February 2013 Blog with Durk and Sandy


Wiley’s Dictionary: Perfect health:
The slowest possible rate at which one can die.
— John L. Hart Studios

Scientists have odious manners, except when you prop up their theory; then you can borrow money of them.— Mark Twain

The society which scorns excellence in plumbing as a humble activity and tolerates shoddiness in philosophy because it is an exalted activity will have neither good plumbing nor good philosophy; neither its pipes nor its theories will hold water.— John W. Gardner

There is no such thing as philosophy-free science; there is only science whose philosophical baggage is taken on board without examination.— Daniel Dennett

An object in possession seldom retains the same charm that it had in pursuit.— Pliny the Younger, Letters

The difference between death and taxes is death doesn’t get worse every time Congress meets.— Will Rogers

No very deep knowledge of economics is usually needed for grasping the immediate effects of a measure, but the task of economics is to forestall the remoter effects, and so to allow us to avoid such acts as attempt to remedy a present ill by sowing the seeds of a much greater ill for the future.— Ludwig von Mises, Austrian economist


Protection Against Atherosclerosis in Rats

A new paper1 reports protection by hydrogen-rich saline against oxidative stress and markers of atherosclerosis following balloon angioplasty in rats. This is a commonly used animal model of endothelial injury that induces atherosclerotic changes. Balloon angioplasty is, of course, a clinical method commonly used in the treatment of arterial hyperplasia (proliferation) of vascular smooth muscle cells in humans. It is a rather blunt instrument treatment, basically smashing down the neointimal growth of proliferating vascular smooth muscle cells that threaten to occlude an artery. The endothelial injury that accompanies this medical treatment and frequently leads to reocclusion is a highly undesirable side effect; much research has been done to find ways to prevent it. Treatments that have been reported to have preventive effects against vascular smooth muscle cell hyperplasia in response to oxidative stress and inflammation have included powerful antioxidants/antiinflamatories, such as resveratrol2 or omega-3 fatty acids EPA and DHA.3

Hydrogen has some advantages over other antioxidants in that as a gas it can penetrate biomembranes, such as mitochondrial membranes and the blood-brain barrier, thus reaching tissues harder to access with most other antioxidants. Moreover, hydrogen is more active against the highly toxic hydroxyl radical and the potent oxidant peroxynitrite and less active against other ROS (reactive oxygen species), such as superoxide and hydrogen peroxide that, at low concentrations, are important as physiological signaling molecules. “[Hydrogen’s] mild reductive reactivity allows it to minimize the disturbance on metabolic oxidation-reduction or ROS involved cell signaling …”1 “Moreover, H2 also acts as an anti-inflammatory agent in acute pancreatitis, colon inflammation, and liver inflammation.”1 To find out more on hydrogen therapy, see our article , “Hydrogen Therapy,” in the June 2012 issue of Life Enhancement.

The researchers1 first detected macrophage infiltration at the injured site, indicating the release of inflammatory molecules that attract macrophages there. Treatment with hydrogen-rich saline reduced the number of infiltrating macrophages, consistent with the expected antiinflammatory effect of hydrogen. The proinflammatory cytokine IL-6 levels were observed to be decreased at both the mRNA and protein levels, and the TNF-alpha/NF-kappaB proinflammatory pathway was inhibited by hydrogen.1 The authors suggest that “[d]rinking HRSS [hydrogen-rich saline] may be a simple, economic and safe supplemental treatment for percutaneous coronary intervention (PCI) [balloon angioplasty] patients.”1 This does not represent a major advance in the therapy of vascular smooth muscle hyperplasia (even in rats), but you have to remember that the hypotheses for the protective effects of hydrogen against oxidative stress and inflammation have to be proven by experiment, not just asserted.

“Proof of principle” in animal models leads the way to consider hydrogen as a therapeutic intervention for a variety of medical disorders in humans caused by oxidative stress and/or inflammation. Since it is possible to increase the endogenous production of hydrogen by the gut microbiota with appropriate prebiotics, the use of hydrogen for medical therapies can be cheap, safe, and has the distinct advantage of not requiring one to jump over government-imposed hurdles such as “qualifying” for treatment under the rules and regulations of Medicare bureaucrats or even the hassle of getting a prescription. Although you don’t need a prescription for prebiotics to increase hydrogen production by your hydrogen-producing gut microbiota, we highly recommend working with a knowledgeable nutrition-oriented physician who can help make sure you get appropriate lab tests and help you evaluate the results.


  1. Qin et al. Hydrogen-rich saline prevents neointima formation after carotid balloon injury by suppressing ROS and the TNF-alpha/NF-kappaB pathway. Atheroscler220:343-350 (2012).
  2. Csiszaar et al. Age-associated proinflammatory secretory phenotype in vascular smooth muscle cells from the non-human primate Macaca mulatta: reversal by resveratrol treatment. J Gerontol A Biol Sci Med Sci 67(8):811-820 (2012).
  3. Pakala et al. Eicosapentaenoic acid and docosahexaenoic acid selectively attenuate U46619-induced smooth muscle cell proliferation. Lipids 34(9):915-920 (1999).


We have written about the healthful effects of the natural osmolyte trehalose before, once in our writeup on osmolyte protection against protein misfolding (see “The Origami of Aging” in the September 2008 issue of Life Enhancement) and also in our Sept. 2012 (Vol. 15 No. 5) issue of this newsletter. Here we describe a new paper on trehalose1 in which it is reported that trehalose inhibits the aggregation of mutant alpha-synuclein that is believed to be a cause of Parkinson’s disease due to its neurotoxic effects for dopaminergic neurons. Moreover, trehalose was also shown in this study to disaggregate existing aggregated alpha-synuclein fibrils. The authors1 suggest that trehalose “might hold the promise as a novel treatment for PD [Parkinson’s disease], a strategy which has been similarly investigated in other neurodegenerative disorders.” As this work was done in vitro, the authors note that in vivo follow-up work will be required to evaluate its potential in treating PD.

The authors explore other papers that have been published on trehalose, including one that showed trehalose to have autophagy-enhancing effects (helping to clear away unwanted and/or neurotoxic debris), antiinflammatory effects, to slow aging in C. elegans, and to reduce the formation of polyglutamine aggregates and motor dysfunction in a transgenic mouse model of Huntington’s disease (another disorder involving abnormal protein deposits in the brain). The authors report that studies of trehalose for treating PD in vivo (presumably in animal models) are under way.


  1. Yu et al. Trehalose inhibits fibrillation of A53T mutant alpha-synuclein and disaggregates existing fibrils. Arch Biochem Biophys 523:144-150 (2012).


Dutching makes a difference in the health value of cocoa. A 2008 paper1 measured the ORAC (antioxidation efficacy), the TP (total polyphenol content) and content of flavanols (procyanidins) in natural cocoa (pH 5.39) and cocoa that was lightly alkalized (pH 6.5–7.2), medium alkalized (pH 7.21–7.60) and heavily alkalized (pH ≥ 7.61).Cocoa is frequently dutched—treated with alkali in a 180 year old process — for several reasons. “The process darkens the cocoa ingredients, changes the taste by reducing bitterness, and increases the dispersability of cocoa powder for various applications such as beverages.”1 In the U.S., food labeling regulations require that alkalized cocoa powder or liquor must be declared as “cocoa (liquor) treated with alkali.” Labeling requirement in other parts of the world differ, making it difficult for consumers to ascertain whether imported cocoa powder or cocoa liquor has been treated in this way.

The results showed that natural cocoas tend to group with the highest total flavanols ranging from 22.86 to 40.25 mg/g. The lightly alkali processed cocoa powders ranged from 8.76 to 24.65 mg/g total flavanols, the medium alkali treated powders from 3.93 to 14.00 mg/g, and the heavily alkali treated powders from 1.33 to 6.05 mg/g total flavanols. The natural cocoas showed the highest levels of ORAC and TP. Both antioxidant capacity and TP were highly negatively correlated with pH.

The flavanol content of cocoa is importantly related to many of the most significant beneficial effects of cocoa ingestion.2–6 (Note, much of cocoa research has been funded by Mars, Inc., which uses a process to retain flavanols in their flavanol-rich cocoa, so that their flavanol-rich cocoa, as used in papers #2, #3, #5, and #6 have higher levels of flavanols than ordinary natural cocoa. Their flavanol-enriched cocoa, Cocoapro™ is, after several years of published research, still not widely available or possibly not available commercially at all; we don’t know where to get it and we sure can’t understand what is holding up the release of this product. Possibly it would be relatively expensive as compared to ordinary natural cocoa and Mars, Inc. is not prepared (yet) to invest in a costly promotional campaign. Still, you have to imagine that they are spending money on research in preparation for marketing it, probably to substantiate health claims they want to make for it.)

The data in paper #1 show that the treatment of cocoa with alkali does have a detrimental impact on what you get from eating natural cocoa by reducing flavanols; about 40% of the natural level of flavanols is retained on average for lightly Dutched powders and an average of about 22% is retained in medium alkali treated powders.1Since natural cocoa has a very high content of flavanols, even the losses seen in the light and medium alkali processing still leave the flavanol content in the top 10% of measured foods with detectable flavanols in the USDA database.1 Nevertheless, as the authors note, compared to natural cocoa powder, alkali treatment or Dutching does substantially reduce the level of flavanols in cocoa powders and represents an important processing step during which losses can occur.”1

The authors also point out that there can be a 20-fold difference between the lightest alkalized powder (24.56 mg/g) and the most heavily alkalized powder (1.33 mg/g), making the ingredient statement that tells you that the cocoa has been treated with alkali “almost meaningless as a tool to predict the total level of flavanols in the final product.”1 We avoid alkalized cocoa entirely, purchasing natural cocoa in bulk and using it for any foods we want to contain cocoa, such as smoothies and baked goods.


  1. Miller et al. Impact of alkalization on the antioxidant and flavanol content of commercial cocoa powders. J Agric Food Chem 56:8527-33 (2008).
  2. Francis et al. The effect of flavanol-rich cocoa on the fMRI response to a cognitive task in healthy young people. J Cardiovasc Pharmaco 47(Suppl. 2):S215-20 (2006).
  3. Schroeter et al. (-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci USA 103(4):1024-9 (2006).
  4. Kang et al. Cocoa procyanidins suppress transformation by inhibiting mitogen-activated protein kinase kinase. J Biol Chem 283(30):20664-73 (2008).
  5. Grassi et al. Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension 46:398-405 (2005).
  6. Rein et al. Cocoa inhibits platelet activation and function. Am J Clin Nutr 72:30-5 (2000).


Here we go with yet another paper reporting beneficial effects of caffeine or coffee.1 Earlier studies have been reported to be inversely associated with with the risk of developing dementia and Alzheimer’s disease.1 In this new study, rats were fed low-dose caffeine (5 mg/kg) in their drinking water or water alone (containing no caffeine) from the age of ~3.9 months for six months, e.g., from young to middle aged. This is very roughly equivalent to one cup of coffee or two caffeinated soft drinks per day for a human. The animals were evaluated by a battery of tests for various aspects of cognition two weeks after caffeine withdrawal.

The animals experienced a mild diuretic action from the caffeine, drinking more water and urinating more, hence requiring a change of their litter more frequently. There was no effect of caffeine on weight.

“The main finding of the present study was that prolonged caffeine treatment (from ~4 to ~10 months of age) given to adult male rats caused a significant attenuation of some indexes of behavioral decline associated with aging: (1) preserving their locomotor habituation in the OF [open field], (2) maintaining their exploratory drive for completing the minimum of nine arm visits required to calculate the alternation performance in the Y-maze in a greater proportion than control animals, and (3) maintaining their alternation percentage [a measure of working memory] above chance level.”1 “The SAB [spontaneous alternation behavior] is considered a test of working spatial memory because animals need to remember the arm [in the elevated plus maze] that was previously visited in order to sequentially explore the three arms of the maze. The expression of the SAB requires an intact hippocampal function and it is a behavior that deteriorates during the aging process.” In the animals that received only water, only half of them tested after six months completed the minimum of nine arm visits required to reliably calculate the alternation performance, whereas all but one of the rats that received caffeine for 6 months met that criterion.

The authors reported that the age-associated decline was not reduced or prevented in ALL measures. “These findings agree with those of an earlier study showing that healthy mice chronically treated with caffeine for 10 months (from 5½ to 15½ months of age) did not improve their cognitive performance in a battery of memory tests; neither were ­sensorimotor or anxiety measures affected when compared with control animals consuming only water.”1 Nevertheless, the results of the study reported here1 showed that even after several weeks of caffeine withdrawal, the rats that consumed low doses of caffeine during 6 months exhibited improved performance in some memory tests as compared to their controls.

The researchers further observed that the rats getting the low-dose caffeine treatment had hippocampal neurons with increased dendritic branching, total dendritic length, and increased spine density in distal dendritic branches (greater in the basal but not the apical dendrites of CA1 pyramidal neurons). The experimental design did not permit it to be determined whether these morphological changes took place during the chronic caffeine administration or after its withdrawal.

As you may have noticed, tests for anti-aging remedies never seem to have “definitive” results because of the complexities of biological systems in general and the differences in individual genetic makeup (even from one strain of rodent to another) that make generalization of results such a tricky puzzle. We expect, therefore, that this study will not be the last on the effects of caffeine on cognition. The results so far look promising.


  1. Vila-Luna et al. Chronic caffeine consumption prevents cognitive decline from young to middle age in rats, and is associated with increased length, branching, and spine density of basal dendrites in CA1 hippocampal neurons. Neurosci202:384-395 (2012).


We reported in the October 2012 issue of this newsletter on a very recent study1 in mice that found that when the mice were restricted to eating only at night, they could eat as much as they wanted of a high fat diet and not become obese, whereas mice that could eat whenever they wanted (day and night) of the same diet would become obese. Most interestingly, the mice eating only at night ate the SAME AMOUNT OF FOOD as the mice that ate day and night, yet those eating only at night did not become obese whereas those eating at any time did become obese. Note that humans and mice have opposite circadian rhythms for activity. Humans are normally inactive at night and mice are normally inactive during the day.

By an odd coincidence, a similar paper was published in the FASEB J2 about a month later, but the second paper didn’t seem to be aware of the first paper’s publication and didn’t cite it. In fact, the authors of the second paper thought that their paper was the first to be published on the subject of time restricted feeding of a high fat diet. “Although nocturnal mice fed an HF [high fat] diet during the whole of the light phase gained significantly more weight than mice fed during the dark period [cites given: shown as 3 & 4 below] an HF [high fat] diet has never been tested for its effect under RF [restricted feeding].”2

The differences between the papers were interesting, however. The first paper reported on the effects of feeding mice a high fat diet restricted to eating only at night (during the normal active period for mice) as compared to mice eating a high fat diet ad lib (any time of the day or night). The results showed a significantly higher weight gain in the mice eating the high fat diet day and night as compared to the mice eating the same diet but only at night. The photographs in the paper showing a typical example of a mouse that ate only at night and a typical example of a mouse that ate at any time of the day or night were very impressive, with the mouse eating only at night having an obviously leaner appearance as compared to the fat looking mouse that ate at any time.

The second paper, however, fed their RF (restricted feeding) mice for 18 weeks for 4 hours a day (from 4 to 8 hours after lights on (in other words, during the light period of the day), rather than (as in the first paper) during the dark period of the day. The researchers2 state that “[w]e have recently shown that long-term daytime RF can increase the amplitude of clock gene expression, increase expression of catabolic factors, and reduce the levels of disease markers, leading to better health.” The also note that “[m]any physiological activities normally dictated by the SCN [suprachiasmatic nucleus, location of the endogenous circadian clock] are altered by daytime RF.”

The implication is that RF, restricted feeding, can produce beneficial effects whether the feeding is restricted to night or to day. Interestingly, it has been found that animals exposed less than about 8 hours a day to a potentially addictive drug do not develop addiction. Since chronic overeating involves similar physiological pathways as drug addiction2b it may be that it is the period of restriction that is important in the weight gain-limiting effects of food restriction, not the part of the day that the eating is restricted to.

The researchers2 also included a group of mice that ate the RF (restricted diet) but with an LF (low fat) content. They measured several markers of metabolic activity and adiposity (fatness) in the four groups of mice, RF-HF, RF-LF, and AL-HF (ad lib high fat diet), and AL-LF (ad lib low fat diet). Results included, for example, that the AL groups had higher levels of the adiposity hormone leptin as compared with the RF groups. Leptin levels were 2-fold higher in the RF-HF group as compared to the RF-LF group, a marker of increased satiety in the RF-HF group. The daily levels of TNF-alpha, a major proinflammatory cytokine, were ~10% up-regulated in the AL-HF group, whereas the RF-HF group had levels similar to those of the AL-LF group, which indicates less inflammation on the high fat diet when fed for a restricted time.

The restricted time-fed high fat diet group had reduced cholesterol levels and the development of insulin resistance was prevented or delayed as compared to the AL-HF diet. Moreover, the researchers found that the shifts induced in circadian clock genes by a high fat diet can be rectified by timed feeding.

The authors conclude that “[o]ur results show that the timed HF diet leads to a unique metabolic phenotype of calorie intake equal to that of AL-HF mice but with reduced body weight. The total activity of RF-HF mice was higher than that of AL-HF and lower than that of RF-LF mice, correlating with their body weight.” They suggest that timed meals on a high fat diet may be easier to achieve than attempting to avoid high fat diets, since the latter are so much more palatable than low fat diets.


1. Hatori et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high fat diet. Cell Metab 15:848-60 (2012).

2. Sherman et al. Timed high-fat diet resets circadian metabolism and prevents obesity. FASEB J 26:3493-502 (2012).

2b. Johnson & Kenny. Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat Neurosci 13(5):635-41 (2010).

3. Arble et al. Circadian timing of food intake contributes to weight gain. Obesity 17:2100-2 (2009).

4. Salgado-Delgado et al. Food intake during the normal activity phase prevents obesity and circadian desynchrony in a rat model of night work. Endocrinol 151:1019-29 (2010).



Scientists are hard at work trying to learn more about the interesting ecosystem at deep-sea hydrothermal vents that emit various nutrient-enriched fluids and the organisms that live on those nutrients. The organism community includes hydrogen producing microbes and microbes that consume hydrogen and produce methane. There is much in common with our colon ecosystem that includes hydrogen-producing microbes and microbes that consume hydrogen and produce methane. Of course, the temperatures near the hydrothermal vents are far higher than the temperatures found in the human colon (or the colon of any mammal), but temperatures at a distance from the vents are considerably cooler and may still include these types of microbes. As reported in a recent paper,1 hydrothermal fluids with temperatures ranging from 2.7 degrees Centigrade (background seawater) to 353 degrees Centigrade were collected in order to study hydrogen concentrations and the effect that hydrogen concentration had on the growth of methanogens.

The researchers found that the hydrogen emitted by the hydrothermal vents was not the only source of hydrogen available for methanogenesis, as “some hyperthermophilic, anaerobic heterotrophs produce H2 [hydrogen] as an end-product, even when grown with sulfur as a terminal electron acceptor. In two of our MPN tubes, methanogens were found growing in coculture with hyperthermophilic heterotrophs where no H2 had been added initially, suggesting syntrophic (or at least commensal) growth between the two organisms.”1 “Previous estimates of H2 production rates by a hyperthermophilic heterotroph and H2 consumption by Methanocaldococcus strain JH146, based on a 4:1 H2 consumption-to-CH4 [CH4=methane] production ratio, suggest that 27–47 hyperthermophilic heterotrophs could produce enough H2 to sustain a single Methanocaldococcus cell.”1

This and other results reported in this study suggests that scientists know more about the relationship between hydrogen producing and hydrogen-consuming-methane-producing microbes at hydrothermal vents than they do about the similar goings on right inside our own guts!

The study was funded by a grant from the National Science Foundation Division of Ocean Sciences, other National Science Foundation grants, with additional funding from the National Aeronautics & Space Administration (NASA!) Astrobiology Institute Director’s Discretionary Fund, and yet more funding for the publication of the study by other government entities. It is not our purpose here to complain that the government is not funding studies of microbes in the human colon as we, in agreement with published statements by Milton Friedman,2 do not think government should be funding scientific research (same as choosing winners and losers in an economic context). Your taxes and ours at work …

(We were able to get Dr. Friedman to autograph the page in our copy of Sciencecontaining this article. He was greatly surprised, saying that he had never expected any scientist to want his autograph on this particular article. A photocopy of the page with the original autograph is currently displayed prominently on a wall of our house.)


  1. Ver Eecke et al. Hydrogen-limited growth of hyperthermophilic methanogens at deep-sea hydrothermal vents. Proc Natl Acad Sci USA 109(34):13674-9 (2012).
  2. Nicholas Wade. Why Government Should Not Fund Science” (an interview with Milton Friedman) Science 210:33 (3 Oct. 1980).


Although some studies have reported significantly fewer impulsive violent crimes and suicides in areas where the water is naturally enriched in lithium (though at far lower levels than the therapeutic concentrations of lithium used in the treatment of bipolar disorder, also called manic-depression), there has never been a pool of lithium identified in the brain according to a new study.1 The new study now reports that using a sophisticated method of measurement in post-mortem human neocortex (quadrupole inductively coupled plasma-mass spectroscopy), researchers have found that lithium is present as a physiological trace element.

Moreover, they also found that cortical levels of lithium are found to be significantly elevated (about twice as high) in the cortexes of bipolar patients as compared to the cortexes of normal controls. They found the cortical lithium levels to average 11.5 ± 5.3 µg/kg in normal controls, 12.5 ± 10.2 µg/kg in schizophrenics and 21.2 ± 11.3 µg/kg in those with bipolar disorder. Importantly, these bipolar subjects had no past history of lithium pharmacotherapy. The researchers report that the lithium levels reported in their study were comparable to plasma reference values and three orders of magnitude lower than therapeutic levels in clinical lithium treatment.

The finding of significantly elevated lithium in the cortexes of bipolar subjects could be, propose the authors as one possible explanation, a compensatory response against a deficient lithium-dependent pathway in bipolar disorder. This is, we think, a very plausible hypothesis. The authors also mention an alternative, that lithium could be accumulated as a pathological sequestration, with secondary deficiency in lithium bioavailability.

As the authors note, remote lithium use by some of the bipolar subjects could not be entirely ruled out because, although they had a board-certified psychiatrist comprehensively evaluate medical records, laboratory results and questionnaires completed by next of kin, there is always the possibility of missing something.

As you may recall, we added lithium at concentrations found in naturally lithium-enriched mineral water that is commercially available to one of our brain health maintenance formulations. (See “Maintain Your Brain” in the May 2004 issue of Life Enhancement.)


  1. Friedlich. Neocortical levels of lithium are increased in bipolar disorder. Mol Psychiatry 17:3-4 (2012) doi:10.1038/mp.2011.90; published online 2 Aug. 2011.


“We attended Obama’s victory party in Chicago (we go so you don’t have to) and asked his supporters what Obama’s reelection means for freedom. People reacted as if they didn’t understand the question.

“Freedom?” one asked.

“Um, yes, I have no idea,” said another.

“It’s not on their radar, and that’s upsetting. Some wouldn’t know freedom if they fell over it. To many, ‘freedom’ means getting the government to force women’s employers to pay for birth control.

“Sorry, that’s not freedom. That’s force.

“My hope for now: gridlock.”


We have written about “fairness” before in this newsletter. It joins other personality traits that have been identified as being at least in part inherited. “Fairness” is famously studied in experimental games like the ultimatum game where one person, the proposer, holds a sum of money (provided by the experimenters) and divides it into an amount he proposes to keep and another part of which he proposes to be given to another person; that second person may accept the split as offered or may reject it. If the deal is accepted, each person gets the amount agreed upon, but if the deal is rejected, they each get nothing. The tremendous amount of scientific interest that has developed around this game has to do with the fact that, even though being offered 20% (say) of a sum of money is a lot better than nothing, offers below 30% are usually rejected as “unfair.” There has been considerable research looking into what environmental factors and personality traits are associated with what percentage split is rejected as “unfair.” A recent paper1 has focused upon a gene that may be linked to a specific preference for “fairness.”

Fairness (equality/inequality) is something that is of considerable importance to many people, important enough that to punish somebody who makes an “unfair” offer in the ultimatum game, they are willing to forego a sum of money they are offered in the ultimatum game. In real life, the perception of fairness (or equality/inequality) is a major source of political dissension. Note the focus by many politicians on whether certain people pay their “fair” share of taxes or the remarkable statement by President Obama that he wants to increase taxes on the wealthiest Americans for “fairness,” even if it brings in less tax revenue for the government! There is a lot of subjective emotional baggage contained in the concept of “fairness.” As revealed by games such as the ultimatum game, many different factors can distinguish those who have a high tolerance for “unfair” offers as compared to those who don’t.

The recent paper mentioned above where researchers were looking for possible links between genes and tolerance for “unfair” offers identified the dopamine D4 receptor (DRD4) gene as a gene with a significant association with fairness preference. The gene comes in different variations (alleles). A highly polymorphic region in exon 3 is a 48 bp (base pair) repeat. In Caucasian populations, the most common repeat allele is the 4-repeat allele, followed by the 7-repeat allele and the 2-repeat allele. In Far Eastern groups, the 7-repeat allele is said to be extremely rare1 and is “displaced” by the 2-repeat allele as the second most common allele. The authors present evidence that the 2-repeat allele may have similar functionality as the 7-repeat allele, with association studies showing similar occurrence in attention-deficit hyperactivity disorder (ADHD).

“The DRD4 48 bp VNTR is known for contributing to individual differences in traits including novelty seeking, financial risk taking, self-report altruism, ADHD, mood, and substance abuse.”

The researchers also found that the season of birth (SoB) affected the expression of the gene. For example, non-winter born children carrying the DRD4 48 bp VNTR 7-repeat allele showed higher scores for venturesomeness. The authors interpret the interaction of season of birth and the effects on personality traits of the DRD4 48 bp VNTR polymorphism as reflecting an environmental risk factor in which individuals carrying “risk alleles” and born at certain times have a vulnerability to developing maladaptive behaviors. Season of birth would pose additional envirnomental challenges on the developing fetus that might predispose to the emergence of these behaviors. The authors note that “SoB has been associated with a wide range of behavioral traits, including suicide, schizoid-like features in non-clinical groups, impulsivity and sensation seeking, novelty seeking, self-mutilating behavior, schizophrenia, and eating attitude.”1

The different alleles of subjects playing the ultimatum game showed variations in “fairness preference.” For example, “the non-winter born male and winter-born female subjects with the 4/4 genotype tend to have a higher minimum acceptable offer than subjects with 2/2 & 2/4 genotype.”1 These subjects were more likely to reject an offer as unfair.

In another study involving 15 small societies that the authors cite, mean offers in the ultimatum game ranged from 26% to 58% with rejection rate for low offers of 20% or less ranging from zero to 100%. Hence, there is a tremendous effect of culture on the perception of “fairness,” though there was apparently no genetic analysis done in that study to distinguish the different societies and their tolerance to “unfair” offers.


  1. Zhong et al. Dopamine D4 receptor gene associated with fairness in ultimatum game. PLoS One 5(11):e13765 (3 Nov. 2010).



In the August 2012 issue of this newsletter we reported on a remarkable unanimous decision at the U.S. Supreme Court that a woman had standing to challenge her indictment under a federal law on the basis that her case involved a local matter that, under the Tenth Amendment, should have been dealt with by state law (and which would have resulted in a much shorter prison sentence). As you will recall, the Tenth Amendment states: “The powers not delegated to the United States by the Constitution, nor prohibited by it to the States, are reserved to the States respectively, or to the people.”

In a rare federalism issue, the Court upheld Bond’s standing to challenge her indictment under the Tenth Amendment, ruling that “[f]ederalism secures the freedom of the individual” as well as the prerogatives of state governments. (This was reported in The Volokh Conspiracy Daily, a blog by a constitutional attorney at www.Volokh.com.)

The Case Isn’t Over

As the Volokh report continues, it explains that the case is not over. “When it was returned to the lower federal courts for a decision on the merits, the U.S. Court of Appeals for the Third Circuit under which Bond was convicted is authorized by an international treaty.” (D&S Comment: Words seem to be missing here after the word “convicted.” It is likely that what it said was probably something like “was upheld on remand and is authorized by an international treaty.”) As Volokh notes, this raises the question of whether the federal government can use treaties to extend its authority to areas under which it has no Constitutional authority, eg. to areas beyond its authority. Volokh reports that the Cato Institute has filed an amicus brief urging the Supreme Court to hear an appeal to this decision by the U.S. Court of Appeals for the Third Circuit and to reverse it. It would, of course, require the highly unusual action by the Supreme Court of hearing a case twice.

Volokh writes that the brief for the case was authored by Georgetown law professor Nicholas Rosenkranz (a leading academic expert on the constitutional law of treaties), Ilyo Shapiro, and Trevor Burrus and quotes from the brief: “Bond has thus brought her case back to the Supreme Court, asking the Court to clarify and cabin Holland [Missouri v. Holland, 1920, which appears to be the source of a single sentence by Justice Oliver Wendell Homes that has been interpreted to mean that Congress’s constitutional powers can be expanded by treaties]. In this, our third brief in the case, we are joined again by the Center for Constitutional Jurisprudence in arguing that allowing Congress to broaden its powers via treaties is an astounding manner in which to interpret a document that creates a federal government of limited powers. Not only would this mean that the Executive has the ability to expand federal power by signing a treaty, but it would mean that foreign governments could change federal power by abrogating a previously valid treaty—thus removing the constitutional authority from certain laws. We also point out how the most influential argument supporting Holland is based on a clear misreading of constitutional history that has gotten repeated without question and that the ruling is in deep tension with other cases. We’re in a quagmire with respect to the treaty power that can only be escaped by limiting or overturning Missouri v. Holland.”

Though it is unlikely that the Supreme Court will take the case, we can only hope they do. If treaties can override Constitutional limits without an Amendment, as indicated above, the federal government of “limited” powers can be expanded without limit by treaties created by the Executive branch and approved by a vote of 2⁄3 of the Senate. The requirement of a 2⁄3 vote for approval by the Senate is a significant hurdle but is far less than the 2⁄3 vote of both Houses of Congress to propose an Amendment or 2⁄3 of the States to call a Convention to propose Amendments, after which 3⁄4 of the legislatures of the States must approve it (or them). See Article V of the Constitution.

Get Rid of Private Gun Ownership With a U.N. Treaty

An example of the sort of thing that is being sought by the Obama Administration in the form of a treaty that would make hash of an important right in the Bill of Rights of the Constitution is a United Nations treaty currently in the works to severely limit, regulate, or ban the private ownership of small arms. (At present we think—and certainly hope—it unlikely that 2⁄3 of the Senate would vote to approve such a treaty.) The treaty, if it passed the Senate, though, would wreck the Second Amendment because, in light of Missouri v. Holland, a treaty restricting or prohibiting ownership of small arms might “override” the Second Amendment. (The scary question to consider here is: WHAT IS THE PURPOSE the Obamaistas have for disarming the American populace?)


In the October 2012 issue of this newsletter, we wrote about the strong relationship between increased levels of the hormone leptin, secreted primarily by adipocytes (fat cells), and increased body fat. Leptin levels are known to be elevated in obese individuals. This elevation is now thought to be associated with leptin resistance, the failure of leptin signaling to properly regulate energy balance by acting as a negative feedback adiposity signal, decreasing food intake and increasing energy expenditure. In an apparent attempt at compensation for the leptin resistance, more leptin is secreted.

Leptin resistance is increased under proinflammatory conditions, such as the low-grade inflammation of obesity and diabetes. A fairly recent paper1 reported that leptin resistance was induced through direct interaction with the proinflammatory C-reactive protein (CRP). The researchers found that “CRP not only binds to plasma leptin but also impairs leptin signaling and attenuates its physiological effects in vivo.”1 “We also report here a stimulatory effect of physiological concentrations of leptin on the hepatic [liver] expression [in mice] of human CRP. This finding is consistent with recent reports that human plasma CRP concentration is independently correlated with leptin concentration.”1

Leptin resistance is also induced by a high fat diet via two independent causes: “an apparent defect in access to sites of action in the hypothalamus that markedly limits the ability of peripheral leptin to activate hypothalamic STAT signaling, and an intracellular signaling defect in leptin-responsive hypothalamic neurons that lies upstream of STAT3 activation.”1b

Aged rats are reported to have increased fat mass, central leptin and insulin resistance, and hyperleptinemia. The consequences of leptin resistance are failure to inhibit food intake, deplete fat stores, down regulate its own expression in adipose (fat) tissue, and increase energy expenditure.1c A current hypothesis suggests that “during aging, progressively elevated levels of leptin result in an activation of sympathetic nervous system (SNS) that brings about its desensitization, thus at advanced ages leptin fails to increment energy expenditure.”1c

Increasing Leptin Transport Into the Brain

In order for leptin signaling to reach brain areas controlling feeding and body temperature, it must pass through the blood-brain barrier. Indirect evidence suggests that in obesity there is impaired transport of leptin across the blood-brain barrier (BBB).2Direct evidence is provided by a study which showed that obese outbred mice transport leptin into the brain less rapidly than lean mice, while two other studies were cited that found reduced leptin transport in inbred strains of obese rats, including Koletsky and Zucker (papers cited in reference #2). The paper2 reported that leptin transport across the BBB was enhanced by alpha1-adrenergic agents, such as epinephrine (adrenaline). Ephedrine also worked. Tyrosine, an amino acid precursor of catecholamines (including adrenaline) was also a potent stimulator of the leptin transporter at the BBB and was the only amino acid tested that did so.

The author notes a caveat: if adrenaline levels are maintained at chronic high concentrations, there can be a desensitization in the ability of adrenaline to suppress leptin levels.

A later paper by the author of paper #2,2b notes that serum levels of leptin are elevated more than in the CSF (cerebrospinal fluid), additional evidence that the transport of leptin across the BBB is inhibited. Indeed, obese rodents are reported to respond to leptin delivered directly into the brain but not to leptin given peripherally.2b The paper also reports that “[s]everal labs have now examined transport rates [of leptin] in obese rodents. In several cases, the transport rate is dramatically reduced.”2b Finally, the author notes that leptin transport shows a diurnal rhythm and is affected by sex steroids, insulin, glucose, and epinephrine (adrenaline).2b

Another paper3 reported that green tea extract protected leptin-deficient ob/ob obese mice from fatty liver. Leptin deficiency resembles leptin resistance even with high leptin levels. The mechanism(s) by which green tea extract significantly reduced liver lipids and triglycerides along with improved liver function in these leptin-deficient obese mice was, however, unclear. A number of possible mechanisms were described. ob/ob mice were reported in a study cited in paper #3 to have decreased norepinephrine that inhibits adipocyte lipolysis and favors lipid storage. However, not mentioned was the possibility that reduced sympathetic nervous system activity may reduce the transport of leptin to the brain across the BBB. ob/ob mice treated with norepinephrine have also been reported to have decreased pro-inflammatory cytokines.3


1. Chen et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med 12(4):425-32 (2006).
1b. El-Haschimi et al. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 105(12):1827-32 (2000).
1c. Carrascosa et al. Changes in the neuroendocrine control of energy homeostasis by adiposity signals during aging. Exp Gerontol 44:20-5 (2009).
2. Banks. Enhanced leptin transport across the blood-brain barrier by alpha-1-adrenergic agents. Brain Res 899:209-17 (2001).
2b. Banks. Is obesity a disease of the blood-brain barrier? Physiological, pathological, and evolutionary considerations. Curr Pharm Des 9:801-9 (2003).
3. Bruno et al. Green tea extract protects leptin-deficient spontaneously obese mice from hepatic steatosis and injury. J Nutr 138:323-31 (2008).

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