY FACTOR THAT CAUSES IT POINTS TO TREATMENT, WITH NATURAL PRODUCTS ACTING AS VALUABLE ADJUNCTS
BY SANDY SHAW

A paper (Shimada, 2014) Durk found in a search provides an excellent summing up of how inflammatory prostaglandins, products of the omega-6 fatty acids through their conversion to arachidonic acid, are critically involved in epilepsy and what takes place during a seizure, whether it is tonic-clonic or temporal lobe epilepsy (the latter may have no convulsive features at all, resulting in sometimes subtle changes in mental state, to a sort of disassociated state, akin to the infamous “split personality” of schizophrenia, which may make it difficult to diagnose).

The paper describes the process as follows: “In addition to inflammatory cytokines, prostaglandins (PGs) are major factors that stimulate inflammation processes. PGs are known to markedly increase following seizures and they contribute to epileptogenesis and reduction in seizure threshold.” “The enzyme cyclooxygenase (COX) converts arachidonic acid to PGH2 and the specific PG synthase converts PGH2 to various PGs such as thromboxane A2, PGF2alpha, PGE2, PGI2, or PGD2.”

“Because PGs play an important role in inflammatory responses, the function of PGs in epileptogenesis have been studied for a considerable amount of time” One thing the researchers pointed out is the discrepancy in effects of COX inhibitors in the treatment of epilepsy, with some having positive effects, while others can even increase damage and mortality. The reason for this discrepancy is, I believe, due to failing to recognize that the release of prostaglandins in pulses can be antiinflammatory (with PGD2 being an excellent example, discussed at length in my niacin paper) while their release over an extended period of time is likely to be proinflammatory. So the time course of the release of prostaglandins resulting from the inhibition of COX is not being considered, so far as I have seen in the literature on prostaglandins. As prostaglandins are crucially involved in inflammatory diseases, which include just about every important disease afflicting man, this time course of the release of prostaglandins by COX inhibitors is itself critical to the outcome of treatment.

This information fits nicely into the paper I wrote on the niacin flush (which is caused by a pulsatile release of a particular prostaglandin, prostaglandin D2 (PGD2) and which has powerful antiinflammatory effects) and I have added it as part II of my niacin flush/inflammatory diseases paper at the Life Enhancement website www.life-enhancement.com. (See “Why the Niacin Flush May Be Surprisingly Beneficial to Your Health” in the August 2015 issue.)

The researchers go on in their analysis of epilepsy: “…PGD2 and PGF2alpha can exhibit anticonvulsive functions. PGD2 synthase H-PGDS knockout (KO) mice [they cannot make PGD2] or PGD2 receptor DP1R-KO mice showed more severe seizures after pentylenetetrazol (PTZ) treatment than wild type mice whereas deficiencies of the other synthase L-PGDS or receptor DP2R did not alter seizure severity.” “By contrast, PGE2 mainly functions as a promotor of epileptogenesis and ictogenesis.” “…COX2 coupled PGE2 production can promote seizures through mechanisms that drive epileptogenesis.”

It is very interesting to note that PGD2 can act as a counter-regulatory factor to PGE2 but only when it is released in pulses, as occurs during the niacin flush. See my niacin flush paper PART I near the start of the text, just after the discussion of “What Is the Niacin Flush.”

Prostaglandin D2 release as an antiinflammatory pulse can be effected by a number of dietary supplements, including curcumin (and other constituents of turmeric root), niacin (in the immediate release form that causes flushing), selenium (shunts arachidonic acid production to antiinflammatory prostaglandins such as PGD2), EGCG (inhibits PGE2 production, possibly by releasing PGD2 in a pulse), ginger, sulforaphane (as found in cruciferous vegetables; stable metabolites with potent antiinflammatory activity also contained in the herb Moringa oleifera). These are just a few examples.

• Shimada, Takemiya, et al. Role of inflammatory mediators in the pathogenesis of epilepsy. Mediators Inflamm. 2014;2014:901902. doi: 10.1155/2014/901902. Epub 2014 (Aug 13, 2014).
• Why the Niacin Flush May Be Surprisingly Beneficial to Your Health. Part I, (Aug. 2015), free access at www.Life-Enhancement.com and Part III (Sept. 2015), the discussion of epilepsy.

LYCOPENE—A CAROTENOID WITH POWERFUL
ANTI-INFLAMMATORY POWERS
BY SANDY SHAW

The data in a paper I was reading (Rafi, 2007) indicated potent antiinflammatory effects of the carotenoid lycopene that as part of a natural chemical pathway inhibits COX, which, via its two forms COX1 and COX2, converts arachidonic acid to inflammatory prostaglandins, such as the powerful inflammatory prostaglandin E2 (PGE2) (under some conditions it can be anti-inflammatory). PGE2 is a known factor in virtually all inflammatory diseases, including cardiovascular disease, cancer, diabetes type 2, arthritis, inflammatory bowel disease, epilepsy, and many others.

COX-1 is constitutively expressed, while COX-2 is an inducible enzyme that “mediates acute and chronic inflammation, pain, and cellular repair mechanisms.” (Rafi, 2007) The authors believe that the results of data from studies of lycopene “suggest that inhibition of COX2 may be effective in preventing inflammatory-associated cancers.” (This suggestion, from 2007, was supported by later work.) The authors concluded: “Therefore, using lycopene or [lycopene-containing] tomato-based products to regulate the production of NO and COX-2 may be classified as a therapeutic approach for the treatment or prevention of chronic inflammatory disease.”

DURK AND SANDY GET RELIEF FROM THE PAIN OF
THEIR ARTHRITIC KNEES WITH LYCOPENE

Unfortunately, both of us have moderate cases of knee osteoarthritis, with Sandy’s knees significantly more painful. We had run out of lycopene and after a few days to a couple of weeks we both noticed more pain in our knees. The day we went back on lycopene (we started on 15 mg. a day, though Sandy has upped hers to 30 mg. a day now that she has felt the difference), we were both aware of much more comfort in walking. The best way to take it is with the fattiest meal of the day, as it is absorbed best with fats.

It is also interesting that lycopene is another one of the natural products that inhibits for formation of inflammatory prostaglandins. See (Shaw, 2015) “Why the Niacin Flush May Be Surprisingly Beneficial to Your Health” by Sandy Shaw for a discussion—in Part I under the subheading “What Is the Flush?”—of inflammation and the prostaglandins that play such a major role in it, particularly PGE2 and PGD2. PGD2 is prostaglandin D2 that is the cause of the niacin flush and which counters the effects of inflammatory PGE2 when released as a pulse, but there are many ways other than taking niacin to interfere with PGE2-induced inflammation. Lycopene is one such effective antiinflammatory nutrient.

References

• Shaw (2015) paper, Part I, is found on the Life Enhancement website, www.life-enhancement.com, August 2015.
• Rafi, Yadav, Reyes. Lycopene inhibits LPS-induced proinflammatory mediator inducible nitric oxide synthase in mouse macrophage cells. J Food Sci. 72(1):S69-S74 (2007).

APPETIZERS

The ideal form of government is democracy tempered with assassination

(D&S: Not in our neighborhood!)

After a shooting spree, they always want to take the guns away from the people who didn’t do it.

What, sir, would the people of the Earth be without woman? They would be scarce, sir, almighty scarce.

Men are easy to get but hard to keep.

On one issue at least, men and women agree: they both distrust women.

Love is like a good dinner; the only way to get satisfaction out of it is to enjoy it while it lasts, have no regrets when it is over and pay the price with good grace

APPETIZERS

America can cease to be the wealthiest nation on Earth and remain America. It can cease to be the most powerful nation on Earth and remain America. It cannot cease to be the land of the free and remain America.

—Charles Murray,
Rebuilding Liberty Without Permission, 
CATO’S LETTER (CATO Institute)
Vol. 13 No. 2 Spring 2015

The physician can bury his mistakes, but the architect can only advise his client to plant vines.

—Frank Lloyd Wright, New York Times 4 Oct. 1953

The Puritan hated bear-baiting, not because it gave pain to the bear, but because it gave pleasure to the spectators.

—Lord Macauley, A History of England Vol. Ch. 2 (1849)

If you’re in Amish country and you see a man with his hand buried in a horse’s ass, remember he’s just a mechanic.

—Robin Williams, 2003

Well, he thought, you can fool some of the people all the time, and all the people some of the time, which is just long enough to be President of the United States.

—Spike Milligan, 1963

Take the hair, it is well written
Of the dog by which you are bitten
Work off one wine by his brother
One labour with another.

—Antiphanes (400 BC), hangover cure

(D&S comment: a combination of Vitamin B1, the amino acid cysteine, and Vitamin C—as in Party Pill—is a better remedy, we think. Even back then, they may have heard of drinking orange juice (vitamin C) with a raw egg (cysteine) for hangover.)

Whilst Titian was mixing rose madder,
His model posed nude on a ladder,
Her position to Titian
Suggested coition,
So he climbed up the ladder and had ’er.

—Anon.

THE MYSTERY OF THE RISING IQS MAY BE SOLVED

Sandy has a hypothesis (though it is entirely possible that others have also suggested this) to explain the widely discussed fact of a rising IQ over six countries in the past 100 years that has been getting a lot of press. See, for example, the Sat./Sun. May 30-31 2015 The Wall Street Journal, pg. C2.

You will have noticed if you’ve read about this—and this has been discussed—that the greatest increase in IQs has taken place during periods of prosperity. Right now, the IQs are still increasing but only slowly. Consistent with the trend, the present economy is not a very prosperous one.

Sandy proposes that the rising IQs are occurring as a result of ENVIRONMENTAL ENRICHMENT, which has been studied extensively in the scientific literature using both animals and humans as subjects. Environmental enrichment is robustly linked to an increase in neurogenesis. It appears to explain quite nicely how, during periods of prosperity characterized by the availability of many opportunities (like putting lots of toys and things to do in an animal’s cage), an increase in neurogenesis is likely to be taking place with IQs being a rough indicator of that.

How Much of the Obesity Epidemic Is Real?
The Bad News and the Worse News

The bad news is that there is certainly a lot of obesity around. You can see it by looking at people in shopping centers or schools or anywhere there are large numbers of people.

But what do official counts of the rising number of obese Americans really mean? Consider: Durk points out that the new medical coding that requires doctors to assign numbers to patients that represent their medical condition is behind a phenomenon called “overcoding” where it is to the advantage of the doctor or hospital to code a patient as “obese” even if he or she is merely overweight to allow for increased reimbursement through government health “insurance” schemes or even private insurance. And perhaps the scariest part of this is that those designations follow the patient all the way from the doctor’s records for that patient to scientific research on obesity as a public health problem to government health surveys, with the designation “obese” being used to describe somebody only overweight making it appear that there is an epidemic of obesity.

We’re still waiting to hear about disappearing bedbugs

EPA RELEASES DRAFT PLAN TO CONTROL BEDBUGS
FOLLOWING THE FIRST NATIONAL BED BUG SUMMIT

As reported in the Sept. 9, 2013 Chemical & Engineering News. As of that date, the article says, the federal government announced a draft plan putting itself on top of the bed bug problem, so relax, we can assume that by now everything is under control. Everything except that taxes keep going up because, hey, Bed Bug Summits cost money, don’t you know.

Admitting from the start that bedbugs can be a health problem, carrying allergens for example, one wonders whether the federals simply have too much money to spend when they are developing a national plan to control bedbugs that included representatives from EPA, the Centers for Disease Control & Prevention, and the Departments of Defense, Housing & Urban Development, and Agriculture. The Department of Defense?? Oh, don’t they have something more important to spend their budget on than fighting bedbugs? Have the bedbugs developed weapons of mass destruction or something? Can’t the military use good old DDT on infected beds? We wonder how the Department of Homeland Security feels about being left out of this proposed spendfest.

We note, first, that there is nothing in the Constitution authorizing the federals to do anything about bedbugs, though the States are not prohibited therein from doing so and presumably could, if they wanted to and had the money, do something about bedbugs and it would be Constitutional, though almost certainly expensive and ineffective.

The federals are way beyond having any concern about being authorized in the Constitution to do anything, so now we have a national plan putting a bureaucracy together for dealing with the bedbug disaster, which we imagine would be far more dangerous than bedbugs themselves, leading us to conclude that: “We have nothing to fear but the bureaucracy set up to ensure that we have nothing to fear.”

We wonder whether the group did a comprehensive survey of the hotels that participated in the national summit of bedbugs to determine how many bedbugs had also attended the summit. Did they have a representative from an ethics advisory group on whether it would be ethical to kill bedbugs with chemical weapons? Extinction is forever; therefore, consistent with the precautionary principle, we had better not take the chance that bedbugs being eliminated from the ecosystem is of no consequence.

Is There a Real Bedbug Problem and, If So, What Is It?

There IS an actual problem, however. What this is all about is that hotels are now having a serious problem with bedbugs driving away customers precisely because the EPA itself has banned nearly any insecticide that could be used to kill bedbugs. The military has the same problem because even though the military could actually tell the EPA to take their insecticide ban and shove it, the Prez won’t let them do that. No doubt he has a reason for forcing the military to comply with the EPA’s rules on the use of insecticides for killing bedbugs, but we doubt that national defense played any part in his analysis.

COMPLAINTS FROM THE PAST
ANYTHING ABOUT THIS SOUND FAMILIAR?

If anybody is interested, the historical course of the Roman Empire looks almost exactly in its declining years like what is going on now in the U.S. and the modern world, with our advanced technologies mostly speeding up the changes but otherwise things look almost the same. Remember it was the collapse of the plumbing, e.g., the Roman water supply and sewage systems, that ultimately (as the proximal cause) depopulated the city by killing people with repeated plagues of diseases resulting from the poorly maintained fresh water and sewage systems. And, of course, it was Benjamin Franklin who has been given credit for saying, as he left the Constitutional Convention of 1789, “you have a Republic … if you can keep it.” Well, so did the Roman Empire and they failed to keep it. The [Roman] Republic entered the dustbin of history and it was followed by …. well …

Here’s the complaint. The poet Virgil narrowly avoided losing his estates during the period when Octavian took over Spain, Sardinia, and Africa, and undertook to put down Sextus Pompeius (the son of Pompey). Virgil alluded to this in his first Eclogue:

“To think of some godless soldier owning my well-farmed fallow, A foreigner reaping these crops!

“To such a pass has civil Dissension brought us; for people like these we have sown our fields.”¹

Reference

1. Virgil’s The Eclogues 1.70 ff, trans. C. Day Lewis, in The Eclogues, Georgics and Aeneidof Virgil, Oxford Univ. Press (1966), cited in Stephen Kershaw, A Brief Guide to Classical Civilization (Running Press, 2010).

Letter to Virgil

Dear Virgil,

We were sorry to hear of your problems with various military invaders from the Roman Empire. We do hate to tell you this but even if you could get to our time via time travel, it would do you no good as the situation hasn’t improved at all. They do it (sow crops in your field) with regulations rather than (usually) outright invasion, but the result is the same: your crops disappear and you don’t get to eat or sell them. Of course, there are a lot of interesting new things (such as telephones, the Internet, jet planes, etc.) available nowadays, so you still might like to make the trip. We just thought you ought to know that your crops will not be any safer from state predators today than they were then. See the US Supreme Court decision called KELO.

If you do decide to take the trip, available at your local time travel provider, please come and visit us. One caution, though, governments and predators (though sometimes in disguise) are everywhere and at all times.

We had a Republic, Virgil, but we couldn’t keep it.

Sorry about that.

SURPRISE! KAPPA OPIOID RECEPTORS MEDIATE THE ANTIDEPRESSANT-LIKE ACTIVITY OF HESPERIDIN IN MICE

Who would have thought it? That hesperidin could exhibit anti-depressant effects in mice subjected to the forced swim test and do so by interacting with the kappa opioid receptor. But that’s one thing about biomedical science—there are always lots of surprises.

The kappa opioid receptor is one of the three currently known opioid receptors, that also includes mu and delta opioid receptors. Hesperidin, a naturally occurring flavonone glycoside, is found in rich quantities in citrus fruits and has been reported to have antioxidant, neuroprotective, and anticancer effects. An earlier paper² reported that in traditional Mexican medicine, infusion of flowers of the Citrus genera are used as a sedative to treat insomnia. That paper explored this interesting property of Citrus; the authors reported that, in an earlier study, hesperidin in the methanol extract of Citrus sinensis was identified as the sedative active principle of the plant. Others had described the involvement of opioid receptors to the behavioral and antinociceptive (anti-pain) effects of hesperidin.

The immobility period of the mice subjected to the forced swim test (freezing as a result of fear) was significantly reduced by treatment with hesperidin at doses of 0.1, 0.3, and 1 mg/kg. Pretreatment with naloxone (a nonselective opioid receptor antagonist) reversed the antidepressant-like effect of hesperidin, evidence that that effect of hesperidin was mediated by an opioid receptor.

Because of scientific evidence supporting hesperidin’s neuroprotective effects (such as its antidepressant activity in mice subjected to a severe stress), we included hesperidin at a dose of 100 mg per capsule in our special lithium formulation, same as the lowest dose of hesperidin that had antidepressant effects in the mice in this study. If you are a mouse, we suggest you consider the secure feeling you’ll get by taking a hesperidin supplement. If you are a human, we don’t know exactly what dose is going to provide the exact same effects as in the mice, but that hesperidin will activate the kappa opioid receptor seems very likely as there is no evidence to our knowledge that mice and humans differ in this particular respect.

There is much scientific evidence for beneficial effects of hesperidin, such as providing protection against amyloid beta induced neurotoxiciy (as occurs in Alzheimer’s disease),³ reducing neuroinflammation in an animal model of stroke,⁴ protecting against ischemia-reperfusion injury in rats,⁵ as just a few examples.

YOU CAN GET HESPERIDIN FROM ORANGE JUICE, BUT …

To get the amount of hesperidin contained in a single capsule of our lithium formulation would require drinking 400 ml of raw orange juice. Delicious, but there is a very large amount of natural sugars and calories in all that OJ. Besides, it is a lot more expensive than our lithium formulation. [See “Announcing Durk & Sandy’s New Lithium Formulation” in the May 2014 issue.]

1. Filho et al. Kappa-opioid receptors mediate the antidepressant-like activity of hesperidin in the mouse forced swimming test. Eur J Pharmacol.698:286-91 (2013).
2. Guzman-Gutierrez and Navarrete. Pharmacological exploration of the sedative mechanism of hesperidin identified as the active principle of Citrus sinensis flowers. Planta Med.75:295-301 (2009).
3. Wang et al. Protective effects of hesperidin against amyloid-beta induced neurotoxicity through the voltage dependent anion channel 1 (VDAC-1)-mediated mitochondrial apoptotic pathway in PC-12 cells. Neurochem Res.38:1034-44 (2013).
4. Raza et al. Hesperidin ameliorates functional and histological outcome and reduces neuroinflammation in experimental stroke. Brain Res.1420:93-105 (2011).
5. Gaur and Kumar. Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction. Pharmacol Rep.62:635-48 (2010).

THE DIFFERENCE BETWEEN MODERN MEN AND THOSE THAT PRECEDED THEM

A philosophical speculation

by Sandy Shaw

An interesting thing to think about is: when were men smart enough to realize that everything might be explainable as the result of a natural process? You go back to Benjamin Franklin (not so long ago) and if you showed him, say, an iPOD, he would not know how it worked but he would be quite sure that there was a natural explanation for what it did, that it was not MAGIC.

Then go back to Leonardo da Vinci (1459-1512?), if you showed him an iPOD, he too wouldn’t have any idea how it worked, but we are sure (though we can’t prove it) that he would believe it to be a device explainable by natural processes, not MAGIC. You can go back pretty far in recorded history and there were men of genius who would be capable of such a distinction, natural processes explained how things worked, MAGIC was not needed. An example was very early astronomical theorists who thought that stars in the sky were probably natural bodies much like our sun or perhaps like planetary bodies. These men had little actual data but were using a large brain capable of very sophisticated thoughts to imagine what might explain lights they saw in the sky. So how far back would you have to go to reach a point where some humans had just begun to think that natural processes could explain everything and you didn’t need to invoke MAGIC. I think that was when you could say that modern man had arrived.

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?

Why Getting Enough Choline is Vitally Important—
It Is An Essential Nutrient—
And Why Your Health, Quality of Life, and Probably
Your Lifespan Depends on Getting Enough of It

POSTOPERATIVE COGNITIVE DECLINE

Postoperative Cognitive Decline and Infections Prevented by Stimulation of the Cholinergic Antiinflammatory Pathway in Mice

Another 2014 paper⁵ reported on research attempting to determine how to prevent the all too common cognitive deficits that occur following surgery after acute illness and hospitalization. Mice were subject to tibia fracture (surgery) and infection (postoperative administration of lipopolysaccharide (LPS) to induce inflammation as occurs in a natural infection). The results of these procedures were, indeed, increases in measures of inflammation. However, in those mice that were treated with a selective activator of the n-7 nicotinic cholinergic receptor, which activates the cholinergic antiinflammatory pathway, 2 hours after the administration of LPS, resulted in significant improvement of the neuroinflammation in the hippocampus of the mice compared to mice receiving surgery or LPS alone.

The authors conclude that “[o]verall these results suggest that it may be conceivable to limit and possibly prevent postoperative complications including cognitive decline and/or infections, through stimulation of the cholinergic antiinflammatory pathway.”

5. Terrando, Yang, Ryu, et al. Stimulation of the alpha7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice.Mol Med. 20:667-75 (2014).

NOTE that the galantamine in our galantamine formulation is a selective activator of the alpha-7-nicotinic cholinergic receptor, [See “Maintain your Brain the Durk Pearson & Sandy Shaw Way” in the May 2004 issue of Life Enhancement.]

OBESITY

Dysregulation of Metabolism and Immune Function in Obesity Points to Novel Therapeutic Approaches Involving the Cholinergic Antiinflammatory Pathway

A 2012 review paper⁶ describes how “cholinergic mechanisms within the inflammatory reflex have, in the past 2 years, been implicated in attenuating obesity-related inflammation and metabolic complications. This knowledge has led to the exploration of novel therapeutic approaches in the treatment of obesity-related disorders.”

As the authors note, “[d]ecreased vagus nerve activity in the context of obesity has been reported. Selective cholinergic activation within the efferent vagus nerve-mediated arm of the inflammatory reflex can suppress obesity-associated inflammation and reverse metabolic complications. These findings raise the intriguing possibility that dysregulation of vagus nerve-mediated signalling might contribute to the pathogenesis of obesity and its related comorbidities.” Later in the paper, the authors describe how the cholinergic antiinflammatory pathway suppresses the production of major inflammatory cytokines such as TNF-alpha, via the administration of alpha-7-nicotinic acetylcholine receptor agonists (which includes the nutrient choline^6B) or a centrally-acting acetylcholinesterase inhibitor, such as galantamine. [See “Maintain your Brain the Durk Pearson & Sandy Shaw Way” in the May 2004 issue of Life Enhancement.] The authors describe how galantamine treatment of mice with high-fat induced obesity and hyperglycemia had reduced plasma levels of IL-6, CCL2, leptin, and resistin levels to levels detected in lean control mice.⁷ They further explain that cholinergic signaling, such as that of alpha-7-nicotinic acetylcholine receptor agonists in brain regions such as the lateral hypothalamus, implicated as part of the brain’s control system for appetite and feeding behavior, can suppress food intake.

6. Pavlov and Tracey. The vagus nerve and the inflammatory reflex—linking immunity and metabolism. Nat Rev Endocrinol.8(12):743-54 (2012).
   Mike, Castro, Albuquerque. Choline and acetylcholine have similar kinetic properties of activation and desensitization on the alpha7 nicotinic receptors in rat hippocampal neurons. Brain Res. 882:155-68 (2000).
   7. Satapathy, Ochani, et al. Galantamine alleviates inflammation and other obesity-associated complications in high-fat diet-fed mice. Mol Med. 17(7-8): 599-606 (2011).

OBESITY

Dysregulation of Metabolism and Immune Function in Obesity Points to Novel Therapeutic Approaches Involving the Cholinergic Antiinflammatory Pathway

A 2012 review paper⁶ describes how “cholinergic mechanisms within the inflammatory reflex have, in the past 2 years, been implicated in attenuating obesity-related inflammation and metabolic complications. This knowledge has led to the exploration of novel therapeutic approaches in the treatment of obesity-related disorders.”

As the authors note, “[d]ecreased vagus nerve activity in the context of obesity has been reported. Selective cholinergic activation within the efferent vagus nerve-mediated arm of the inflammatory reflex can suppress obesity-associated inflammation and reverse metabolic complications. These findings raise the intriguing possibility that dysregulation of vagus nerve-mediated signalling might contribute to the pathogenesis of obesity and its related comorbidities.” Later in the paper, the authors describe how the cholinergic antiinflammatory pathway suppresses the production of major inflammatory cytokines such as TNF-alpha, via the administration of alpha-7-nicotinic acetylcholine receptor agonists (which includes the nutrient choline^6B) or a centrally-acting acetylcholinesterase inhibitor, such as galantamine. [See “Maintain your Brain the Durk Pearson & Sandy Shaw Way” in the May 2004 issue of Life Enhancement.] The authors describe how galantamine treatment of mice with high-fat induced obesity and hyperglycemia had reduced plasma levels of IL-6, CCL2, leptin, and resistin levels to levels detected in lean control mice.⁷ They further explain that cholinergic signaling, such as that of alpha-7-nicotinic acetylcholine receptor agonists in brain regions such as the lateral hypothalamus, implicated as part of the brain’s control system for appetite and feeding behavior, can suppress food intake.

6. Pavlov and Tracey. The vagus nerve and the inflammatory reflex—linking immunity and metabolism. Nat Rev Endocrinol.8(12):743-54 (2012).
   6B. Mike, Castro, Albuquerque. Choline and acetylcholine have similar kinetic properties of activation and desensitization on the alpha7 nicotinic receptors in rat hippocampal neurons. Brain Res.882:155-68 (2000).
   7. Satapathy, Ochani, et al. Galantamine alleviates inflammation and other obesity-associated complications in high-fat diet-fed mice. Mol Med. 17(7-8): 599-606 (2011).

CHOLINE COADMINISTERED WITH ASPIRIN HAS SYNERGISTIC EFFECT ON PAIN RELIEF: HIGHER POTENCY, LONGER DURATION, FEWER SIDE EFFECTS

The results published in a new paper¹ will likely be of interest to anybody taking regular NSAID (nonsteroidal antiinflammatory drugs, such as aspirin, Naproxen, or ibuprofen) pain killers, particularly for chronic inflammatory conditions such as arthritis. The researchers report that choline, an alpha7 nicotinic receptor agonist (a natural endogenous activator of this particular type of cholinergic receptor) has anti-nociceptive (anti-pain) effects of its own in a variety of pain models. They were, therefore, interested in a possible positive interaction between choline and aspirin in the treatment of pain and thus carried out experiments with two inflammatory pain models in mice. One of the models they studied was the writhing test, where acetic acid is injected into the lower left quadrant of the abdomen of mice causing what must be excruciating pain as the pain behavior is manifest by writhing and evaluated by the number of writhes. We have chosen not to discuss this gruesome model as the results in terms of the observed pain relief to treatment with choline, aspirin, and a combination of the two were similar to the results of the inflamed paw test, described below.

The other model of pain studied was that caused by subcutaneous carrageenan injection into the paw of a mouse, which caused pain behavior assessed by how long it took the mouse to withdraw its injected paw (the Pain Withdrawal Latency, or PWL) in response to the application of heat; the heat would cause pain to the inflamed paw. The results showed that the administration of a single dose of choline (48 mg/kg, i.v., 1 hour after carrageenan injection) or a single dose of aspirin (30 mg/kg i.v., 1 hour after carrageenan injection) significantly suppressed the carrageenan-produced reduction in PWT only at 2 hours post carrageenan; thus, this time point was used as the test time in the remaining tests. (This is equivalent to less than one serving of our Memory Upgrade III.™) [See http://www.life-enhancement.com/shop/product/mu3-memory-upgrade-iii.]

“Choline (4–48 mg/kg, i.v.) produced a dose-dependent inhibition of carragennan-induced thermal hyperalgesia [pain], which was significant at doses of 16, 24, and 48 mg/kg (F(6,68)=10.8; P<0.01)). Aspirin (0.3125-30 mg/kg) also produced a dose-related inhibition of the carrageenan-induced thermal hyperalgesia, with significant effects at doses of 1.25, 2.5, 10, and 30 mg./kg. (F(5,54)=6.6; P<0.01)).

At low doses, choline (4 and 8 mg/kg, i.v.) or aspirin (0.3125 and 0.625 mg/kg, i.v.) administered alone were reported to have no effect on the carageenan-produced reduction in PWT, but when choline (8 mg/kg) was coadministered with aspirin at 0.6125 mg/kg or choline at 4 mg/kg + aspirin at 0.3125 mg/kg, the combination of drugs significantly reversed the carrageenan reduction of PWT. The effects were observed at 2 hours after carrageenan injection, but also at 3 hours and 4 hours after injection. Hence, the anti-pain effects of the coadministered choline and aspirin was prolonged. (If you wake up with aches in the morning, this mouse dose is equivalent for a human to about one serving of SleepScape™). [http://www.life-enhancement.com/shop/product/sls45-sleepscape]

Attempts to Find Mechanisms for the Observed Synergy Between Choline and Aspirin

The authors attempted to identify mechanisms that could help explain the interaction between choline and aspirin (and other NSAIDS).¹

Curiously, pretreatment with one alpha 7 nicotinic cholinergic antagonist, MLA, blocked the anti-pain effects of choline, while a different antagonist, alpha-bungarotoxin, enhanced the choline-induced anti-pain effect.¹ The researchers propose that the carrageenan-induced hind paw edema in mice is a biphasic event, with an early phase of inflammation resulting from the release of histamine, serotonin, and similar substances, while a later phase is associated with the activation of kinin-like substances. This biphasic behavior may result in different responses to the two alpha-7-nicotinic cholinergic antagonists. Another complication they point out is that choline is a partial agonist of alpha-9 alpha-10 nicotinic cholinergic receptors. “Taken together, the antinociceptive effect of systemic choline seems to be dependent upon the presence of inflammation and its activity may be mainly via attenuating the release of inflammation cytokines through activation with peripheral macrophages and monocytes through alpha-7-nicotinic receptors, but this needs further studies in more pain models.”¹

The researchers also note that in their study¹ the analgesic effect of choline was inhibited by naloxone, which suggests that opioid receptors are involved in choline’s anti-pain behavior, but that the data from some other studies (for which they provide references) are not consistent with this.

“These results provide support for further study of the synergistic antinociceptive mechanisms of coadministration of choline and NSAIDS such as aspirin, and they provide a basis for exploiting new analgesic treatments using low antinociceptive dose, long antinociceptive course, and reduced side effects.”¹

Cholinergic Control of Inflammation May Be a Mechanism for Its Effects on Pain

There has been a considerable amount of research supporting an antiinflammatory function of the cholinergic nervous system.² One paper³ reported that choline itself, by its signaling via the alpha-7 subunit nicotinic acetylcholine receptor, modulates the release of tumor necrosis factor (TNF), a major proinflammatory cytokine. TNF synthesis and release has been identified in various types of pain.^4,5 Blocking TNF-alpha has been very effective in the treatment of rheumatoid arthritis, with sometimes dramatic reductions in both the pain and tissue damage resulting from the disease.⁶

In a study of the antiinflammatory effects of choline (50 mg/kg, intraperitoneally (i.p.) in mice, this treatment prior to endotoxin (a bacterial cell wall constituent that activates the immune system) administration significantly reduced systemic TNF levels. In the same study, though, mice that did not have alpha-7-nicotinic acetylcholine receptors (knockout mice) did not have reduced systemic TNF levels in response to the same dose of choline, showing that these receptors were required for the reduced TNF (anti-inflammatory) effect of choline. In cells studied by the researchers,³ choline incubation prior to exposure to endotoxin suppressed both TNF and NFkappaB, another major regulatory molecule in inflammation. Choline also suppressed TNF production from endotoxin-stimulated human whole blood and cultured macrophages. As the researchers³ noted, “[t]he effective doses of choline used in the present study (25-50 mg/kg, i.p.) are within the dose range used in [] other studies. It is important to note that we did not observe any adverse neurobehavioral effects of these choline doses, which are comparable with the recommended tolerable upper limit of dietary choline intake in humans.”

Finally, one more curiosity: A paper on the effect of aspirin and opioids on pain was published in the 11 Dec. 1997 Nature;⁷ the accompanying commentary⁸ described the findings of the study that the combination of aspirin and opioids is more analgesic than the summed effect of each drug separately with an attempt to identify mechanisms. Here is another example of the difficulty of identifying the pathways of pain regulation. It could link to the choline-aspirin work described above if the analgesic effect of choline is actually inhibited by naloxone (an opioid antagonist).

References

1. Yong-Ping et al. Pharmacological action of choline and aspirin coadministration on acute inflammatory pain. Eur J Pain.15:858-65 (2011).
2. Rosas-Ballina and Tracey. Cholinergic control of inflammation.J Intern Med.265:663-79 (2009).
3. Parrish et al. Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling.  Med.14(9-10):567-74 (2008).
4. Richter et al. Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats. Arthritis Rheum.62(12):3806-14 (2010).
5. Xu et al. The influence of p38 mitogen-activated protein kinase inhibitor on synthesis of inflammatory cytokine tumor necrosis factor alpha in spinal cord of rats with chronic constriction injury. Anesth Analg.105:1838-44 (2007).
6. Basbaum et al. Cellular and molecular mechanisms of pain. CELL 139:pg. 275 (2009).
7. Vaughan et al. How opioids inhibit GABA-mediated neurotransmission. 390:611-4 (1997).
8. The painless synergism of aspirin and opium. Nature.390:557-9 (1997).

SATIETY SIGNALING AT THE END OF A MEAL MAY BE DUE TO ACTIVATION OF THE CHOLINERGIC NERVOUS SYSTEM—AN EXPLORATION OF POSSIBLE MECHANISMS REGULATING INGESTION

This article will be of interest only to the highly technically inclined, especially if they are overweight.

Hypothesis:

Activation of Cholinergic Nervous System May Promote Satiety by Signaling the End of a Meal Could the Widespread—92% Deficiency of Choline Ingestion Be Contributing to the Obesity Epidemic?

A new paper¹ propose that activation of cholinergic interneurons in the nucleus accumbens (NAc) and cholinergic projections to the ventral tegmetal area affect feeding behavior. “In vivo microdialysis studies in rats have revealed that the cessation of a meal is associated with a rise in acetylcholine (ACh) levels in the NAc.” Moreover, the researchers note, “ACh activation will suppress feeding, and this is also associated with an increase in synaptic accumulation of ACh.”¹

The paper also discusses the relationship between cholinergic activity and drug addiction and withdrawal. “Studies reveal that accumbens ACh is increased during withdrawal from several different drugs of abuse (including cocaine, nicotine and morphine). This rise in extracellular ACh, coupled with a decrease in extracellular levels of DA [dopamine] is believed to contribute to an aversive state, which can manifest as behaviors associated with drug withdrawal.” The authors suggest that these changes, observed both in the cessation of feeding and in drug withdrawal, may point to a form of “food addiction” and “withdrawal” from overeating.¹

Acetylcholine participates in the regulatory pathways of many behaviors, including (for example) learning and memory and muscular contraction. Particularly interesting is, as the authors explain, that, “two major ACh projections innervate key components of the reward system.” The authors then propose that these projections may play a key role in the reward of drug addiction as well as in the promotion of either satiety or appetite, depending upon their specific co-transmitters.

As explained above, the rise in extracellular ACh, coupled with a decrease in extracellular levels of dopamine (DA) are part of the regulatory pathway that is observed both in the cessation of feeding and in drug withdrawal. The rewarding signal at the start of a meal that stimulates eating includes increased DA: “The dorsal striatum plays a role in consummatory food reward, and striatal dopamine receptors are reduced in obese individuals, relative to lean individuals, which suggests that the striatum and dopaminergic signaling in the striatum may contribute to the development of obesity.”²The researchers found in their study² that there was a blunted dopaminergic response to food which, they surmise, “implies that individuals may overeat to compensate for a hypofunctioning dorsal striatum, particularly those with genetic polymorphisms thought to attenuate dopamine signaling in this region.” Unfortunately, the latter study did not include examining the effects of acetylcholine.

In another paper,³ researchers reported that “[o]ur recent data suggest that one such interaction is the regulation of ACh of DA synapse signalling of reward-related activity.” This comment was in relation to interactions between ACh and DA in the striatum in motor response selection, particularly in reward-related learning of stimulus-response associations or habits, acquired through positive reinforcement. “… striatal ACh neuron activity and ACh release are inhibited by DA.”³ This cross-talk between striatal ACh and DA in reward-related motor activity would be consistent with another appetitive activity (meal cessation) associated with ACh increase and DA decrease in the striatum.

As noted earlier, microdialysis studies have shown that there is an increase in extracellular ACh in the NAc at the end of a meal.¹ “Further support for the theory that increased extracellular levels of accumbens ACh are associated with the cessation of feeding comes from data showing that when rats binge eat sugar while at a reduced body weight, or when they are sham fed(*) sucrose using a gastric cannula, accumbens ACh is blunted.”¹

“Other studies suggest that food intake can be promoted by depleting ACh via local injection of the selective cholinergic neurotoxin ethylcholine azirdinium mustard (AF64A) into the NAc. In an acute (1 wk) feeding test, rats that were given this lesion showed a 2-fold increase in food intake.”¹ (There was, however, a significant and lasting lag in body weight gain in these animals, which the authors of paper#1 suggest may point to a compensatory mechanism when cholinergic function is ablated.)

Nicotine-induced decreases in eating by mice may be, as suggested by recent studies, due to the activation of cholinergic nicotinic receptors in the hypothalamus, which activates pro-opiomelanocorin neurons leading to the activation of melanocortin 4 receptors critical for nicotine-induced decreases in food intake in mice.¹

In comparing the biochemical pathways that involve the cholinergic nervous system in both drug or food withdrawal, the authors suggest: “Thus, rats in withdrawal from palatable food appear to show the profile of ACh in the NAc that has been seen in withdrawal from drugs of abuse.”¹

The researchers conclude that “increased levels of ACh in the NAc act to promote satiety.”¹ Also, another paper^1B reports that cholinergic interneurons in the brain’s accumbens play a role in the regulation of body weight and metabolism.

In a 2011 paper,⁴ researchers examined cholinergic function in the regulation of reward, noting that “[m]ore than three decades of research into the neurobiological substrates of reward have focused attention on the nucleus accumbens (NAc)…” “The preponderance of this research effort has centered on dopamine (DA) as the primary neurotransmitter in this regard.” “Studies by Hoebel and colleagues have demonstrated increases in the release of DA in the NAc as a function of a variety of behaviors including feeding, rehydration, models of binge eating, and hypothalamic stimulation.” The authors⁴ then point to the work of Hoebel and other scientists for contributing work that has brought about an increasing appreciation of the importance of the role of acetylcholine in the brain reward circuit.

Interestingly, older people and animals have been found to drink less water in response to thirst as compared to younger individuals, thus being at increased risk of dehydration under hot, dry conditions.^4B The above suggests that it might be a deficiency in the release of DA in the NAc during rehydration that is involved.

The RATIO of the Release of Dopamine to Acetylcholine May Regulate Ingestive Behavior

Eating Too Much? Choline to the Rescue?

As the authors of paper #4 indicate, the fact that dopamine (DA) plays a major role in the modulation of ingestive behavior is now well documented. They describe studies in hungry rats showing that “hungry rats stop feeding if the DA/ACh balance in the NAc is tilted in favor of excess cholinergic tone.” In the rat study, rats were implanted with bilateral microdialysis probes in the NAc and allowed to eat ad lib during their active period (night). When the probes implanted in the animals were perfused with an acetylcholinesterase inhibitor (which increases cholinergic activation), neostigmine, there was an almost complete discontinuation of eating, which did not happen in the control animals that received perfusion of standard Ringer’s solution. The animals treated with neostigmine continued to drink water, though, showing that the discontinuation of eating was not caused by malaise or immobility.

A 1998 paper⁵ was an early paper describing increased dopamine release combined with reduced acetylcholine release as a possible mechanism for hypothalamic initiation of feeding behavior. Using adult male Sprague-Dawley rats as subjects, animals received microinjections of the hormone galanin, neuropeptide Y, or saline into the hypothalamic paraventricular nucleus (PVN). The results showed that the injection of galanin in the PVN induced eating, causing the release of dopamine in the NAc and decreasing the release of ACh in the NAc. (The injection of neuropeptide Y also induced eating, but had no effect on either dopamine or acetylcholine.)

In a 2007 paper,⁶ researchers reviewed studies on the effects of the ACh/DA ratio on approach and avoidance. They examine several animal models of human behavior on meal satiation, taste aversion, escape from aversive brain stimulation, depression, drug withdrawal, and sugar withdrawal (following binge eating of sugar). They explain that in their own work, they tested the opposite effects of DA and ACh in the accumbens loop controlling motivation and some aspects of learning by injecting neurotransmitter agonists and antagonists into the NAc to reveal their effects on ACh/DA balance and observing animal behaviors. They also observed avoidance behaviors to see whether ACh is released in the NAc. “The evidence suggests that ACh inhibits the approach system via muscarinic M1 [cholinergic] receptors, and thereby counteracts the effects of DA at the D1 [dopaminergic] receptors.”⁶

One study they reviewed, for example, showed the effect of a mildly distasteful (bitter) solution that, when drunk, triggered injection of a nutritious ingredient into the stomachs of the subject rats. Ordinarily, rats avoid bitter tasting substances, but in this case, as compared to a bitter tasting solution that triggered only a water injection into the stomach, the animals soon developed a preference for the bitter tasting solution that delivered nutrition. The researchers found that squirting the (mildly) bitter flavor into an animal’s mouth (after it had developed a preference for its taste) resulted in the release of DA in the NAc, to which the authors attribute the approach behavior (the desire to eat). On the other hand, rats generally like sweet tastes, including that of sugar or saccharin. In a study where rats have developed an aversion to saccharin (because of pairing the saccharin with nausea) the taste significantly increases ACh release in the NAc, with the induction of avoidance (not wanting to eat).

The implications of these observations, that feeding behavior may be initiated by increased dopamine accompanied by decreased acetylcholine in the NAc and that feeding behavior may be terminated by decreased dopamine release accompanied by increased acetylcholine release, should they be affirmed in further studies (especially ones with human subjects), is that one may be able to induce the cessation of feeding by taking a cholinergic agonist (a substance like choline itself that increases acetylcholine production and release) at an appropriate time at the start of a meal or slightly before starting the meal. Another possible way to get the increased cholinergic activity in the NAc is to take a cholinesterase inhibitor such as galantamine, that increases cholinergic activity by causing acetylcholine to remain in the neuronal synapse for a longer period of time.

A couple of things to keep in mind: (1) the timing of the increase in cholinergic neuronal activity in relation to the cessation of eating is going to be important. That information may not yet be available; hence, some experimentation using safe ways to increase cholinergic activity (such as supplemental choline or the cholinesterase inhibitor galantamine) will be required. (2) A cholinergic agonist such as choline is going to be used throughout the body and brain, not just in the NAc, for the synthesis of acetylcholine, hence, side effects of excessive cholinergic activity, such as headache caused by increased muscle tone, could occur that have nothing to do with the desired effect on eating and, indeed, nothing to do with the NAc, another reason that some experimentation would be required.

References

1. Avena and Rada. Cholinergic modulation of food and drug satiety and withdrawal.Physiol Behav.106:332-6 (2012).
   (*) The sham feeding of sucrose through a gastric cannula means the animals are fitted with a gastric cannula, but do not receive sucrose. That way, there is no confounding effect in the interpretation of the effects of sucrose feeding as compared to placebo by possible effects induced by receiving—or not receiving—a gastric cannula. The goal in experiments is to change only the variable you are studying and to keep everything else the same.
   1B. Hajnal, Szekely, et al. Accumbens cholinergic interneurons play a role in the regulation of body weight and metabolism. Physiol Behav.70:95-103 (2000).
   2. Stice et al. Relation between obesity and blunted striatal response to food is moderated by TaqlA A1 allele. Science. 322:449-52 (2008).
   3. Cragg et al. Striatal acetylcholine control of reward-related dopamine signaling. In The Basal Ganglia VIII, eds Bolam JP, Ingham CA, Magill PJ. New York: Springer;99–108 (2005).
   4. Mark et al. Cholinergic modulation of mesolimbic dopamine function and reward. Physiol Behav. 104:76-81 (2011).
   4B. Mack et al. Body fluid balance in dehydrated healthy older men; thirst and renal osmoregulation. J Appl Physiol (1985). 76(4):1615-23 (1994).
   5. Rada et al. Galanin in the hypothalamus raises dopamine and lowers acetylcholine release in the nucleus accumbens: a possible mechanism for hypothalamic initiation of feeding behavior. Brain Res. 798:1-6 (1998).
   6. Hoebel et al. Accumbens dopamine-acetylcholine balance in approach and avoidance. Curr Opin Pharmacol. 7:617-27 (2007).

APPETIZERS

He who has learned, unlearns with difficulty.

—ancient Greek proverb

The more laws, the more offenders.

—ancient Latin proverb

Even a hare will insult a dead lion.

—ancient Latin proverb

Small favors conciliate, but great gifts make enemies.

—ancient Latin proverb

(Source of proverbs: There’s a Saying for That: PROVERBS from Around the World,edited by Bob Blaisdell, Dover Publications, 2013)

FDA APPROVED ANTICHOLINERGIC DRUGS PRESCRIBED FOR “OVERACTIVE BLADDER” MAY INCREASE THE RISK OF DEMENTIA AND ALZHEIMER’S DISEASE

We have found additional reports in the literature, as far back as 2003,^1,2 that warn of increased Alzheimer pathology in anticholinergic (antimuscarinic) drugs prescribed to treat “overactive bladder” in the elderly. These drugs do not have black box warnings about these disastrous potential side effects.

Although mildly effective in treating motor symptoms in Parkinson’s disease, but more often prescribed in these patients for bladder dysfunction, the use of antimuscarinic drugs has been shown to be associated with impaired neuropsychiatric and cognitive function. Clinical evidence suggests that M1 mAChR [M1 muscarinic acetylcholinergic receptor] antagonism may account for these unwanted side effects, as M1 AChR antagonists such as benztropine, orphenadrine, and trihexyphenidyl (Artane^®) have been shown to increase amyloid plaque and neurofibrillary tangle densities similar to that found with Alzheimer’s disease pathology.

A 2003 paper¹ reported on the autopsy findings for 120 neuropathologically confirmed Parkinson’s disease (PD) cases. The PD cases were divided into three subgroups depending on how long they had been using anti­muscarinic drugs for movement or bladder control. “None” indicated no use of such drugs, short term use was less than 2 years, long term greater than 2 years. They also had two subgroups according to the use for 1–10 years of tricyclic antidepressants (also antimuscarinics).

As we indicated in the first part of this article (see it in the May 2015 Life Enhancementmagazine), one way to test for anticholinergic effects is whether or not a drug causes dry mouth. Tricyclic antidepressants do that. Not all drugs that cause dry mouth, however, are anticholinergics, so if you do experience dry mouth, you will need to check a reference to find out whether what you are taking has anticholinergic effects.

The results¹ showed that there were no differences in Alzheimer pathology between the short-term use or no use (“None”) of antimuscarinics. However, plaques were more than twofold higher in the group chronically treated long term with antimuscarinics, tangles were twofold higher in the long-term treated as compared to the group exposed to no antimuscarinics. In the group treated with tricyclic antidepressants, plaques and tangles were more than twofold higher in the treated as compared to the untreated group though this did not reach significance and the authors note that depression itself may promote Alzheimer pathology. The authors conclude that their data are consistent with the possibility that prolonged use of antimuscarinic drugs “accelerates beta amyloidosis and senile plaque formation in the aging brain in subjects with PD.”

The commentary² that discussed the above paper mentioned several anticholinergic medications used in the treatment of movement disorders (trihexyphenidyl, benztropine), urinary incontinence (tolterodine, oxybutynin) and dizziness (meclizine). The commentary notes that “[a]bundant evidence now implicates amyloidogenesis as a critical event in AD pathogenesis.” The authors then refer to evidence that muscarinic cholinergic stimulation can reduce amyloid beta formation in vitro and in vivo in animal studies, thus suggesting the way that antimuscarinics could be deleterious in AD. “The significance of these findings for the millions of healthy elderly patients taking anticholinergic drugs remains to be clarified.” They suggest that physicians prescribe these drugs cautiously and with frequent review and assessment of their benefits. We think that a strong warning should be required. When using a drug to treat a non-life threatening condition (urinary bladder incontinence), the acceptable potential downside should certainly itself be non-life threatening. That does not appear to be the case with anticholinergics for the treatment of urinary incontinence and we ourselves would avoid them entirely for this purpose.

References

1. Perry, Kilford, Lees, et al. Increased Alzheimer pathology in Parkinson’s disease related to antimuscarinic drugs. Ann Neurol.54:235–8 (2003)
2. Allan I. Levey, MD, PhD. Chronically made as a hatter: anticholinergics and Alzheimer’s disease pathology. Ann Neurol.54(2):144–6 (2003).

REVOLUTIONARY NEW VIEW OF CONSCIOUSNESS:
THE BRAIN AS A COMMUNITY OF INTERACTING AREAS

We were amazed to see that, in the May 2015 Nature Neuroscience, a paper was published (Wan et al. Neural encoding of opposing strategy values in anterior and posterior cingulate cortex. pp. 752–9; commentary on pp. 616–7) that goes a very long way in supporting the notion that the brain is made up of discrete areas that, in decision-making, come to a decision by a consensus process, with competition between the differing areas as to what the areas would prefer as a decision. In other words, the idea that our personalities are not homogeneous, there really may be different characters inside our heads, and there is a continuous process of negotiation going on between these characters to produce a single decision that includes “everybody” in the decision-making process. What was nuts yesterday could be scientifically respectable today!

The way the authors of the commentary put it: “This result speaks to the idea that decisions may be realized via a distributed consensus, a viewpoint that argues that no single brain area is critical in decision-making, but that decisions instead emerge via competitions occurring in many brain regions.”

The process called “automatic writing,” which, since William James’^A early writings on the subject (1885–1899), was used to describe how an author of fiction could write a story and just let the words flow effortlessly—it seems as if the text writes itself—without consciously interceding in the process would be entirely consistent with this viewpoint of distributed consciousness. The flow is where you allow the different brain areas to interact, watching them while they do this rather than directing them via central control. You might have to be a fiction writer to have had the experience of writing this way, with characters seeming to emerge spontaneously from the subconscious.

This dissociation of the consciousness into mutually exclusive parts is evidently a phenomenon destined, when understood, to cast a light into the abysses of Psychology.

—William James^A

Reference

1. See Koutstaal. Skirting the abyss: a history of experimental explorations of automatic writing in psychology. J Hist Behav Sci.28:5–27 (1992).

Getting to the actual experiments described in Nature Neuroscience: The researchers used a Japanese game called shogi in which the players make decisions concerning moves that have either an offensive or a defensive purpose. The game is well suited to this, it is said, because the moves are so clear as to whether they are defensive or offensive. So while the players are making these decisions/moves, they are followed by fMRI to identify, which parts of the brain are interacting. The result was that they found very specific areas worked together when you made a defensive decision and very specific other areas worked together when you made an offensive decision. Posterior cingulate cortex reflected the subjective value of offensive strategies, while rostral anterior cingulate cortex activated as a function of the subjective value of the defensive strategy. These two regions interacted with the dorsolateral prefrontal cortex, which is said to be implicated in cognitive control. The commentary’s authors put it this way: “… the functional connectivity results of Wan et al^1–2 suggest that, in addition to distributed competition, changes in connectivity could be crucial for understanding how flexible choices could be implemented.”

This is a revolutionary view of human consciousness that appears now to have emerged from science fiction to reach the pages of a highly respectable scientific journal.

References

1. The commentary: Nils Kolling & Laurence T. Hunt. Divide and conquer: strategic decision areas. Nat Neurosci.18(5):616–7 (2015).
2. The paper: Wan, Cheng, Tanaka. Neural encoding of opposing strategy values in anterior and posterior cingulate cortex. Nat Neurosci.18(5):752–9 (2015).

NATURALLY GM

NATURALLY GENETICALLY MODIFIED SWEET POTATO
FOUND TO NATURALLY CONTAIN GENES FROM BACTERIA

Whoops. It may come as a shock to some people but genetically modified (GM) crops are not just created by humans, but also occur naturally. A news report in the 23 April 2015 Nature (pg. 410) reports on the discovery of a sweet potato cultivar that had apparently been infected by Agrobacterium bacteria in the past. These bacteria infect plants and transfer DNA into their host’s genome, which is how the genes ended up in the sweet potato. (In fact, modern genetic engineering commonly uses these bacteria as vehicles to transfer genes into plants they want to genetically modify.) The original paper on this subject was published in the Proceedings of The National Academy of Sciences,² in which the authors concluded, “This finding could influence the public’s current perception that transgenic crops are ‘unnatural.’”

References

1. Harvey Silverglate. Three Felonies a Day: How the Feds Target the Innocent. Encounter Books, 2011 explains why ALL Americans are now felons as a result of the expansion of prohibited acts in the lawbooks.
2. Kyndt, Quispe, Zhai, et al. The genome of cultivated sweet potato contains Agrobacterium T-DNAs with expressed genes: an example of a naturally transgenic food crop. Proc Natl Acad Sci U S A. 112(18):5844–9 (2015).

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

WHEN ACTIVATED IN WOMEN CAN PRODUCE O R G A S M!

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

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.

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

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

Reference

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

Choline Attenuates Immune Inflammation in Patients with Asthma

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

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

Reference

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

DIETARY CHOLINE AND BETAINE INTAKE ASSOCIATED WITH REDUCED LEVELS OF INFLAMMATORY MARKERS IN HEALTHY ADULTS

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

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

Reference

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

HEART FAILURE

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

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

Reference

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

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

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

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

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

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

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

References

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

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 paper¹ were 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).

APPETIZERS

“Man is so made that he can only find relaxation from one kind of labor by taking up another.”

— Anatole France, The Crime of Sylvestre Bonnard

“You seem … to consider the judges as the ultimate arbiters of all constitutional questions; a very dangerous doctrine indeed, and one which would place us under the despotism of an oligarchy … The Constitution has erected no such single tribunal.”

— Thomas Jefferson, 1820

“One man with courage is a majority.”

— Thomas Jefferson

“Quemadmoeum gladis nemeinum occidit, occidentis telum est. (“A sword is never a killer, it’s a tool in the killer’s hands.”)

— Lucius Anaeus Seneca (“the younger” ca. 4BC – 65 AD)

“Among the many misdeeds of the British rule in India, history will look upon the act of depriving a whole nation of arms, as the blackest.”

— Mahatma Gandhi

(D&S Comment: A very interesting take on the bad deeds of English rule in India by Gandhi. “History” doesn’t yet seem to have come to this view yet. Only in America do we still have sufficiently strong popular support for the right to keep and bear arms that this statement by Gandhi could be understood.)

“Just because you do not take an interest in politics doesn’t mean politics won’t take an interest in you.”

— Pericles (430 BC)

“Politics is the art of looking for trouble, finding it whether it exists or not, diagnosing it incorrectly, and applying the wrong remedy.”

— Ernest Benn

“Remind me,” Jubal told her, “to write an article on the compulsive reading of news. The theme will be that most neuroses can be traced to the unhealthy habit of wallowing in the troubles of five billion strangers.”

— Robert A. Heinlein Stranger in a Strange Land, (1961)

The Size of the Sun

“It is immeasurably huge. This you can tell from the following observation. Trees which are planted at the far limits of East and West, nevertheless cast shadows of the same proportions—though these trees are miles and miles apart, the sun appears in the same place, as though centred on either one.”

— Pliny the Elder, Natural History

DID YOU KNOW . . .

CUMULATIVE USE OF STRONG ANTICHOLINERGICS MAY BE ASSOCIATED WITH AN INCREASED RISK OF DEMENTIA

A new paper¹ just published in JAMA INTERN MED reports that, among a cohort population of 3434 men and women aged 65 or older with no signs of dementia at the start of the study, during a mean followup of 7.3 years, higher cumulative use of anticholinergic drugs was associated with an increased risk of DEMENTIA. Anticholinergic drugs are used as, for example, antispasmodics for the gastrointestinal tract, antimuscarinics for the bladder (“overactive bladder”) and antiparkinsonians. The paper notes that the use of anticholinergics in older adults ranges from 8% to 37%.

During the 7.3 years of mean followup, 797 participants (23.2%) developed dementia, with 637 of these reported to develop Alzheimer’s disease. There was a 10 year cumulative dose-response relationship observed for both dementia and Alzheimer’s disease, that is, the higher the cumulative dose used during that period, the greater the likelihood of developing dementia and Alzheimer’s disease.

Though this was an association, not proof of cause and effect, it is important to keep in mind that Alzheimer’s disease and dementia are both positively linked to dysfunction in the cholinergic nervous system in the brain. Hence, this association is likely (but not proven) to be a causative one.

Use It Or Lose It

The relationship between the cholinergic nervous system in the brain and cognitive aging has been a hot research subject for at least the past 40 years.² In an important 1974 paper,² for example, the authors say: “The cognitive and memory disturbances occurring with aging may reflect some relatively specific disorder of cholinergic neurotransmitter function — such as impaired synthesis, release or receptor iuptake of acetylcholine — that is largely reproduced by pharmacologic cholinergic blockade.” The paper² itself was a test of anticholinergic drugs in young subjects and showed memory/cognitive impairment. The authors conclude that their data “raise the interesting association between cholinergic blockade and the mental deterioration of aging, however, and suggest the need for further study of the integrity of the cholinergic pharmacosystem in the elderly.”

Declining Ability of the Older Brain to Transport Choline Across the Blood-Brain Barrier

We have written extensively about the markedly decreasing ability of the human brain, as it ages, to import choline across the blood-brain-barrier into the brain from the general circulation. [See “Maintain your Brain the Durk Pearson & Sandy Shaw Way” in the March 2004 issue.]

Moreover, in the explanatory material in the paper,¹ the authors note that, while “the general view is that anticholinergic-induced cognitive impairment is reversible on discontinuation of medication therapy,” “several investigators have reported that anticholinergics may be associated with an increased risk for sustained cognitive deficits, such as mild cognitive impairment or dementia.” The authors suggest that a plausible biological mechanism for these findings is that “cumulative use of these agents results in pathologic changes in the brain similar to those observed with Alzheimer’s disease (AD).”

All of the first generation and many of the second generation antihistamines have anticholinergic effects, though not the third generation. One way to tell is if the antihistamine you use causes your mouth to become dry, it likely has anticholinergic activity.

References

1. Gray, Anderson, Dublin, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 175(3):401 – 7 (2015).
2. David A. Drachman, Janet Leavitt. Human memory and the cholinergic system. Arch Neurol. 30:113 – 21 (Feb. 1974).

REALLY LOW DOSE LITHIUM STABILIZES ALZHEIMER’S
DISEASE PATIENT COGNITION OVER 15 MONTHS

A group of scientists, concerned about increased toxicity of lithium in the aged at the usual dosages used therapeutically (for bipolar disorder, for example), ranging from 150 to 600 mg daily, as a result of reduced glomerular filtration in the kidney, among other things, decided to do a study on Alzheimer’s patients at a truly tiny dose, 300 micrograms once a day.¹ Well water in areas with higher than usual amounts of lithium may contain that much lithium and commercially-available premium priced mineral waters from some springs and artesian wells often contain water with prized increased amounts of lithium, highly sought after by many looking for the healthful benefits of the mineral at low doses. See next section below for more on lithium in natural sources of water.

The 113 patients included in the study had their mental states evaluated every three months using MMSE (mini-mental state examination) applied in a double-blinded manner at the hospital (the physicians, patients, family, and caregivers did not know which patients received lithium and which received placebo). The MMSE is designed to measure the ability of a person to function doing normal everyday tasks.

During the study, those receiving microdose lithium showed no decrease in performance on the MMSE, whereas the control group (receiving no lithium) had decreasing scores, indicating cognitive decline. The authors note that relying just on the MMSE was a limitation of the study, as it does not give a complete picture for the determination of the assumption of homogeneity between the groups, though they did administer two other statistical tests to verify the homogeneity between groups, the Friedman non-parametric test followed by the Bonferroni test.

The results of this study, using a dose so small and registering a stabilization of the AD patients over such a long period, 15 months, is remarkable and is a worthy subject for determination of the mechanisms involved.

We note that this amount of lithium per day is so small that even our own low dose lithium contains 6 mg in a daily capsule. We based this dose on the amount of lithium you could get from drinking a reasonable amount of famous European health spa mineral water naturally high in lithium sold legally in the United States. The 6 mg dose is 6000 micrograms, 20 times as much as in the 300 microgram microdose used in this Alzheimer disease study.¹

Reference

1. Nunes, Viel, Buck. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Curr Alzheimer Res. 10:104 – 7 (2013).

LOWER DOSE LITHIUM PROTECTS AGAINST AMNESTIC MILD COGNITIVE IMPAIRMENT IN HUMAN STUDY POSSIBLE MECHANISM IDENTIFIED

A small-randomized controlled study of 45 individuals with mild memory impairment received lithium (150 mg a day titrated to serum levels of 0.25 – 0.5 mmol/l, a range lower than the usual dosage used to treat bipolar disorder) or placebo over 12 months. Lithium treatment was associated with a significant decrease in cerebrospinal fluid concentrations of p-TAU (p=0.03) and better performance on the cognitive subscale of the Alzheimer’s disease Assessment Scale and in attention tasks.^1A

The most interesting datum mentioned in the paper was that preliminary data from the lab that performed the study1A described above (data said to be available upon request) showed that lithium treatment in the dose range used in the above study for two weeks in healthy volunteers caused a 50% reduction in GSK3B activity in leukocytes. Although this enzyme is known to be inhibited by lithium at therapeutic doses (those used to treat bipolar disorder) and is thought to be a major mechanism of its action at those doses, this is the first time we’ve seen a measurement at lower doses of lithium. This might suggest that even lower doses of lithium may have an inhibiting effect on the enzyme, though it might be inhibited less than at the higher doses depending on the shape of the dose-response curve.

References

1A. Forlenza, Diniz, Radanovic, et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 198:351 – 356 (2011).

LITHIUM AS AN ESSENTIAL NUTRIENT

A 2012 paper² provided detailed information on the presence of lithium in drinking water and vegetation and on its essentiality in a large number of animal and human studies.

The review reported that there is a wide variation in the amount of lithium found in drinking water, spring water, spa water and bottled water. One study of 132 brands of bottled water from 28 countries found lithium concentrations ranging over 5 orders of magnitude (from 0.057 to 5,460 μ/l. “Li concentrations of 8.7 mg/l and of >9 mg/l have been reported for the Friedrich-Quelle, a famous spring in Baden-Baden/Germany, and for the spa water in Pompeya/Argentina, respectively.”²

“The long-term consumption of low-Li drinking water is regarded as a risk factor for higher incidences of suicides, homicides, and crimes as shown in several studies. For example, in 24 counties in Texas/USA with a total population of 6 million (>60% of the state population), during a 2-year study (1967 – 1969), a significantly inverse relationship between (1) Li concentration of local drinking water, (2) Li concentrations of the urine among the respective residents, and (3) mean annual rainfall amounts in the respective county sites and (1) state mental hospital admission rates, (2) admitting rates for four major mental disorders (psychosis, neurosis, schizophrenia, personality problems), (3) homicide rates, and (4) road distance from resident county to nearest state mental hospital was found (p≤0.05 to <–0.001). The Li levels in drinking water were classified into 4 groups: <11.0; 11.0 – 29.9, 30.0 – 69.9; >70.0 μg/l.”¹

A second study reported in the review² included 27 counties and lasted for 10 years (1978 – 1987) and found that that the incidence rates of suicide, homicide, and rape were significantly higher in counties whose drinking water contained low (0–12 μg/l) and medium (13–60 μg/l) lithium concentrations than in counties whose drinking water had high Li concentrations (79 – 160 μg/l)(p<0.01). They also found associations with the rates of robbery, burglary, and theft significant at p<0.05. These are really remarkable differences that suggest improved mental function with low dose lithium.

On the basis of these and many other studies, the basic requirement of lithium in humans has been assessed at 1 μg/kg body weight/d in humans derived from intake data in Germany, thus, the lithium requirement for an adult of 70 kg body weight would be 70 μg/d. In another assessment study, Schrauzer suggested a provisional recommended dietary allowance (RDA) of 1 mg lithium/day for an adult of 70 kg body weight.³

References

2. Evaluation of beneficial and adverse effects on plants and animals following lithium deficiency and supplementation, and on humans following lithium treatment of mood disorders. Trace Elem Electrolytes. 29(2):91-112 (2012).
3. Schrauzer. Lithium: occurrence, dietary intakes, nutritional essentiality. J Am Coll Nutr. 21:14-21 (2002).

Lithium at Therapeutic Doses Protects Neurons Robustly Against NMDA-induced Excitotoxicity

In another study,⁴ lithium at therapeutic doses in cultured cerebellar granule cells from 8 day old Sprague Dawley rats pretreated with lithium chloride for 6 – 7 days and then exposed to 100 μM of glutamate for 24 hours. Preincubation of the cultures with 2mM lithium chloride for 7 days markedly protected the neurons against glutamate-induced excitotoxicity. Although significant protection was detected at 0.5 μM lithium, the maximal effect detected in this study occurred at 3 μM.

Of course, the therapeutic dose of lithium is far higher than that in commercially available high lithium containing mineral water or tap water with naturally high levels of lithium. We are stunned by the findings reported in the study above of protection against cognitive decline in AD patients over 15 months from only 300 μg per day.

Also, see Will Block’s review of other papers on lithium in brain health ( “Can Lithium Benefit Brain Health?” in the June 2004 issue of Life Enhancement.)

References

1. Nunes, Viel, and Buck. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Curr Alzheimer Res. 10:104 – 7 (2013).
4. Nonaka, Hough, Chuang. Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx. Proc Natl Acad Sci U S A. 95:2642 – 47 (March 1998).

Lithium, an Essential Nutrient, Has Neuroprotective Effects at Low Dosage

Lithium salts act as a drug at high doses, but act as a neurologically beneficial essential nutrient at much much smaller amounts.

First, a brief description of the very high dose medical use of lithium — it can be effective as a drug treatment for manic-depressive (or bipolar) illness. It provides nearly complete protection against attacks in about 1⁄3 of bipolar patients, improved symptoms in another 1⁄3, and is ineffective in the remaining 1⁄3.^A However, the treatment of bipolar illness requires high doses of lithium, close to the toxic dose. The clinically effective dose range is 0.6 – 1.0 μM serum level, while the toxic level begins at about 1.2 μM or greater. Symptoms in the dose range of 1.2  –  2.0 μM are said to be usually mild and to seldom cause death or permanent neurological damage.¹ Lithium is excreted via the kidneys or in sweat. Because the toxic dose is not much higher than the therapeutic dose and because prolonged exposure to serum levels of 2μM or greater may cause liver and kidney damage,¹ though, it is necessary for those receiving pharmacological doses for bipolar disorder to receive periodic blood tests to ensure the lithium blood levels remain in the therapeutic range and that liver and kidney functions remain normal.

What is more interesting to us than its use at the highest level that is tolerable before toxic effects ensue is what lithium does at low doses, a dose so low that it would NOT be an effective treatment for bipolar disorder and, hence, the mechanisms of its actions may differ from those that take place at a high dose. It is particularly interesting in light of the fact that, as mentioned above, lithium at small amounts has been found to be an essential mineral with a suggested RDA of 1 mg/day for a 70 kg adult human.

Lithium in Spring Water Reported to Be Positively and Significantly Associated with Brain-Derived Neurotrophic Factor

Brain-derived neurotrophic factor (BDNF) is an important growth factor involved in many cognitive processes including learning and memory, emotional processes, and sometimes psychopathological conditions such as addiction. The effect depends on the specific tissue in which the BDNF is released, the conditions under which it is released, and the dosage released.

In a study of 43 Japanese subjects who did not have psychiatric dysfunction, the participants drank 3.64 liters of spring water from two springs, one of which contained 6.1 mg/liter of lithium and the other contained 15.7 mg/liter, much lower than lithium in clinical use (900 to 1800 mg/day of lithium carbonate, containing 170 – 340 mg lithium/day) but at much higher levels than generally contained in lithium-containing tap water (generally much less than 1 mg/liter). Their serum lithium levels increased from 0.026 to 0.073 mEq/L, a much lower level than if they had been treated with bipolar treatment levels of lithium. The results of a Profile of Mood States indicated that most ratings were significantly improved (though whether this was caused by lithium is unclear  —  the authors suggested it could possibly be a placebo effect). More interestingly, however, serum lithium levels were significantly and positively associated with BDNF levels. BDNF was also negatively and significantly associated with changes in the State-Trait of Anxiety Inventory scores. The researchers cited an earlier study in which lithium had been reported to increase BDNF levels. As this^B was a small open (no blinding, no placebo control) study, the authors rightly noted that further studies are needed to confirm these findings.

German studies have reported the effects of lithium-deficient diets in animals such as goats, pigs, cattle, broiler chickens, and rats.^C For example, one such study of a 13 year investigation with lithium-deficient goats reported that 41% of the lithium-deficient goats but only 7% of the controls (lithium adequate) died during the first experimental year indicating a highly significant difference (p<0.001) between the groups. Moreover, by the end of the third experimental year, all lithium-deficient goats had died, but 18% of the controls were still alive.^C

The same paper^C also described the analyses of various types of bottled water that included spring water, mineral waters, etc. from 28 countries finding that natural lithium concentration varied over 5 orders of magnitude, from 0.057 to 5,460 mg/l. The waters of the Friedrich-Quelle, a famous curative spring in Baden-Baden, Germany, were reported to be 8.7 mg/l. The upper crust of European society visits there for restorative effects. While there, visitors are encouraged to drink only the spring water.

Few data are available on what mechanisms are operative at the very low doses of lithium (except possibly for an increase in BDNF, as discussed above) as compared to mechanisms that help explain the therapeutic effects of high dose lithium in the treatment of bipolar disorder. Lithium has been reported to inhibit phosphatases in both plant and animal cells but we didn’t find any specific data on how this might be involved in (for example) suicide or homicide rates.

Lithium is reported to have a small ionic radius that results in lithium having the highest electronegativity and strongest polarization power among all alkali metal ions and is said to have a relatively large stable radius of the hydrated ion.^C The implications of all this obviously bears upon its biological effects. We await with great interest an elaboration of the effects of lithium that provide mechanistic data explaining its biological properties. In the meantime, lithium is an essential nutrient, appears safe to use at low doses, is very inexpensive, and is available without a prescription!

References

A. Young. Review of lithium effects on brain and blood. Cell Transplant. 18:951 – 75 (2009).
B. Shiotsuki et al. Drinking spring water and lithium absorption: a preliminary study. German J Psychiatry. 11:103 – 6 (2008).
C. Schafer. Evaluation of beneficial and adverse effects on plants and animals following lithium deficiency and supplementation, and on humans following lithium treatment of mood disorders. Trace Elem Electrolytes. 29(2):91 – 112 (2012).

Possible Life Extending Effects of Low Dose Lithium

A large epidemiological study^D has reported that there was an inverse correlation between drinking water lithium concentrations and all-cause mortality in 18 neighboring Japanese municipalities with a total population of 1,206,174 people. The researchers also found that, lithium chloride at a similar dose to that ingested by the humans in their drinking water, extended lifespan in C. elegans.^D

The authors^D adjusted the mortality data for suicide rates (as higher levels that would still be considered low dose lithium has already been found to be associated with reduced suicide rate) and found that overall mortality rate was still inversely associated with tap water lithium levels. In the roundworm Caenorhabditis elegans, mortality in populations exposed to 10 μM of lithium chloride was reduced, while roundworms exposed to 1 μM of lithium chloride showed no effect on mortality rate. These results are consistent with a possible life extending effect of low dose lithium. A dose of 6 mg/day of lithium for an adult human is higher than the lithium level found to be effective in the roundworms.

Chronic Supplementation with Low Dose Lithium May Protect Against Ischemic Damage as Occurs in Stroke

A further study of low dose lithium^E reports neuroprotective effects in a rat model of ischemia (inducing ischemia by middle cerebral artery occlusion for 90 minutes followed by reperfusion). The experimental animals received lithium at 1 mmol/kg (given subcutaneously) for 14 days prior to middle cerebral artery occlusion and then 2 days following. Lithium chloride significantly reduced the infarct volume (number of cells killed by the procedure) by 32.7% compared to the animals receiving vehicle containing no lithium. The chronic treatment with low-dose lithium increased the expression of the antiapoptotic protein Bcl-2 and reduced the expression of the apoptotic-inducing proteins p53 and Bax. The low dosage administered to the experimental animals here was about six times higher than would be ingested from a single serving of our lithium capsules (6 mg per cap).

References

D. Zarse et al. Low-dose lithium uptake promotes longevity in humans and metazoans,” Eur J Nutr. 50:387 – 389 (2011).
E. Xu et al. Chronic treatment with a low dose of lithium protects the brain against ischemic injury by reducing apoptotic death,” Stroke. 34:1287 – 1292 (2003).

Neuroprotective Effects of Chronic Low Dose Lithium in Traumatic Brain Injury in Mice

Considering the high number of automobile accidents and falls resulting in injury or death in the U.S. every year, it would be expected that many incidents of traumatic brain injury occur. The sequelae of such injuries may take place over a period of time and may not receive timely or adequate treatment to prevent temporary (or even permanent) cognitive dysfunction. It is of considerable interest, therefore, to find that, as reported in a recent paper,^F chronic low dose lithium can provide substantial protective effects against a negative outcome in traumatic brain injuries, at least as demonstrated in a mouse model. Since the mechanisms responsible for the damaging effects of such injuries are very similar for mice and men, we consider low dose lithium to be plausibly protective against brain damage, as could occur in a car accident or a fall.

SIDEBAR: In fact, falls are becoming much more common as the population ages and can result in considerable disability or even death as a result of brain damage. Sandy’s mother and father both died as a result of falls, so even at 85 (her mother) and 91 (her father) they might have lived on for years had they not fallen. Her mother died of a neck fracture after falling, while her father died of a stroke resulting from brain damage induced by a fall. We reported earlier (in Vol. 6 No. 3 of the June 2003 issue of this newsletter) the results of a human clinical trial of 122 elderly women in a geriatric long-stay care facility, that receiving 1200 mg calcium plus 800 IU of cholecalciferol (vitamin D) per day over 12 weeks resulted in 49% reduction in falls as compared to calcium alone!*

As the authors of the paper explain, the initial mechanical damage in traumatic brain injury results in blood-brain barrier disruption, cerebral edema, and subsequent increase in intracranial pressure. Later, the secondary effects emerge as a result of an inflammatory response with the release of pro-inflammatory cytokines and the subsequent death of neurons. Cognitive deficits may linger.

The mice were treated daily for 2 weeks with 1 mmol/kg of lithium chloride by intraperitoneal injection and then, under deep anesthesia, were subject to a “controlled cortical impact” to simulate the result of an accidental traumatic brain injury. The researchers found that the animals receiving low dose lithium had significant reduction of loss of hemispheric brain tissue and lesion volume as compared to saline treated controls also subject to traumatic brain injury but receiving no lithium. Low dose lithium also attenuated the learning and memory deficits resulting from the experimental brain injury (as assessed by how long it took the animals to find the hidden platform in the Morris Water Maze).

The authors^F conclude that “[t]aken as a whole, these observations suggest lithium may be a beneficial ‘preventive’ therapeutic approach for reducing the neuronal degeneration and related behavioral dysfunction associated with neurodegenerative illnesses.”

We are personally aware of the extent of cognitive deficits that can ensue following a vehicular accident as a result of what happened to a longtime dear friend of ours. She had been involved in a serious accident while riding a bus and has never been the same since then, a few years later. Since we knew her well before the accident, the changes were very clear to us, that she has problems now with learning and memory that she didn’t have before and overall a substantial decline in her quality of life. She constantly needs reminding of things, even while keeping extensive lists to try to remember. We don’t know how much of this could have been prevented by regular low dose lithium taken before the accident, but we certainly wish she’d had the chance to find out.

Reference

F. Zhu et al. Neuroprotective effect and cognitive outcome of chronic lithium on traumatic brain injury in mice. Brain Res Bull. 83:272 – 7 (2010).
* Bischoff et al. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res. 18(2):343 – 51 (2003).

Daily Injections of Low Dose Lithium for 14 or 28 Days in Wistar Mice Resulted in Increased Size of Neurons and a Denser Dendrite Network

Finally, a paper partly in French and partly in English reported interesting effects of low dose lithium (80 ng/kg lithium carbonate) in the brain cortex of mice: larger neurons and a denser dendrite network.^G These changes remind us of those observed (via fMRI) in the brains of humans receiving lithium at therapeutic levels for bipolar disorder, where brain grey matter volume is increased after 4 weeks of treatment. The increased volume (about 3%) was observed in 8 out of the 10 patients studied.^H

G. Neiri et al. Effects of low doses of Li carbonate injected into mice. Functional changes in kidney seem to be related to the oxidative status. C R Biol. 331:23 – 31 (2008).
H. Moore et al. Lithium-induced increase in human brain grey matter. The Lancet. 356:1241 – 2 (2000).

HERE’S TO YOUR HEALTH WITH BEER, THE DRINK RECOMMENDED BY BENJAMIN FRANKLIN!

New and very convincing evidence for the health benefits of moderate drinking of beer appears in a recent paper.¹ Read it just before you take that nice cold one out of your refrigerator and feel the goodness as it passes into your gastrointestinal tract in the service of your health. Have another cold one if you like. Then have a nice day!

If you recall, Benjamin Franklin was the Founder who expressed a wish to have his body preserved in a vat of wine for later revival to see how the U.S. fared. Perhaps, had he known the results of this study, he might have considered being preserved in a vat of beer.

In this study,¹ researchers investigated whether moderate drinking of beer would provide protection against coronary artery disease. The lucky (well, not so lucky because they had induced heart attacks and were later “sacrificed” for the purpose of examining their heart and other organs) participants were 30 month old commercial female pigs weighing about 35 kg, who were randomly distributed to receive during 10 days, a Western hypercholesterolemic diet, same diet + low beer intake (12.5 g alcohol/day; about 1 bottle/day), same diet plus moderate beer intake (25 g alcohol/day; about 2 bottles/day) or the same diet + alcohol-free moderate beer intake (same amount of beer as the moderate beer intake but without alcohol). All groups contained 7 pigs except for the group receiving only the Western hypercholesterolemic diet (no beer), which contained 9 pigs. This is a particularly interesting study for the use of pigs as subjects. Pigs have a gastrointestinal tract very much like humans (both are omnivores) but are not usually used as subjects in nutritional studies because pigs cost a lot more than rats or mice do. The pigs received their beer split into two portions, taken in the morning and in the evening with their chow.

All the animals were, after ten days on the diet plus beer, subject to a process whereby, under anesthesia, they had a heart attack induced by 90 minutes of total balloon occlusion of the mid-left anterior descending coronary artery. Then, 21 days after this induced heart attack, the animals were all killed for examination.

RESULTS: First, there were no deaths among the pigs receiving beer, while two control animals died from refractory ventricular fibrillation during the induction of the heart attack.

2. ARRYTHMIA  —  Animals required cardioversion after the induced heart attack to control arrhythmia. Cardioversion was required in 6 out of 7 survivors of the control Western diet group, 5 out of 7 of the diet + alcohol-free moderate beer, 2 out of 7 in the diet + low beer intake, and 1 out of 7 in the diet + moderate beer intake group.

3. REDUCED SCAR FORMATION  —  The scar size was significantly lower (about 50% less) in the alcohol-beer fed animals as compared to the Western diet only control group. There was a trend toward reduction in the animals receiving alcohol free moderate beer, which did not reach significance.

4. GENETIC CHANGES  —  All beer-fed animals were reported to have an almost twofold increase of Sirt-1 gene expression (reflecting a protective effect against cell death) and a six-fold decrease in active caspase-3 (reflecting reduced cellular apoptosis) in the ischemic cardiac region.

5. CHANGES IN COLLAGEN DEPOSITION IN SCAR TISSUE  —  Matrix metalloprotease 9 (MMP9) activity was fourfold decreased in the beer-fed animals. This reflects a favorable change in the deposition of collagen in scar tissue, with a reparative level induced but excessive fibrosis reduced by the lower level of MMP9.

6. IMPROVEMENT OF HEART PERFORMANCE  —  “… both intergroup and intra-animal analysis revealed a significant improvement in global cardiac performance (LVEF) in beer-fed animals as compared to HC [Westernized hypercholesterolemic diet] controls.¹

7. INCREASED HDL ANTIOXIDANT CAPACITY  —  Beer intake improved HDL antioxidant potential and, in fact, the HDL from beer-fed animals continued to have protective activity against LDL oxidation. The same authors reported observing that moderate (25 g alcohol/day) and regular beer intake for 31 days was associated with an increase in HDL plasma levels.

8. BEER-INDUCED ACTIVATION OF CARDIAC AMPK AND ITS DOWNSTREAM EFFECTOR eNOS —  The researchers suggested that these effects, also observed in the pig beer study¹ may have contributed to the protection seen in the infarcted myocardium.

These are very impressive results. It is nice to know that that nice cold beer waiting for you at home in your refrigerator supplies you with such a terrific package of benefits for your health. (The subjects in this study were female pigs; we would expect similar but not necessarily exactly the same beneficial effects in male pigs. We would also expect similar benefits in humans.)

Reference

1. Vilahur, Casani, et al. Intake of fermented beverages protect against acute myocardial injury: target organ cardiac effects and vasculoprotective effects. Basic Res Cardiol. 107:291 (2012).

ALL NATURAL ANTIMICROBIAL IN FOOD PRESERVATION

KILLING FOOD-BORNE PATHOGENS WITH LIQUID SMOKE ESTIMATED EPISODES OF FOODBORNE ILLNESS IN THE U.S.

Two lengthy recent review papers^1,2 on foodborne illness report that each year 31 major pathogens caused an estimated 9.4 million episodes of foodborne illness, with 55,961 hospitalizations and 1,351 deaths. In addition to that, there were another 38.4 million estimated episodes (90% credible interval 19.8 to 61.2 million) of domestically derived foodborne illnesses caused by unknown or unspecified agents, resulting in another 71,878 hospitalizations. When you include known agents not known to be transmitted in food and microbes, chemicals, or other substances in food that might transmit disease, you end up with even more. Clearly, the burden on stricken individuals and overall social costs of these illnesses are immense. Data were derived from multiple sources. For example, the authors¹ estimated total deaths caused by acute gastroenteritis by using multiple cause-of-death data from the National Vital Statistics System (2000 – 2006).

Liquid Smoke As An All-Natural Antimicrobial for Preventing Foodborne Illness

In addition to adding a very pleasant taste and aroma to food at appropriate concentrations, liquid smoke is reported³ to be an effective way to kill many common foodborne pathogens.

Liquid smoke is made commercially by condensing smoke from various types of wood (as chips or sawdust) using a controlled process of minimal oxygen pyrolysis. The gases released in the process are chilled in condensers, which liquefies them. Then the liquid smoke is forced through refining vats and filtered to remove toxic and carcinogenic impurities such as polynuclear aromatic hydrocarbons (PAH). The paper³reports that although PAH are highly toxic, they also have very low water solubility allowing for relatively easy removal by liquid smoke manufacturers.

Different types of wood result in liquid smoke with varying degrees of microbicidal activity against particular pathogens. There were a lot of details³ concerning the use of liquid smoke to treat various types of food. Incorporating liquid smoke in a food product such as frankfurters at 2.5%, 5%, or 10% wt/wt in Zesti Smoke, a branded liquid smoke, suppressed the growth of Listeria but at 10% liquid smoke sensory taste panels rated the frankfurters as somewhat less acceptable than lower concentrations of liquid smoke. The treatment of meats (by infusing them with liquid smoke, for example) intended to be frozen for a period of time appears to be the most likely use by consumers as exposure of the food to the liquid smoke for an extended period would appear necessary to get the microbicidal effects. Generally cooking meat to a high enough temperature would eliminate the need for microbicides, but it is probably more common than not for consumers to fail to use a thermometer to ensure reaching an adequate temperature for a long enough period of time to eliminate the microbes.

References

1. Scallan et al. Foodborne illness acquired in the United States  —  Unspecified agents. Emerg Infect Dis. 17(1):16 – 22 (2011).
2. Scallan et al. Foodborne illness acquired in the United States  —  Major pathogens. Emerg Infect Dis. 17(1):7 – 15 (2011).
3. Lingbeck et al. Functionality of liquid smoke as an all-natural antimicrobial in food preservation. Meat Sci. 97:197 – 206 (2014).

WEIGHT AND THE PERCEPTION OF SEXUAL ATTRACTIVENESS

People are rightfully concerned about their weight and body composition, especially lean vs. fat tissue weight, as it relates to health. But we wonder how many women would be even more interested in how men perceived their sexual attractiveness from the point of view of their body shape and weight. (Men might be interested in how women — or other men — perceived their sexual attractiveness based on similar considerations, but we have data just on the perception of attractiveness of women by men.)

The data come from an interesting little study published in the Aug. 15, 1998 The Lancet.¹

The first consideration is that, from the point of view of reproductive potential, we would expect that the more fertile a woman’s build appears to be, the more likely she is to appear sexually attractive to a man. Therefore, the researchers began with an impression that the waist/hip ratio would be of particular importance for sexual attractiveness, with a ratio of 0.7 (curvaceous) being the most attractive waist/hip ratio for a woman.

The researchers, therefore, gave 40 male undergraduates color frontal views of 50 women to rate for sexual attractiveness. They then drew ten women from each of the body-mass index categories: emaciated (<15 kg/m²), underweight (15 – 19 kg/m², normal (20 – 24 kg/m², overweight (25 – 30 kg/m²) and obese (>30 kg/m²). Within each of the body mass index categories the women had different waist/hip ratios, typically ranging from 0.68 to 0.90. The sexual attractiveness ratings were significantly explained by body-mass index and waist/hip ratio, but the magnitude of the effect differed strikingly and perhaps surprisingly. Body-mass index accounted for 73.5% of variance, whereas waist/hip ratio accounted for only 1.8%. In this particular study, body-mass index came out by far as the most important factor in determining sexual attractiveness, with the authors rating it as a good predictor of health and reproductive potential.

The curve for attractiveness rating vs. body-mass index showed a peak at about 21 kg/m².

Even the “bust/hip” ratio (hourglass figure) did not contribute significantly to attractiveness ratings more than body-mass index and waist/hip ratio alone.

Reference

1. Tovee, Reinhardt, et al. Optimum body-mass index and maximum sexual attractiveness. The Lancet. 352:548 (1998).

DIP IN AFFLUENT CONSUMERS’ SPENDING IN 4TH QUARTER OF 2014
SHOWS SHARP DROP IN CONFIDENCE AMONG THE MOST WELL-OFF

You do hear a lot of lies these days about how well the economy is doing, mostly from the government and those who’d like you to think that higher taxes and more government spending is a great idea. Here are some numbers to help provide some perspective.

Unity Marketing conducted a survey from Oct. 9 – 15, 2014 among 1,330 affluents, which includes those with household income of $100,000 and above. The survey showed a drop in affluent consumer confidence of 12.3 points to 46.4, the lowest mood since Quarter 4 of 2008 to Quarter 1 of 2009. Since the affluent households represent only 20% of U.S. households (24.5 million out of 122.5 million) but account for more than 40% of all consumer spending, this is a very major decrease. The demographics of this survey sample was an average income of $259,000 and average age of 47.9 years.

The sort of goods and services surveyed include art galleries, craft stores, home stores such as Restoration Hardware, Crate & Barrel, IKEA, fashion and clothing, jewelry, and general merchandise such as Macy’s, Target, Costco, Bloomingdale, JC Penney’s. This is the sort of marketing survey conducted to help companies follow the sales of products they offer or are thinking of offering, not a survey for the general public. The purpose of the survey is not political, e.g. to point fingers at anybody, but to help marketers decide what is selling and who is buying.

Reference

1. Danziger. Five Luxe Trends for 2015. Luxury Consumption Index. Unity Marketing.http://www.unitymarketingonline.com/ cms/uploads/white_papers/five_key_luxury_market_trends_final_new.pdf. Accessed April 30, 2015.

NEW EXECUTIVE ORDER ISSUED ON APRIL 1ST IS NO JOKE BUT MAYBE THAT’S WHAT THEY HOPED YOU’D THINK

This Executive Order was issued on April 1, 2015 under the authority of the International Emergency Economic Powers Act (50 U.S.C. 1701 et seq.) (IEEPA), the National Emergencies Act (50 U.S.C. 1601 et seq.) (NEA), Section 212(f) of the Immigration and Nationality Act of 1952 (8 U.S.C. 1182(f), and Section 301 of Title 3, United States Code. Durk checked this by going to the White House website and verified that it was NOT an April Fools Day joke but a bona fide dangerous ukase emanating officially from the 21st century czar in the White House.

Oh no! Not another disaster to add to your growing list of disasters to worry about!! Sorry, this was NOT our idea and we sure don’t like having to add it to our own list of growing disasters, but here it is. This one is, sad to say, something to REALLY worry about. What can you do about it? Perhaps not much at the moment, but it is something you ought to know. Not knowing about it may be a good way to be surprised when the authorities find you to somehow come under the “authority” of this monstrosity.

“BLOCKING THE PROPERTY OF CERTAIN PERSONS ENGAGING IN SIGNIFICANT MALICIOUS CYBER-ENABLED ACTIVITIES”

1. The first provision asserts the power of the President of the United States, Barack Obama, to declare a national emergency because of the activities of persons located in whole or in substantial part outside of the U.S. to constitute a threat to the national security, foreign policy, and economy of the United States.

(Comment: That appears broad enough to include economic competitors to U.S. companies that are located in whole or in substantial part outside of the U.S. if, for example, they undercut the prices of American companies and, hence, “threaten” those companies by competing with them. An excellent excuse for special privileges for crony capitalists in addition to subjecting their competitors to the “blocking,” eg., freezing, of their properties in the United States)

(Comment #2: According to an analysis of this Executive Order, it allow the government to bypass due process and seize the assets (or at least to “block” them, whatever that means) of anybody suspected (suspicion does not require the filing of charges against or convicting anyone of anything) of hacking.

2. Under this Executive Order, President Obama orders that any person determined by the Secretary of the Treasury in any cyber-enabled activities that represent threats to those activities listed in point #1 above or an entity that has materially contributed to activities posing such threats may have their property and interests in property blocked pursuant to this order. The difference between civil forfeiture and “blocking” is not here defined.

The making of donations of specific types (as specified in section 203(b)(2) of IEEPA (50 U.S.C. 1702(b)(2)) are hereby prohibited by section 1 of this order. For example, if you donated money to an event at which Snowden gave a talk, you might come under this prohibition, in which case your assets might be “blocked” (frozen). The feds don’t even need to tell you whether prohibitions to that event are going to be treated as coming under this prohibition. Talk about having a chilling effect on freedom of speech!!

Other provisions include prohibition of “any transaction that evades or avoids, has the purpose of evading or avoiding, causes a violation of, or attempts to violate any of the prohibitions set forth in this order …” and also prohibitions against “any conspiracy formed to violate any of the prohibitions set forth is this order…”

The executive order also “determines” that “there need be no prior notice of a listing or determination made pursuant to section 1 of this order.”

THE COMING OF MARTIAL LAW?

If you have been waiting for Executive Orders to invoke martial law, we may be seeing the first of the modern ones. “Hackers” are here being targeted as enemies of the state with the government setting them up to be deprived of their liberty and property without due process of law. And lest you think that although you use a computer, you aren’t a hacker, so you are safe from this, remember what happened to the Jews… “And when they came for me, there was nobody left who hadn’t already been taken away to help defend me.”

Don’t forget that we are still officially in a state of emergency as a result of executive orders from WWI, WWII, the Korean War, etc. etc.

NEW TECHNOLOGY DOESN’T HAVE TO BE
EXPENSIVE OR COMPLICATED REDUCE CALORIES IN COOKED RICE BY UP TO 60% USING SIMPLE NEW COOKING METHOD

Although this article for the Durk & Sandy Life Extension News was written on April 1st, it is NOT an April Fools Day joke. This is a very real, very exciting method released by the American Chemical Society by press release on April 1st.

Like so many starch-laden foods, rice is high in starch (1.6 ounces in a cup, about 240 calories) and high in available calories. The starch is mostly in the form of amylopectin, easily broken down into glucose for immediate use, stored in the liver and muscles as glycogen for quick energy, with all the rest stored as fat. A very fattening food.

A group of scientists led by Sudhair A. James, at the College of Chemical Sciences, Colombo, Western, Sri Lanka, thought that increasing the content of resistant starch, the amylose form of starch—it cannot be digested for storage as fat—and passing on to the colon where resident microbes ferment it, would produce healthful short chain fatty acids and hydrogen gas in the process.

The scientists developed a simple cooking process to convert much of the starch in rice into resistant (amylose) starch. Here’s how they did it: They added a teaspoon of coconut oil to boiling water. [It is the MCTs, medium chain triglycerides, in the oil that do the trick.] They added a half-cup of rice to the boiling water containing the coconut oil and simmered for 40 minutes. (The researchers say that 20–25 minutes boiling would be long enough.) Then, they refrigerated the cooked mixture for 12 hours. The refrigeration is necessary because it leads to the formation of hydrogen bonds between the amylose molecules outside the rice grains, turning it into resistant starch. The scientists report that this procedure increased the resistant starch content of the rice by 10 times that of rice cooked the usual way.

Dr. James explained that their oil enters the starch granules during the cooking, changing its structure so that it becomes resistant to digestive enzymes. Said Dr. James, “The cooling is essential because amylose, the soluble part of the starch, leaves the granules during gelatinization. Cooling for 12 hours will lead to formation of hydrogen bonds between the amylose molecules outside the rice grains, which also turns it into a resistant starch.” Reheating the rice for consumption doesn’t affect the resistant starch, he adds. Dr. James notes that his group will be exploring what forms of rice work best in this process and whether another type of oil might work.

We think it possible that potato starch might also be converted to amylose (resistant) starch using this method. We would suggest shredding the potato to increase its surface exposed to the action of the oil (we would suggest using MCT oil) and then cooking as they describe with the cooling period they used for the rice. Using this method, you may get high amylose potato starch, far lower calories, and all using a simple cooking protocol, nothing fancy such as modifying the potato’s genome to increase its production of amylose starch.

The final note in the press release explained that the scientists studied 38 different varieties of Sri Lankan rice and found that the resulting rice (after cooking with the oil and then cooling) had a resistant starch concentration ranging from 0.30 to 4.65% and that the traditional varieties had significantly higher resistant starch than old varieties and new “improved” varieties. Still, the overall result was that the method increased resistant starch by at least 10 times.

BRAVO!! We have not tried this yet or verified the method. But, assuming that the ACS would have checked the facts, this is superior chemical science in the service of better health. We hope to see this methodology spreading rapidly to prepared foods, restaurants, and so on.

MEDIA CONTACT: 303-228-8406 (Denver Press Center, Mar. 21–25); Michael Bernstein, 202-872-6042 (D.C. Office); 301-275-3221 (cell); m_bernstein@acs.org (mailto:m_bernstein@acs.org) or Katie Cottingham, Ph.D., 301-775-8455 (cell); k_cottingham@acs.org (mailto:k_cottingham@acs.org)