December 2012 Blog with Durk and Sandy

APPETIZERS

He that falls in love with himself will have no rivals.
— Benjamin Franklin, 1758

Torture numbers, and they will confess to anything.
— Gregg Easterbrook

All men with power ought to be mistrusted.
— — James Madison (1751-1836)

Givers have to set limits because takers rarely do.
— Irma Kurtz

While there is no reason to panic, it is only prudent to make preparations to panic.
— cartoon caption by Robert Mankoff

The reason it takes a million sperm to find an egg is that none of them will stop to ask for directions.
— Adam Ferrara

I should have loved freedom, I believe, at all times, but in the time in which we live I am ready to worship it.
— A. de Tocqueville (quoted in
F. A. Hayek, The Road to Serfdom)
Today’s literature: prescriptions written by patients.

— Karl Kraus, Viennese dramatist,
critic, and satirist, b. 1874

HYDROGEN THERAPY

Here we continue our series on the emerging new field of medical therapy with hydrogen, where researchers have published studies (mostly so far in cell cultures and animal models of human disease) using hydrogen gas administered by breathing hydrogen or drinking hydrogen dissolved in water or saline solution. Excitingly, hydrogen gas is available as endogenous hydrogen gas produced by gut microbes living in your lower digestive tract and the consumption of select prebiotics can enhance this production. Hydrogen is known to be a very selective antioxidant that scavenges the highly toxic hydroxyl radical and also the potent oxidant peroxynitrite (created in the body by the chemical reaction of nitric oxide and superoxide radical). Hydrogen diffuses to reach all tissues, even including mitochondria, and it passes the blood-brain barrier. See our article “Hydrogen Therapy” for an introduction to this exciting new biomedical science, where the medicine (the hydrogen) can be conveniently produced by your own resident gut microbiota [see “Hydrogen Therapy” in the June issue of Life Enhancement]. NO prescription required!

Safety of Hydrogen Inhalation in Human Study

A new study1 focuses on safety issues in relation to the use of hydrogen therapy. As the authors explain. [i]n animal experiments, use of molecular hydrogen (H2) has been regarded as quite safe and effective, showing benefits in multiple pathological conditions such as ischemia-reperfusion injury of the brain, heart, kidney and transplanted tissues, traumatic and surgical injury of the brain and spinal cord, inflammation of intestine and lung, degenerative striatonigral tissue and also in many other situations. However, since cerebral ischemia patients are in old age group, the safety information needs to be confirmed.”1 The delivery of hydrogen by inhalation via a facemask was the focus of the safety test, with three patients as the subjects studied for the hydrogen concentration (HC) in arterial and venous blood before, during, after 4% (case 1) and 3% (case 2, 3) of hydrogen gas inhalation with simultaneous monitoring of physiological parameters. For a consistency study, HC in the venous blood of 10 other acute ischemic cerebral disease patients were obtained at the end of 30-minute hydrogen inhalation treatment.

What they found was that “the HC gradually reached a plateau level in 20 min after H2 inhalation in the blood, which was equivalent to the level reported by animal experiments. The HC rapidly decreased to 10% of the plateau level in about 6 min and 18 min in arterial and venous blood, respectively, after H2 inhalation was discontinued. Physiological parameters on these 3 patients were essentially unchanged by use of hydrogen.”

The only difficulties were in the consistency study. Consistency is important because of the need to achieve the same level of HC with each treatment. In this study, the researchers found considerable variability in HC in the 10 subjects studied and that this was due to the facial mask inhalation. “In unattended patients particularly with neurologically compromised condition, the facial mask was frequently not in the appropriate position when our staff returned to stop the inhalation at the end of 30-min treatment.” “Use of respiratory assistance and even a body position may have to be considered for the consistency of inhalation treatment.” There were other comments. However, these difficulties pertained to the administration of hydrogen by inhalation through a facemask. For those using prebiotics for enhancing endogenous hydrogen production by resident microbes, these issues are not relevant.

The important findings here were that there were “no significant change in the physiological parameters during and after H2 administration … except in some indices associated mainly with hyperventilation or breath holding.”1 (The latter were problems associated with the face mask.) As the author note, the number of subjects was small; hence, a larger study specifically for safety issues would be informative, especially if it could dissociate the safety of increased hydrogen from side issues such as face masks.

The most important data from our point of view was the kinetics—how fast the hydrogen concentration increased after administration began, how long it took to reach a steady state plateau, and how quickly it left both the arterial and venous blood.

The way that hydrogen reacts with hydroxyl radicals and the powerful promiscuous oxidant peroxynitrite is the same in mice and men. Because humans are far larger than mice, the blood and tissue hydrogen concentrations will change over time in a very different manner. This paper provides us with this very important data.

Hydrogen levels drop quickly after administration ceases. We believe that outside of a hospital, the best way to obtain benefits of hydrogen is from continuous 24/7/365 administration via colonic hydrogen producing bacteria. The use of carefully selected prebiotics can help assure a comfortable and beneficial rate of continous hydrogen production.

Reference

1. Ono H et al. A basic study on molecular hydrogen (H2) inhalation in acute cerebral ischemia patients for safety check with physiological parameters and measurement of blood H2 level. Med Gas Res 2(1):2 (2012).

Researchers Report Hydrogen Protects Mice from Radiation-induced Thymic Lymphoma

A recent study1B on hydrogen as a possible radioprotectant in experiments with BALB/c mice begins by explaining that “… studies of mouse thymic lymphomas, one of the classic models in radiation carcinogenesis, demonstrated that multi-steps and many factors, like Ras, PTEN, and Fas, were involved in radiation-induced carcinogenesis.” Earlier work by the authors of paper#1B also identified ERK1/2, STAT3 and SHP-2 as other factors involved in radiation-induced thymic lymphoma formation in BALB/c mice.

As the authors note, hydroxyl radicals are the main mediators of radiation injury and are able to react indiscriminately with nucleic acids, lipids, and proteins resulting in damage that can include DNA fragmentation, lipid peroxidation, and protein inactivation. In their earlier work, they showed experimentally that hydrogen treatment could protect cultured cells and mice from radiation damage using a single high dose model. “Importantly, these previous studies also showed that H2-rich saline/water is safe, easy to administer, and cost-effective.”

The experimental animals (but not the controls) were subject to whole body radiation to induce the development of lymphomas. The experimental group was given hydrogen-enriched saline by intraperitoneal injection five minutes prior to each dose of radiation. The control group received saline containing either hydrogen or no hydrogen via the same route as the irradiated mice. Results showed that the hydrogen significantly increased the survival rate of the mice 30 weeks after the radiation. Moreover, the radiation-induced thymic lymphoma rate in the hydrogen group was significantly lower than in the irradiated group that did not receive hydrogen and hydrogen also increased the latency period (the time to develop lymphoma) in the hydrogen-treated animals that developed lymphoma as compared to the irradiated group that didn’t receive hydrogen treatment.

The researchers evaluated the levels of intracellular ROS (reactive oxygen species) in peripheral blood mononuclear cells (PBMC) from the irradiated and control (nonirradiated) mice. ROS levels were much lower in the irradiated group that received hydrogen than in the irradiated control group. Extracellular serum ROS showed similar results. The levels of antioxidant enzymes SOD (superoxide dismutase) and GSH (glutathione) were at 4 hours after the last radiation treatment in the hydrogen treated group significantly higher than that of the control group, while MDA (malondialdehyde, a lipid peroxidation product) concentrations were significantly lower in the hydrogen group as compared to the controls.

Hence, as shown in this study,1B hydrogen therapy may reduce radiation-induced carcinogenesis.

Reference

1B. Zhao et al. Hydrogen protects mice from radiation induced thymic lymphoma in BALB/c mice. Int J Biol Sci 7(3):297-300 (2011).

Very Large Prospective Study Reports Protection Against Diverse Causes of Death by Dietary Fiber: Possible Role of Hydrogen Unmentioned
A huge prospective study of fiber intake and cause-specific mortality2 has reported impressive protection by dietary fiber in both men and women against total mortality and circulatory, digestive, respiratory, and inflammatory diseases (non-cardiovascular disease and noncancer types).

The study included 452,717 men and women from 23 centers in 10 countries (Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom). Average age at recruitment was 50.8 ± 9.8 years, with women accounting for 71% of participants. Excluded were people who had cancer at baseline, or who reported a history of heart attack, angina, stroke, or diabetes. The dietary fiber was estimated largely by self-administered questionnaires.

Results showed that higher total dietary fiber intakes were associated with lower mortality. Those who ingested 28.5 g/day or more of fiber (the highest quintile) had a 24% lower mortality than those who ingested less than 16.4 g/day, with inverse associations between dietary fiber and mortality from smoking-related cancers, and circulatory, respiratory, digestive, and non-cardiovascular disease noncancer inflammatory diseases. The beneficial effects were derived mostly from cereal and vegetable fiber, with no effects from fruit fiber shown in men but an inverse relationship with mortality for respiratory diseases and non-cardiovascular/ noncancer inflammatory diseases in women consuming higher amounts of fruit fiber.

The models for analyzing the results were corrected for education, smoking status, alcohol consumption, BMI (body mass index), physical activity, total caloric intake, and ever use of menopausal hormone therapy in women.

Dietary fiber was found to reduce endotoxin concentration. Endotoxin (lipopolysaccharide) is released by bacteria and activates the immune system. Higher endotoxin levels in the circulation are generally associated with higher levels of inflammatory markers such as C-reactive protein, IL-6, and tumor necrosis factor-alpha. As the authors note (and we have reported in earlier newsletters), changes in gut microbiota as a result of a high fat meal may increase gut permeability, thereby increasing the endotoxin levels in the general circulation.

The authors briefly discussed the possible causes of the health benefits of dietary fiber. They mention SCFA (short chain fatty acids), produced by gut microbiota that consume dietary fiber (undigested carbohydrates that reach the lower digestive tract), as modulators of immunity. They also suggest that the reduction of systemic inflammation (via the decrease by dietary fiber of plasma endotoxin levels) may play a role. However, not mentioned was the release of hydrogen by gut bacteria that consume dietary fiber and the ability of hydrogen as a selective antioxidant (scavenging hydroxyl radicals and the oxidant peroxynitrite) to reduce inflammation and oxidative stress. In the case of those consuming large amounts of dietary fiber, considerable amounts of hydrogen could be produced and diffuse throughout the body, with most of it eventually being excreted via exhalation through the lungs.

There appears to be very little awareness at present of hydrogen as a likely source of at least a part of the health benefits derived from a diet high in dietary fiber, but the discovery of the major impact of the gut microbiota on health has attracted considerable interest. It cannot be long before the relationship between the gut bacteria and the hydrogen they produce from dietary fiber becomes a very hot research subject.

We couldn’t agree more with the author of the accompanying commentary piece3 on the dietary fiber study described above, when he titled his article, “Dietary fiber and mortality: convincing observations that call for mechanistic investigations.”

Finally, we note that it is not possible from the data2 to identify the numerous types of dietary fiber people get in a fiber-rich diet and to correlate those with the health benefits reported here. For example, different types of fiber consumed by the gut microbiota release different amounts of hydrogen and at a different rate. For more on this subject, see our article on “Hydrogen Therapy” in the June issue of Life Enhancement.

References

2. Chuang et al. Fiber intake and total and cause-specific mortality in the European Prospective Investigation into Cancer and Nutrition cohort. Am J Clin Nutr 96:164-74 (2012).
3. Landberg. Dietary fiber and mortality: convincing observations that call for mechanistic investigations. Am J Clin Nutr 96:3-4 (2012).

DO PRIONS PLAY A UNIFYING ROLE IN NEURODEGENERATIVE DISEASES, SUCH AS ALZHEIMER’S DISEASE?

An article in a recent Science¹ by Stanley B. Prusiner, the discoverer of prions, suggests that neurodegenerative diseases develop as a result of a native protein becoming refolded into a misfolded infectious state known as a prion.

As Prusiner explains in his article, “[t]he self-propagation of alternative conformations is a key feature of all prions.” He describes a study published in 2006 [cited in Prusiner’s article] in which researchers “inoculated human AD [Alzheimer’s disease] brain homogenates intracerebrally into marmosets. The marmosets developed Abeta [amyloid beta] plaques with incubating periods exceeding 3–5 years.” These results showed that the disease could be infectiously transmitted and, thus, Prusiner concludes, demonstrated the existence of a disease-causing prion in AD. “Similar results have been shown by Walker and Jucker and others [citation provided in paper] using transgenic AD mice.”¹ Prusiner notes that the disease agent has been identified as being amyloid beta prions.

Prusiner points out that the amyloid beta proteins, consistent with (but not proving) the concept that they are prions, spread throughout the brain from the entorhinal cortex to many regions of the cortex. He concludes that “[m]eaningful treatments are likely to require cocktails of drugs that diminish the precursor protein, interfere with the conversion of precursors into prions, and/or enhance the clearance of prions.”

A paper² published just a week before Prusiner’s article appeared in Science reported on how certain neurotoxic oligomers of amyloid beta 42, following a specific “off pathway” (that is, not following the nucleation-dependent fibril formation pathway) can result in “a replicating strain of oligomers that recruit amyloid beta 42 monomers and quantitatively converts them into LFAO [large fatty acid-derived oligomers] at the expense of fibrils, a mechanism similar to prion propagation.”² As the authors summarize their study, “…the unique replicating property of off-pathway oligomers may hold profound significance for Alzheimer disease pathology.”

Finally, a very recent paper^2B that included Stanley B. Prusiner as one of its authors, reported what they believe to be proof that in Alzheimer’s disease, the neurotoxic amyloid beta protein is self-propagating and, hence, is a prion. “Here we demonstrate that widespread cerebral deposition is induced following inoculation of Tg [transgenic] mice with purified brain-derived Abeta fibrils as well as aggregates composed of synthetic Abeta peptides. Although synthetic Abeta preparations exhibited lower specific bioactivity than Abeta aggregates derived from the brain, these results provide compelling evidence that Abeta aggregates are prions and that Abeta alone is sufficient for the formation of a self-propagating protein assembly.”^2B “Although Abeta aggregates clearly behave like prions at the molecular level, there is currently no evidence that AD [Alzheimer’s disease] is infectious in the sense that it is communicable among humans. However, cerebral Abeta deposition in mice can be initiated by injection of Abeta aggregates into the periphery.” (See ^2B for reference to paper that is cited in support of this statement.) “Recent transmission studies in cellular and mouse models of neurodegenerative diseases including the tauopathies, synucleinopathies, and amyotrophic lateral sclerosis (ALS) indicate that those diseases are also caused by self-propagating protein aggregates, i.e., prions.”^2B

The usual way prion diseases from one animal “infect” another uninfected animal is via the uninfected animal eating prion-contaminated tissue, such as in reported cases of humans contracting mad cow disease. The authors of a 2010 paper³ also note that the infectious form of the prion protein is found in the urine of prion-infected animals and they report that the normal form of the prion protein is also found in normal human urine.

If it is true that AD can be caused by an infectious prion, then the approach to developing treatments will obviously have to be radically different. Current treatments are targeted at mechanisms (such as cholinergic dysfunction) that can explain only part of the AD pathology and that can be targeted to slow the development of the disease, but not reverse it. There has been some research on how to treat prion diseases, especially in the aftermath of the mad cow scare, and some of these treatments have been reported to prevent the conversion of the native species to the toxic prion or to enhance the clearance of prions. See, for example, references.^4–10 (Note the promise of curcumin, resveratrol, and trehalose in the papers cited below.) [See “The Origami of Aging” in the September 2008 issue and See “Maintain your Brain the Durk Pearson & Sandy Shaw Way” in the May 2004 issue.]

References

1. Prusiner. A unifying role for prions in neurodegenerative diseases. Science 336:1511-3 (2012).
2. Kumar et al. Specific soluble oligomers of amyloid-beta peptide undergo replication and form non-fibrillar aggregates in interfacial environments. J Biol Chem 287(25):21253-64 (2012).
2B. Stohr et al. Purified and synthetic Alzheimer’s amyloid beta (Abeta) prions. Proc Natl Acad Sci USA 109(27):11025-30 (2012).
3. Dagdanova et al. Characterization of the prion protein in human urine. J Biol Chem285(40):30489-30495 (2010).
4. Ahmad and Lapidus. Curcumin prevents aggregation in alpha-synuclein by increasing reconfiguration rate. J Biol Chem 287(12):9193-9 (2012).
5. Gu and Singh. Doxycycline and protein folding agents rescue the abnormal phenotype of familial CJD H187R in a cell model. Mol Brain Res 123:37-44 (2004).
6. Marambaud et al. Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides. J Biol Chem 280(45):37377-82 (2005).
7. Farquhar et al. Prophylactic potential of pentosan polysulphate in transissible spongiform encephalopathies. Lancet 353:117 (1999).
8. Bravo et al. Sulfated polysaccharides promote the assembly of amyloid beta1-42 peptide into stable fibrils of reduced cytotoxicity. J Biol Chem 283(47):32471-83 (2008).
9. Necula et al. Small molecule inhibitors of aggregation indicate that amyloid beta oligomerization and fibrillization pathways are independent and distinct. J Biol Chem282(14):10311-24 (2007).
10. Sarkar et al. Trehalose, a novel mTOR-independent autophagy enhancer accelerates the clearance of mutant Huntingtin and alpha-synuclein. J Biol Chem2828:5641-52 (2007).

GAMMA TOCOPHEROL PROTECTS HEALTHY YOUNG MEN FROM GLUCOSE INDUCED INCREASES IN POSTPRANDIAL METHYLGLYOXAL

Postprandial hyperglycemia is recognized as a risk factor in many diseases—including diabetes and atherosclerosis—in part because of the oxidative stress and endoplasmic reticulum stress that is caused by it. The reactive dicarbonyl methyglyoxal, a precursor to AGEs (advanced glycation end products) is created as a result of glucose metabolism and increased via oxidative stress in vitro. Additionally, oxidative stress reduces the glutathione-dependent detoxification of methylglyoxal.¹

Researchers tested the hypothesis that gamma tocopherol would, as a result of its potent antioxidative properties, decrease hyperglycemia-mediated postprandial increases in plasma methylglyoxal (MGO) after ingesting glucose.¹ The participants were 12 healthy college-age men (22.3 ± 1.0 years old with mean BMI of 29.3 ± 2.4 kg/m²). The subjects fasted 10–12 hours and then received an oral dose of 75 g of glucose prior to and following 5 day ingestion of a vitamin E supplement of mixed tocopherols enriched in gamma tocopherol (containing 500 mg/day of gamma tocopherol and 60 mg/day alpha tocopherol, 170 mg/day delta tocopherol, and 9 mg/day of beta tocopherol).¹ Blood samples were collected at several time points: 0, 15, 30, 45, 60, 120, 150, and 180 minutes after glucose ingestion.

MGO was significantly reduced (p < 0.05) with the supplementation of gamma tocopherol than without (778 ±1010 vs. 2277 ± 705). Plasma concentrations of gamma-carboxyethylhydroxychroman, reduced glutathione, and markers of total antioxidant capacity increased after supplementation and these markers and plasma gamma-tocopherol were inversely correlated with plasma MGO (r = 20.48 to 20.67, p < .05). The authors conclude that “[t]hese data suggest tht short-term supplementation of gamma-tocopherol abolishes the oral glucose-mediated increases in postprandial MGO through its direct and indirect antioxidant properties and may reduce hyperglycemia-mediated cardiovascular disease risk.”¹ The authors also claim that “[t]o our knowledge, this investigation provides the first evidence that improvements in gamma-tocopherol status attenuates glucose-induced postprandial increases in MGO, without altering postprandial hyperglycemia.”

Postprandial oxidative stress following glucose consumption contributes to endothelial dysfunction, a failure of arterial vasodilation in response to acetylcholine signaling.²Moreover, increased levels of methylglyoxal induces significant generation of nitric oxide and superoxide anion in rat vascular smooth muscle cells, which chemically react to form the potent oxidant peroxynitrite.³ The increased reactive oxygen species and reactive nitrogen species (ROS/RNS) resulting from elevated methylglyoxal contributes to insulin resistance.³

As we have written before [See “Reducing Glycation Reactions for Better Health and Longer Life” in the February 2008 issue of Life Enhancement], advanced glycation endproducts (AGEs) are risk factors in aging, cardiovascular disease, diabetes, some types of cancer, insulin resistance and other aspects of the metabolic syndrome, as well as other diseases. Increased circulating levels of methylglyoxal is one pathway that leads to higher levels of AGEs.

References

1. Masterjohn et al. Gamma-tocopherol abolishes postprandial increases in plasma methylglyoxal following an oral dose of glucose in healthy, college-aged men. J Nutr Biochem 23:292-8 (2012).
2. Dhar et al. Methylglyoxal scavengers attenuate endothelial dysfunction induced by methylglyoxal and high concentrations of glucose. Br J Pharmacol 161:1843-56 (2010).
3. Chang et al. Methylglyoxal-induced nitric oxide and peroxynitrite production in vascular smooth muscle cells. Free Radic Biol Med 38:286-93 (2005).

ANOTHER ELECTION LOOMS, SO IT BEARS REPEATING:

The Demopublicans and the Republicrats are the
Lizards. You are the People. Vote for the Lizard of
Your Choice. Nothing Will Change.

With thanks to Douglas Adams for the brilliant satire that follows:

“‘On its world, the people are people. The leaders are lizards. The people hate the lizards and the lizards rule the people.’

‘Odd,’ said Arthur, ‘I thought you said it was a democracy.’

‘I did,’ said Ford. ‘It is.’

‘So,’ said Arthur, hoping he wasn’t sounding ridiculously obtuse, ‘why don’t the people get rid of the lizards?’

‘It honestly doesn’t occur to them.’ said Ford.

‘They’ve all got the vote, so they all pretty much assume that the government they’ve voted in more or less approximates the government they want.’

‘You mean they actually vote for the lizards?’

‘Oh yes,’ said Ford with a shrug, ‘of course.’

‘But,’ said Arthur, going for the big one again, ‘why?’

‘Because if they didn’t vote for a lizard,’ said Ford, ‘the wrong lizard might get in.’”

— Douglas Adams “So Long and Thanks for all the Fish”

(Our thanks again to Douglas Adams for this brilliant piece of satire, but also our apologies to actual lizards, which are not responsible in any way for the political machinations referred to herein.— Durk & Sandy)

COST/BENEFITS STUDY

Public Spending on Biomedical Research:
How Many Extra Lives Saved With Treatments
Funded By Taxpayers’ Money

An interesting analysis¹ was published in a recent Science on increased public support for biomedical research on certain diseases and the effects of the extra spending on the number of drugs developed to treat those diseases. The author compiled longitudinal data from six sources, including a commercial database of pharmaceutical R&D, and National Institutes of Health project descriptions and awards. She analyzed how the effect of spending on 67 different diseases affected the number of drugs being developed to treat those diseases. “Consistent with prior research, analysis of grants awarded from 1975 through 2006 showed that a sustained 10% funding increase targeting a specific disease led to a 4.5% increase in the number of drugs targeting that disease entering Phase I clinical trials, with a lag of up to 12 years. In contrast, she found no evidence that changes in the allocation of funds across the NIH disease portfolio affect industry’s decisions to invest in Phase III clinical trials for treatments for those diseases. Thus, NIH funding influences the early stages of drug discovery and testing but may not affect the later, more costly stages of drug development.”

What this says to us is that the FDA’s approval process is a gigantic roadblock preventing the development of drugs after they have made it to the relatively cheap Phase I (which requires a relatively small number of subjects for a safety study after doing previous work in cell cultures and, especially, animal models and finding the drug safe and apparently effective in those studies). By the time a drug has reached Phase III, the drug company has to conduct further studies, which require a huge amount of money (the cost of taking a drug from initial research to FDA approval now costs $3 billion or more). Hence, it is virtually impossible for drug companies to take most potentially useful drugs that have reached Phase I through the development process. Many valuable therapies are thereby dropped out of the process (with only the drugs with the most profit potential being further developed due to the need to recover these huge costs) and, of course, the “lost” drugs are invisible to the general public and the media, which have no idea how much the FDA costs in terms of restricting the numbers of different treatments available and the countless people who have died as a result. The largest pharmaceutical companies benefit from this regulatory scheme as it makes it pretty nearly impossible for small and medium sized companies to compete with them.

As we see it, we (the general public and the two of us) would be much better off if the FDA acted as an advisory agency, providing information and leaving the decision-making to doctor and patient, or, if that is politically impossible because the public demands some level of government drug regulation, the FDA could approve for safety, not for efficacy (just as the agency did before 1965), and leave further decision-making to doctor and patient. We know of no evidence that Americans have more effective drugs now than before the 1965 changes (the Kefauver Amendments to the Food & Drug Act) giving the FDA the power to regulate efficacy. It is the 1965 efficacy requirements that have made it such a lengthy and enormously expensive process to take a drug deemed safe (at least in relation to the risk of the untreated disease) to the market.

Reference

1. “Spend for a Cure?” edited by Mueller and Cruz, Science 336: 1620 (2012).

An unhappy poor person is in a better
position than an unhappy rich person
because he has hope. He thinks money
will help.— Jean KerrThe inherent vice of capitalism is the
unequal sharing of the blessings. The
inherent blessing of socialism is the e
qual sharing of the misery.— Winston Churchill

HAPPINESS RESEARCH: THE LATEST SQUISHY “SCIENCE”

Happiness researchers think that economic growth is not a good measure of the public’s sense of well-being and that perhaps government should be engaging in programs that enhance the public’s “happiness.” Considering what a failure governments have made in recent years in promoting economic growth, it isn’t surprising that (in their own interest) they would want to find an alternative measure of societal well-being.

The first problem with happiness research is that the choice of what questions to ask will determine what research will be done and that will depend upon the values of those holding the money and, hence, determining the questions to be researched. This introduces a bias in the “happiness” research funded by governments. As explained by the principles of public choice economics,* bureaucrats (like other people) tend to favor their own values and this has a major impact on what they spend the public’s money on. Here we look at a recent “happiness” research paper published in a highly respected scientific journal, the Proceedings of The National Academy of Sciences USA.

* James M. Buchanan won the Nobel Prize in Economics in 1986 for his pioneering work establishing the field of public choice economics.

Happiness research as reported by Easterlin et al¹ uses as the principal measure of well-being one of the subjective well-being (SWB) measures said to be recommended in the recent Stiglitz-Sen-Fitoussi report: “All things considered, how satisfied are you with your life as a whole these days? From 0 = dissatisfied to 10 = satisfied.” In a commentary piece² accompanying the Easterlin et al paper, the author cites something he calls the Easterlin Paradox (it must be a Big Deal since the initial letter in each word is capitalized). The Easterlin Paradox is that “economic growth has a positive effect on happiness with other things being equal; however, it also raises aspirations, and aspirations have a negative effect.” ² The commentary author also claims that “aspirations are determined by society, particularly reference group income.^† The continuation of these two effects gives rise to a Hedonic Treadmill.”

† Regarding reference group income: What they may mean here is that society may “determine” how good some people feel about economic growth because what a person earns isn’t as important to some people as how much they earn in relation to what others earn. The Hedonic Treadmill may refer to a Rat Race as you try to keep up with the Joneses. You don’t have to worry about keeping up with the Joneses if there is no economic growth to cause unequal increases in income. But is this happiness or just a sort of satisfaction because everybody is as miserable as you are?

Does the Subjective Well-Being Statement Mean Anything?

All things considered, how satisfied are you with your life as a whole these days, with 0 being dissatisfied to 10 being satisfied?

People in Cuba are reported by happiness researchers to have a level of happiness as high as that of Americans. How can this be reconciled with the fact that a significant number of Cubans are willing to face death to escape from Cuba to America, while no Americans are trying to escape to Cuba? This suggests that whatever the happiness research is measuring, if anything, it is not happiness because we would not expect Cubans as happy as Americans to be desperately attempting to escape to a no more happy America. Of course, it could always be argued that most Cubans are as happy as Americans but the really unhappy ones are the ones trying to escape but that still wouldn’t explain why Cubans are trying to escape to America but not vice versa if people are just as happy (on the whole) in Cuba as in America.

Whether aspirations have a negative effect on happiness will depend on the risk preferences of an individual.³ The perceived satisfaction of having an opportunity to reach a highly desirable goal, such as a higher income, may become an aversion to loss at the time it becomes necessary to perform adequately to receive that higher income.³ Individuals who are less sensitive to the risk of loss across a range of incentives have been shown to do better in pursuing opportunities.³ Those people will not experience a negative effect on happiness as a result of aspirations resulting from opportunities for greater income.

The 0–10 ranking might change on a day to day basis due to myriad factors; for example, report of life satisfaction is influenced by the weather (scoring higher on nicer days^3AA and rankings for life satisfaction would be expected to change with aging (which notably affects values, such as risk preferences^3A) and probably for gender (for the same reason). What corrections are made to the models to account for these biases? As we have seen in other models (for example, the Consumer Price Index, or global climate change models), data corrections can woefully misrepresent the raw data. By not including energy and food costs in the Consumer Price Index (CPI), a fairly recent change in the way government calculates the CPI, the government makes it appear that the CPI has risen much less than it actually has.

Another interesting point about happiness data was made in the work of Nick Crafts (University of Warwick) as cited in Johns & Ormerod. Happiness, Economics and Public Policy” (The Institute of Economic Affairs, 2007) that economic growth promotes life expectancy because of improved nutrition, better hygiene, safer water, improved healthcare, etc. in more affluent societies. “So, as a result of growth extending life, the lifetime TOTAL of happiness of an individual will be far greater, even if at any given moment of time he or she may not be happier in a richer society.” (Quote from pg. 31 of book cited in this paragraph.)

Researchers are finding out a lot about some very complex mechanisms underlying human emotions, such as risk aversion and reward, among many other forms of behavior. There is no single number that could represent the combination of all these ongoing processes.^3B For example, on the matter of gender differences in risk-reward tradeoffs. “[i]t has [] been found that testosterone and its metabolite, 3alpha-androstanediol, have rewarding and addictive properties, largely because they increase dopamine release in the shell of the nucleus accumbens, a brain region found to be stimulated in anticipation of irrational risk seeking. Testosterone may therefore underlie a financial variant of the ‘winner effect,’ in which a previous win in the markets leads to androgen priming and increased (and eventually irrational) risk taking in the next round of trading.”⁴ “If exposure is acute, glucocorticoids [stress hormones] can be euphorogenic, increasing motivation and promoting focused attention.” “However, if elevated glucocorticoids persist, their effects can be debilitating …” by “acting through the amygdala and hippocampus [to] promote a selective attention to mostly negative precedents… and produce a tendency to find threat and risk where none exist.”⁴“Cortisol is likely, therefore, to rise in a market crash and, by increasing risk aversion, to exaggerate the market’s downward movement. Testosterone, on the other hand, is likely to rise in a bubble and, by increasing risk taking, to exaggerate the market’s upward movement.” ⁴

A 2006 paper reported that optimism is associated with psychological well-being.^‡ In a 2007 paper, neuroimaging showed that when the most optimistic subjects imagined future events, they felt that positive future events felt “closer” in time than did negative future events and they rated positive events in the future as more positive than positive events from the past. In addition, several brain regions showed decreased activation in these optimistic subjects when they imagined negative future events, including the amygdala and the rostral (front) portion of the anterior cingulate to which the amygdala is connected.events.^4A,4B When they imagined positive future events, the activities of the ACC and the amygdala were reported to be more correlated with one another than when the subjects imagined negative futureevents.^4A,4B These and other findings reported in the paper suggest, propose the authors, that the brain may often be biased toward promoting a rosy vision of the future and, as reported in a different paper, may be a reason that optimism can be associated with risky behavior. The point here, as far as “happiness research” goes, is that these are examples of very complex mechanisms underlying emotional elements that can be related to “happiness” and, hence, the choice of a number between 0 and 10 to somehow represent the overall picture derived from all this is ridiculously simplistic.

‡ Nes and Segerstrom, Dispositional optimism and coping: a meta-analytic review. Per Soc Psychol Rev 10:235-51 (2006).

How Do You Interpret the Meaning of Rankings of 0-10: A Couple of Examples

Suppose an individual has lost his job and faces a deteriorating personal economic situation; that person might report a very low measure of satisfaction, say 2. But how would you tell the difference between that and a response of 2 from someone who still has his job and who is not facing imminent personal bankruptcy but who has had much higher expectations for his current position in life and who is therefore very dissatisfied?

A day on which a golf professional is asked about life satisfaction could be a day when he has had a recent period of poor performance in his golf game. If so, he might report a lower life satisfaction score than if he had been doing well recently. On the other hand, somebody who was a poor golf player might report a higher life satisfaction than that professional if his golf playing was a major interest in his life and he had been playing well recently for a rank amateur.

“A wealth of brain stimulation reward studies have identified a network of subcortical areas involved in reward processing, notably the lateral hypothalamus, medial forebrain bundle and mesolimbic dopaminergic system. The firing of dopaminergic neurons may be critical for learning, signaling a reward prediction error representing whether the moment at hand is better or worse than expected.”⁵ Moreover, emerging evidence suggests that “reward and punishment may be mediated by separate anatomic systems.”⁵ The subjective well-being question, providing a single number, does not offer an objective measure of any aspect of this complex reward system. Accurate reward prediction would likely represent a significant aspect of an individual’s subjective well being, such that (as an example) one’s actual financial status might be less important to subjective well-being than the congruity of one’s financial status with the financial status that one has EXPECTED. If this were true, then a number between 0 and 10 might tell you only whether the individual providing the number correctly anticipated present circumstances, with 10 representing the highest level of satisfaction because things met his or her expectations.

The subjective feeling of satisfaction in life represented by a particular number between 0 and 10 is going to differ from one person to another and from one period of time to another, particularly when there are rapid changes in the conditions of life and, unsurprisingly,¹ people are affected by changing societal conditions unequally, and² are not equal in their abilities to anticipate and adapt to such changes. What is it that is the same when two people report a “5” in their ranking of satisfaction with their life? What is it that is different? How do you tell?

It is interesting to note that longitudinal data shows that, generally, factors such as stable family life, being married, financial security, good health, having religious faith, enjoying living in a cohesive community where there is a high level of trust, and peaceful government relations contribute to happiness and, curiously, these are not the sort of things that are emphasized by happiness researchers who look far more toward government planning to establish the conditions for people’s happiness. (See Johns & Ormerod. Happiness, Economics and Public Policy,” The Institute of Economic Affairs, 2007.)

In fact, the book cited in the paragraph above, explains that in the happiness timeline data, there does appear to be no correlation with income per head. “But equally, using the same approach, there is no temporal correlation between overall happiness and increased leisure time, crime, declining infant mortality, increased longevity, unemployment, declining inequalities between the sexes, and public spending.” “We also note, for completeness, that the use of multiple regression analysis instead of simple two-variable correlations does not alter the conclusion.” The authors quip that “[t]rying to base policy on this measure would be like the Monetary Policy Committee of the Bank of England, rather than using GDP [Gross Domestic Product] as an indicator of the state of the economy, relying instead on a measure that classified people on whether they felt rich, moderately rich, or poor.”(!)

Overall, we don’t think the life satisfaction question, providing a number from 0 to 10 as an indicator of overall life satisfaction, is useful for public policy. To use this, as the happiness researchers do, to attempt to correlate average life satisfaction numbers across a large population with particular sociopolitical changes that are taking place in that population, such as more or less government central planning, is (in our judgment) an unscientific guessing game. If Cubans are as happy as Americans, it must mean that economic growth isn’t too important and maybe even unnecessary for happiness and possibly the “security” of a government that makes most of your life’s decisions is an important source of happiness! Hey, that’s it! Why don’t we start doing that in America and make everybody happy?? We could call it Obamalife.

References

1. Easterlin et al. China’s life satisfaction, 1990-2010,”PNAS109(25):9775-9780 (2012).
   2. Knight. Economic growth and the human lot. PNAS 109(25):9670-1 (2012).
   3. Chib et al. Neural mechanisms underlying paradoxical performance for monetary incentives are driven by loss aversion. NEURON 74:582-94 (2012).
   3AA. Kahneman and Krueger. Developments in the measure of subjective wellbeing. J Econ Perspect 20:3-24 (2006) as cited in Johns & Ormerod. Happiness, Economics and Public Policy” (The Institute of Economic Affairs, 2007), pg. 27).
   3A. Strough et al. Understanding decisions about sunk costs from older and younger adults’ perspectives. J Gerontol B Psychol Sci Soc Sci 66(6):681-6 (2011).
   3B. Consider a scalar (a single number such as the temperature) and a tensor (that can be represented by a single number, but that also has a direction). You can’t represent a tensor with a single number alone.
   ,4. Coates and Herbert. Endogenous steroids and financial risk taking on a London trading floor. Proc Natl Acad Sci USA 105(16):6167-72 (2008).
   4A. Schacter & Addis. The optimistic brain. Nat Neurosci 10(11):1345-7 (2007).
   4B. Sharot et al. Neural mechanisms mediating optimism bias. Nature 450:102-5 (2007).
   5. Paton & Louie. Reward and punishment illuminated,” Nat Neurosci 15(6):807-9 (2012).

An Additional Note on Happiness Research

There was a brief review (in the “Editors’ Choice” section) in the 27 July 2012 Scienceof a 2012 happiness research paper that we read after completing the discussion above. It brings up in a stark way some of the questions concerning just what is being measured in this research that we described above. The study (as described in the review by Stella Hurtley and Maria Cruz) supposedly compared the relationship between wealth — in the form of income and education — and subjective measures of the meaningfulness of life and happiness of residents of British Columbia. The report was said to find “an inverse relation” between socioeconomic status and the meaningfulness of life for parents when taking care of their children, but there was no such correlation during the part of their day when they were not taking care of their children. An inverse relation between socioeconomic status and the meaningfulness of life (when taking care of one’s children) would mean that the higher one’s socioeconomic status, the lower the meaningfulness of life. This is extremely odd, as the more wealth you have the better the chances are objectively for survival of your offspring. One would expect that there would be a warm and positive feeling that your wealth would provide security for the children you (presumably) love, not the reverse.

Hurtley and Cruz also describe a follow-up field experiment in which “the concept of wealth was casually introduced while asking attendees at a children’s festival about their happiness and sense of meaning.” Again, they describe the study finding no link between wealth and happiness, but there was “a negative relation between thoughts of wealth and a sense of meaningfulness.” There certainly has to be an explanation for what seems to us to be a bizarre way of viewing wealth, but there wasn’t any suggestion for what it might be in the Hurtley and Cruz writeup, though they suggested that “paradoxically, affluence may compromise one of the subjective benefits of parenting — a sense of meaning in life.”

We did not read the original paper. If you would like to do so, we provide the reference at the end of this paragraph. It seems to us that these are the sorts of responses that you would get from people who have biases against the wealthy and who are afraid of a negative response from others to admit to any positive feeling for the possession of wealth. At a children’s festival put on by (say) successful entrepreneurs and their spouses and children, we would expect considerably different results.

Reference

6. J Expsoc Psychol48, 10.1016/j.jesp.2012.06.001 (2012).

If you reduce your expectations to zero, life becomes a series of happy surprises.— — Tuck Andres (D&S: But would that be a 0 or a 10?)The welfare and happiness of millions cannot be measured on a single scale of less and more.— — F. A. Hayek. The Road to Serfdom” (Chapter V); Hayek was co-winner of the Nobel Prize for Economics in 1974

OREGON POLICE FILE SUIT CHALLENGING FINANCIAL PENALTY FOR REFUSING TO JOIN “VOLUNTARY” WELLNESS PROGRAM

In a suit that sounds remarkably like the challenge to the Obamacare “tax” for not buying health insurance (though this suit was filed on Feb. 14, 2012, well before the U.S. Supreme Court decision upholding Obamacare), Oregon state police and corrections officers filed a class-action lawsuit against their forced participation in the Oregon state Health Engagement Model (HEM).¹

The HEM requires health plan participants to fill out an extensive online questionnaire and participate in two ‘e-lessons’ that purportedly provide strategies for achieving good health. The part that has people in an uproar is the requirement that health plan participants who choose not to participate in the HEM survey must pay a $20 per month penalty if they are single and $35 a month if a couple. (Children are not included in the HEM program.) The suit argues that the HEM online questionnaire violates the Fourth Amendment as an unreasonable search and seizure and the Fifth Amendment’s due process protection of privacy and prohibition of compelled self-incrimination.

One difference between this requirement to provide personal information or pay a penalty and the Obamacare command to buy health insurance or pay a tax is that presumably Oregon state employees are not required to join the state health insurance program in the first place, whereas with Obamacare, Americans are required to buy health insurance or pay the “tax.”

We seriously doubt the suit will go anywhere on their stated legal arguments. Under administrative (regulatory) law, people are often required to provide information (such as telling the IRS where you have overseas bank accounts) that, in violation of the Fifth Amendment, requires compelled self-incrimination or (as in OSHA “inspections” of business premises) are carried out without a warrant, in violation of the Fourth Amendment’s prohibition on unreasonable searches and seizures (where searches require a court-ordered warrant). These sorts of constitutional violations by administrative agencies have, sadly, long been upheld by the courts. Hardly anybody noticed until they woke up one day and found out that they would have to buy health insurance they didn’t want or pay a “tax” on the basis (as the Supreme Court decided in the Obamacare case) that even though the Constitution doesn’t give the federal government the authority to force you to buy something, it can always require you to pay a “tax” if you don’t buy that something!

Reference

1. Reported in the Citizens’ Council for Health Freedom “Health Freedom Watch” (Second Quarter 2012).

Hypothesis

ACTIVATION OF CHOLINERGIC NERVOUS SYSTEM MAY PROMOTE SATIETY BY SIGNALING THE END OF A MEAL

A new paper¹ proposes that activation of cholinergic interneurons in the nucleus accumbens (NAc) and cholinergic projections to the ventral tegmental 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.”2 The 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.” Thus, the authors hypothesize. in situations in which it would be physiologically advantageous for the animal to continue to eat, such as when they are underweight or not retaining the food that is consumed, ACh levels in the NAc are not increased.”¹

* 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.

“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 nicotinic cholinergic receptors in the hypothalamus, which activates pro-opiomelanocortin neurons leading to the activation of melanocortin 4 receptors critical for nicotine-induced decreases in food intake in mice.¹

In the mouse neurotoxin study mentioned in the paragraph above, ^1B the researchers noted that their study’s data showed an increase in food and water intake after cholinotoxic lesions (which decreased the number of ACh interneurons and, hence, reduced their inhibitory influence on eating. “Recently, it has been suggested that NAcc [also referred to as NAc] ACh has a unique role in stopping behavior.”1B The latter refers to such stopping effects as when experimental animals discontinue eating when ACh increases in response to exposure to a noxious flavor.

In comparing the biochemical pathways that involve the cholinergic nervous system in both drug or food withdrawal, the authors of paper #1 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.”

The researchers conclude that “increased levels of ACh in the NAc act to promote satiety.”¹

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.

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 one 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 neostigmine, an acetylcholinesterase inhibitor (which increases cholinergic activation), 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 orexigenic (eating inducing) peptide 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, was 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 their other choice, 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 synthesis 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. For example, a choline or galantamine (cholinesterase inhibitor) supplement an hour or two before meals might reduce food intake.

Assuming the hypothesis is correct, there are a couple of things to keep in mind when attempting to make practical use of the ACh/DA balance in regulating the intake of food:

1. 1. The TIMING of the increase in cholinergic neuronal activity in relation to the cessation of eating is likely to be important. That information may not be available from published data, particularly in light of individual variation in sensitivity to cholinergic agonists; hence, some self-experimentation using safe ways to increase cholinergic activity (such as supplemental choline or a cholinesterase inhibitor such as 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 so possible side effects of increased cholinergic activity, such as headache caused by excessive muscle tone, could occur that have nothing to do with the desired effect on eating and, indeed, probably nothing to do with the NAc, another reason that some experimentation would be required.

We note that much of the experimental work resulting in published papers on the interaction of ACh and DA in reward and eating appears to have been done by the same group of researchers. We hope to see additional followup by other groups on the ACh/DA work.

References

1. Avena and Rada. Cholinergic modulation of food and drug satiety and withdrawal.Physiol Behav106:332-6 (2012).
   1B. Hajnal 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. ADV. IN BEHAV. BIOL. 56 (Basal ganglia VIII):99-107 (2005).
   4. Mark et al. Cholinergic modulation of mesolimbic dopame function and reward. Physiol Behav 104:76-81 (2011).
   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).

Every impossible rule has its loopholes; every general prohibition creates its bootleggers.— Robert A. Heinlein (“Time Enough for Love” (1973)

DIETARY RESTRICTION—A NATURAL CHOLINESTERASE INHIBITOR?
DECREASED ACETYLCHOLINESTERASE ACTIVITY IN
BRAINS OF FEMALE MICE UNDERGOING
DIETARY RESTRICTION

Decline of brain cholinergic function is found in normal aging and is associated with impairment of learning and memory. In Alzheimer’s disease (AD), the cholinergic nervous system is a key area of degeneration and many of the drugs used in the treatment of AD are cholinesterase inhibitors. Acetylcholine (ACh), the neurotransmitter of the cholinergic nervous system, is regulated by the enzyme acetylcholinesterase (AChE), which acts to terminate the activity of ACh in the neuronal synapse. Thus, a cholinesterase inhibitor is a substance that prevents AChE from terminating the activity of acetylcholine (ACh) in the synapse, thus prolonging ACh action. In a recent paper1 authors reported that, “AChE [acetylcholinesterase] has been used as a marker for cholinergic function in neural tissue because of its implications in synaptogenesis [formation of synapses] and its involvement in neurodegeneration in adult tissues. Serum AChE evaluation and the checking of different isoforms present in different tissues is being used as an effective marker in detecting several diseases.”

Because of the improved cognitive function, including enhancements of learning and memory and increased neurogenesis, in many strains of rodents subject to dietary restriction (caloric reduction without malnutrition) the authors¹ studied the effects of 3 months of DR (dietary restriction in the form of feeding every other day) on brain levels (in the cerebral hemispheres and the cerebellum) of AChE in female Swiss albino (Balb/C strain) mice. They also examined AChE levels in the same type mice (at 1 month and 18 months) as modulated by 24 hours of fasting and refeeding.

The region of the brain that the researchers studied that contained the highest normal endogenous level of AChE was in the cerebral hemispheres of 1 months old mice, which had declined significantly by 45% in 18 month old mice. They found no significant changes in AChE levels in the cerebellum between the young and old mice. 24 hours of fasting resulted in a decrease of 30% in the level of AChE activity in the cerebral hemispheres of 1 month old mice, but no significant change in the cerebral hemispheres of the 18 month old mice. (There was also no significant change in the cerebellum.) After 24 hours of refeeding, the AChE levels of the 1-month-old mice returned to their initial value, with no significant change in comparison to the age-matched control mice.

The authors suggest that the reduced levels of AChE activity resulting from fasting in the 1 month old mice (a rapid decrease taking place over 24 hours) and suggest that this may reflect the effect of dietary changes on AChE during early development.

A possible explanation for the lack of changes in AChE level of the cerebral hemispheres of the 18 month old mice in the 24 hour fasting and refeeding is that it might reflect age-induced alterations of ACh/DA signaling in the regulation of initiation and discontinuation of eating (as suggested by the cholinergic hypothesis of the regulation of eating behavior discussed above).

The 1-month-old mice on the DR (feeding every other day) had a significant decrease of AChE level (50%, p<0.001) on the non-feeding day and a decrease of 40% (p<0.001) on the feeding day. No significant changes were observed in the cerebellum level of AChE in either 1 month old or 18 month old mice in comparison to their age-matched control mice. As the authors report, these findings are in agreement with earlier findings (a 1973 paper was cited) where the activity of AChE was highest in 9-week-old female rats and decreased by 50% after 29 weeks and which further decreases in old age. The authors suggest that the lower levels of AChE in old rodents may be due to loss of neurons and/or decrease in the rate of protein synthesis of AChE.

In the 18 month old mice, the researchers report a significant decrease of 15% (p<.05) and 12% (p<.05) on the non-feeding and feeding day, respectively.

“In the cerebral hemispheres of older mice where there is less reduction of AChE activity during DR, we suggest that DR might act as a natural cholinesterase inhibitor by maintaining the level of the already declining ACh, thus enhancing cholinergic neurotransmission in the cerebral hemispheres of the aged brain. Alternatively, DR may produce free radical scavengers which prevent the binding of free radicals on the sites of AChE molecules, analogous to reports on inhibitors of AChE that improve brain function.”¹

Reference

1. Suchiang and Sharma. Dietary restriction regulates brain acetylcholinesterase in female mice as a function of age. Biogerontology published online 26 Aug. 2011 DOI 10.1007/s10522-011-9356-1.