APPETIZERS

In order to improve your game, you must study the endgame before everything else, for whereas the endings can be studied and mastered by themselves, the middle game and the opening must be studied in relation to the endgame.

— Jose Raul Capablanca, Cuban chess player who was world chess champion from 1921 to 1927 and one of the greatest players of all time.

(The above wise quote was taken from Endgame by John Mauldin and Jonathan Tepper, Wiley & Sons, Inc., 2011, a book about the Endgame that is the end of the debt supercycle and how it changes everything. The quote could as well apply to the Endgame of life: aging and death.)

We all know we have seen the end of an era, and now we have courtside seats to watch the Endgame unfold. We are watching the end of Act I: the Debt Supercycle. Now we will get to see how Act II: The Endgame plays out.

— John Mauldin & Jonathan Tepper, The Endgame, Chapter I, page 4

I very rarely think in words at all. A thought comes, and I may try to express it in words afterwards.

— Albert Einstein

Nothing gives life more zest than running for your life.

— Robert A. Heinlein, The Cat Who Walks Through Walls, 1985)

When I was a kid I used to pray for a bicycle. Then I realized that the Lord doesn’t work that way, so I stole one and asked him to forgive me.

— Emo Philips

You do not need a parachute to skydive. You only need a parachute to skydive twice.

— unknown

Knowledge is knowing a tomato is a fruit. Wisdom is not putting it in a fruit salad.

— unknown

[Total] Olive Oil Consumption in U.S passed Greece in 2009, with the U.S. becoming the third largest consumer of olive oil, reaching a per capita consumption of 0.9 liters of oil a year. Meanwhile, however, Greece’s per capita consumption was 21 liters/year.

— Catherine E. Watkins, associate editor of Inform in the Sept. 2012 Inform

Thomas Jefferson first saw olive trees in the Alps in 1788 and called them “the richest gift of heaven” and “the most interesting plant in existence.”

— Tom Mueller, author of “Extra Virginity: The Sublime and Scandalous World of Olive Oil” in Watkins, book review in the Sept. 2012 Inform

HAPPY NEW YEAR!

SEX, STRESS HORMONES, AND ADULT NEUROGENESIS

STARTING 2013 WITH SOME GOOD NEWS!

New research suggests that sexual experience is not only pleasurable, but also reduces anxiety and increases adult neurogenesis in adult male rats. We report here on three recent studies.^1–3

Why do rats have all the fun by getting to be the subjects in these sexual studies? First, rats are much easier to maintain under constant laboratory conditions and to sample for plasma constituents such as glucocorticoids, which could inhibit sexual activity, induce anxiety, and inhibit neurogenesis. Rats are also easier to get in groups with similar genetic background, thus avoiding some confounding effects. Anyway, the rats in these studies were very enthusiastic subjects but were still “sacrificed” in the end in order to assess brain effects. Well it was fun while it lasted.

In the first paper,¹ the researchers studied whether sex, a rewarding stressor that, like other stressors, increases glucocorticoids, would have similar negative effects as non-rewarding stressors.

The adult male rats¹ were exposed to a sexually-receptive female rat once (acute) or once daily for 14 consecutive days (chronic) and their levels of circulating glucocorticoids were measured. Their sexual encounters were videotaped and then analyzed for mounts, intromissions, and ejaculations. On the last day, the rats were injected with BrdU (bromodeoxyuridine, a DNA synthesis marker). The scientists explain that “the majority of new cells in the dentate gyrus express the mature neuronal marker NeuN 2 weeks post BrdU labeling.” An additional cohort of naive and sexually-experienced rats were tested for anxiety on the elevated plus maze and on the novelty-suppressed feeding paradigm (where the latency to chew a ~2 g food pellet in the center of a bright area was recorded. The longer latency indicated anxiety).

The results showed that chronic sexual experience enhanced cell proliferation and adult neurogenesis without altering glucocorticoid levels. Sexual experience produced more new neurons (those labeled with BrdU and examined after a 2 week survival). Acute sexual experience (a single encounter with a sexually-receptive female rat) resulted in enhanced cell proliferation in the dentate gyrus despite substantially elevated glucocorticoid levels.

The sexually experienced rats were less anxious than naive controls when tested on the novelty suppressed feeding paradigm.

As the researchers note, despite the increase in glucocorticoids (in the rats receiving a single (acute) sexual experience), neurogenesis still took place, even though stressors that increase glucorticoids generally reduce adult neurogenesis. The authors suggest that whether glucocorticoids increase or not, it is the rewarding (hedonic) aspect of the brain stimulation that overrides the inhibitory effect of glucocorticoids on neurogenesis. As the researchers also note, another example of a rewarding stressor is exercise that, despite increasing glucocorticoids, also reduces anxiety and enhance adult neurogenesis in mice and men.

In the second paper,² researchers studied the effect of oral feeding of Lycium barbarum< (wolfberry, also called Goji) polysaccharides (LBP) in adult male Sprague-Dawley rats for its effects on copulation, ejaculation, and shortening of ejaculation latency. After 21 days of LBP feeding, there was significant improvement of all these sexual functions. Moreover, the sexual inhibition caused by chronic corticosterone (glucocorticoids) was prevented by LBP. While increased corticosterone suppressed neurogenesis in subventricular zone and hippocampus of adult rats, this was reversed by LBP.

“Significant correlation was found between neurogenesis and sexual performance, suggesting that the newborn neurons are associated with reproductive successfulness. Blocking neurogenesis in male rats abolished the pro-sexual effect of LBP.”² “Our results showed that the beneficial effect was not only revealed in normal, healthy rats, but also in rats with sexual inhibition induced by corticosterone. The ‘rescuing’ effect of LBP on male sexual behavior suggests that LBP may be useful to treat male sexual dysfunction.”² As in the study¹ discussed above, adult neurogenesis in the SVZ (assessed by the number of BrdU-positive cells in the corticosterone-treated animals was significantly lower than that in animals not given corticosterone.

An in vitro study carried out by the same researchers as part of the study showed that LBP treatment at 1 μg/ml and 10 μg/ml increased cell proliferation in a neural stem cell line. Corticosterone treatment suppressed the cell proliferation of the neural stem cells, while co-administration with LBP at 10 μg/ml could reverse the suppression.²

Unsurprisingly, the third paper³ is very similar to the second paper² as the researchers were the same; paper #3 was published the year before paper #2. Accordingly, the adult male rats were treated with either corticosterone and/or paroxetine, an SSRI type (similar to Prozac^®) antidepressant. The findings included that corticosterone treatment inhibited male sexual performance, while paroxetine enhanced it. The researchers summed it up: “These results suggest that cell proliferation in the SVZ and hippocampus may be involved in the reproduction of the male rodents, and pharmacological treatments may affect sexual functioning through alteration of neurogenesis.” Paroxetine is an SSRI antidepressant drug that, as a class, have been found to generally increase neurogenesis.

References

1. Leuner et al. Sexual experience promotes adult neurogenesis in the hippocampus despite an initial elevation in stress hormones.PLoS ONE 5(7): e11597, doi:10.1371/journal.pone.0011597.
2. Lau et al. Polysaccharides from wolfberry prevents corticosterone-induced inhibition of sexual behavior and increases neurogenesis.PLoS ONE 7(4):e33374. doi:10.1371/journal.pone.0033374.
3. Lau et al. Effect of corticosterone and paroxetine on masculine mating behavior: possible involvement of neurogenesis. J Sex Med.8:1390-1403 (2011).

AGELESS: DELETING AGES TO PREVENT METABOLIC SYNDROME

HIGH AGE DIET MAY BE “MISSING LINK” BETWEEN ADIPOSE TISSUE ACCUMULATION, INFLAMMATION, AND INSULIN RESISTANCE

As the title of the paper¹ makes clear, the bottom line of the new research is that AGEs promote insulin resistance and diabetes by depleting antioxidant defenses that protect against AGE-induced inflammation, including the AGE receptor-1 (AGER-1), a key anti-AGE defense, and SIRT1, which suppresses inflammatory signals and, importantly, enhances levels of the anti-inflammatory adipokine adiponectin to improve insulin sensitivity and fat mobilization. The researchers found that AGER1 and SIRT1 were independently suppressed by chronic oxidative stress as is found in conditions such as diabetes, obesity, aging, or high AGEs containing diets.Advanced Glycation Endproducts (AGEs) have become a hot research subject because of the coming together of mechanisms where accumulation of AGEs appear to be causative factors that go beyond overnutrition in the “epidemic” of age-associated metabolic diseases including obesity and diabetes. A newly published paper¹ and an accompanying commentary² report some of the new discoveries whereby AGEs have become the centerpiece of the causes and potential prevention of these disorders.

The researchers fed a powerful alpha-dicarbonyl glycating agent, methylglyoxal (MG), found in patients with diabetes and in those consuming high AGE diets, to mice. As we have written in an earlier Durk & Sandy newsletter, one way to reduce dietary AGEs is to cook food at a relatively low temperature, as the AGEs are formed by high temperature heating of foods containing protein and sugars. This process, called the Maillard reaction, creates tasty food that is crispy and has a brown color—hard to resist except when you consider the result of eating too much of it.

The mice on a high MG diet gained weight, with increased adiposity, and metabolic changes as compared to mice on a regular diet. In addition, the MG-fed animals had increased markers of oxidative stress and inflammation, including increased plasma 8-isoprostanes and vascular cell adhesion protein-1 and lower plasma adiponectin levels. Moreover, insulin action was impaired in the MG+ mice. “… levels of AGER1 and SIRT1 were suppressed in primary adipocytes isolated from MG+ WAT [white adipose tissue from MG+ mice], and NF-kappaB acetylp65 and RAGE levels were increased, compared with adipocytes from MG-mice, suggesting the presence of a proinflammatory state in MG+ WAT adipocytes.”¹

The researchers comment: “It is notable that this combination of features is virtually absent in genetically identical mice born and raised in an environment differing only with respect to the lower amount of ingested MG-AGEs.”

“Chronic MG+ intake was also associated with elevated fasting plasma insulin and leptin and suppressed adiponectin levels in MG+ mice. These findings are consistent with an insulin-resistant state, as seen previously in Reg mice, but not in MG– mice.”

According to Leonid Poretsky, the author of the commentary article,² “[n]ew tests measuring AGEs in circulating, including those absorbed from the diet, have been developed and are poised to enter clinical practice.” This is wonderful news and we certainly hope that “poised to enter clinical practice” means pretty soon, not being delayed for years by bureaucratic process at the FDA. As the author² also comments, “[c]irculating AGE levels can be reduced without altering the caloric content of meals simply by changing the way the food is prepared, that is, by using less heat and more water (e.g., stewing instead of frying).” He adds that “[m]edications that can reduce AGE absorption from food need to be developed, and initial steps in this direction have already been taken.”

Nutrients that block the development of AGEs or reduce the damage caused by AGEs include: benfotiamine (a lipid soluble form of thiamine), vitamin B6, alpha lipoic acid, carnosine, histidine, and rutin. We take a formulation containing all these ingredients 3 or 4 times a day. See our interview on reducing AGEs (with included references) “Reducing Glycation Reactions for Better Health and Longer Life” in the February 2008 issue of Life Enhancement.

References

1. Cai et al. Oral advanced glycation endproducts (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1. Proc Nat Acad Sci USA.109(39):15888-93 (2012).
2. Looking beyond overnutrition for causes of epidemic metabolic disease. Proc Nat Acad Sci USA.109(39):15537-8 (2012).

SETTING A TRAP FOR AGES

CURCUMIN ACTS AS METHYLGLYOXAL TRAP IN CELL-FREE SYSTEMS AND IN HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS

But that isn’t the end of the story of ways available to your body for either blocking the formation of AGEs or increasing their disposal. Methylglyoxal is a major precursor of AGEs, the levels of which are elevated in, among other conditions, diabetes, dialysis, and chronic kidney disease. As a 2012 paper¹ reports, “several dietary flavonoids have been shown to inhibit AGE formation through blocking the carbonyl or dicarbonyl groups and thus may prevent diabetes and its complications.”

Curcumin has now been reported¹ to directly trap methylglyoxal, inhiting its conversion to AGEs and, as a result, possibly preventing methylglyoxal-induced endothelial dysfunction. The new paper¹ reveals the chemical mechanism that may be responsible for the methylglyoxal trapping by curcumin. The paper also mentions other trapping agents of reactive dicarbonyl species such as methylglyoxal from dietary sources that includes the tea polyphenol EGCG, apple polyphenols phloretin and phloridzin, cinnamon proanthocyanidins, phlorotannins from brown algae, stilbene glucoside from Polygonum multiflorum Thumb. Remarkably, the researchers report that curcumin significantly and time-dependently trapped MGO (methylglyoxal) for up to 24 hours (51% reduction, p<0.05), and the effect was said to remain unchanged for up to 72 hours of incubation.¹

Curcumin is readily available from turmeric root powder, an inexpensive spice which we take every day in capsules. We also take EGCG in capsules every day, too!

Reference

1. Hu et al. Trapping of methylglyoxal by curcumin in cell-free systems and in human umbilical vein endothelial cells. J Agric Food Chem. 60:8190-6 (2012).

DELAYED AGING AND AGING-ASSOCIATED DECLINE OF PROTEIN FUNCTION BY INHIBITING TRYPTOPHAN DEGRADATION

A very interesting new study reports that preventing the enzymatic degradation of tryptophan has significant anti-aging effects in the nematode Caenorhabditis elegans.The study specifically identifies “the tryptophan-converting enzyme tryptophan 2,3-dioxygenase (TDO-2) as a metabolic regulator of age-related protein toxicity and lifespan in C. elegans.”¹

The researchers found that depletion of TDO-2 suppressed toxicity of aggregation-prone proteins, including alpha-synuclein, amyloid-beta and polyglutamine proteins, associated with diseases such as Parkinson’s, Alzheimer’s, and Huntington’s, respectively. Depletion of TDO-2, the first enzyme in the kynurenine pathway of tryptophan degradation, increased the levels of tryptophan (by decreasing its degradation), but the researchers also found that feeding the worms with extra ­L-tryptophan also suppressed the toxicity of aggregation-prone proteins. (Emphasis added.) Moreover, depletion of TDO-2 extended lifespan in C. elegans. Humans have evolutionarily conserved orthologs of TDO-2 (TDO and indoleamine 2,3-dioxygenase). Hence, the authors conclude, “intervening with tryptophan metabolism may offer avenues to reducing proteotoxicity in aging and age-related diseases.”¹

The researchers also note that as TDO-2 naturally increases during aging, this may contribute to the age-dependent decline in protein homeostasis and, thus, inhibiting TDO (and possibly indoleamine 2,3-dioxygenase) may delay this process.

Other Natural Products Inhibit Indoleamine 2,3-Dioxygenase

Indoleamine 2,3-dioxygenase has been shown to have important effects on the immune system. “By locally degrading tryptophan, IDO inhibits the proliferation of T lymphocytes and induces T cell apoptosis, leading to suppression T cell response.”² In a recent study, EGCG (the major catechin constituent of green tea) was shown to significantly inhibit the expression of IDO (and hence preventing immune suppression of T cells resulting from the degradation of tryptophan) in oral cancer cell lines.²

In another study,³ curcumin was reported to reverse IDO-mediated suppression of T-cell responses in bone marrow-derived dendritic cells stimulated by interferon gamma. The authors suggest that “down regulation of IDO in DCs is an important immunomodulatory property of curcumin that may be exploited therapeutically in the control of cancers.”

A study on the effects of resveratrol on IDO⁴ reports that in a cell culture study, resveratrol (10–100 uM) diminished tryptophan degradation by IDO.

Reduced Neurogenesis by TDO-2 Conversion of Tryptophan into Kynurenine, Catalyzed by Tryptophan-2,3-dioxygenase, is Stimulated By Cytokine-Induced Depression

Another result of degradation of tryptophan by tryptophan-2,3-dioxygenase (TDO-2) is decreased neuro­genesis.⁵ In a 2012 paper,⁵ researchers report that “[t]he first step [in the conversion of tryptophan to kynurenine] is catalyzed by the enzyme tryptophan-2,3-dioxygenase and, especially in response to inflammation, also by indoleamine-2,3-dioxygenase (IDO). This pathway is clearly activated during cytokine-induced depression. For example, administration of LPS [lipopolysaccharide, a component of bacterial cell wall, which stimulates the immune system] in rodents activates IDO and induces depression-like symptoms, which in turn can be prevented by an IDO antagonist.” Importantly, the researchers go on to explain that “[f]ollowing IDO activation, both the reduced peripheral availability of tryptophan (putatively leading to reduced serotonin synthesis in the brain) and the relative balance between QUIN [quinolinic acid] and KYNA [kynurenic acid] [both products of TDO and/or IDO], have been proposed to be of significance in depression and neurodegeneration. Indeed, TDO-/- [TDO knockout] mice show increased neurogenesis.” Accordingly, the researchers chose to test the hypothesis that the kynurenine pathway is involved in the IL-1beta (a proinflammatory cytokine)-induced reduction of neurogenesis.

The researchers report finding that differentiated human hippocampal progenitor cells constitutively express both IDO and TDO, the enzymes that degrade tryptophan into KYN (kynurenine). In culture of the cells, it was found that tryptophan levels decreased by 19% and kynurenine levels increased by 20%, leading to an overall 53 ± 13% (p<0.05) increase in the ratio of kynurenine/tryptophan. In other words, the IL-1beta increased the levels of a functional IDO enzyme.

The authors conclude that “our results show for the first time that IL-1beta reduces human hippocampal neuro­genesis …” “We also show that, upon activation of IDO, treatment with IL-1beta results in a decrease of tryptophan together with an increase in kynurenine levels.”⁵

Another new paper⁶ also reports, in a mouse model of neuroinflammation-induced depression, that the inhibition of indoleamine 2,3-dioxygenase by its competitive inhibitor 1-methyl-tryptophan, prevented the development of depressive-like behavior. This is consistent with current thinking that the activation of IDO by proinflammatory cytokines is a link between IDO and neurodegenerative diseases such as Alzheimer’s disease and depression.⁶

References

1. van der Goot et al. Delayed aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation. Proc Nat Acad Sci USA.109(37):14912-7 (2012).
2. Cheng et al. Indoleamine 2,3-dioxygenase, an immunomodulatory protein, is suppressed by (-)-epigallocatechin-3-gallate via blocking of gamma-interferon-induced JAK-PKC-delta-STAT1 signaling in human oral cancer cells. Jnbsp;Agric Food Chem.58:887-94 (2010).
3. Jeong et al. Curcumin suppresses the induction of indoleamine 2,3-dioxygenase by blocking the Janus-activated Kinase-protein kinasew Cdelta-STAT1 signaling pathway in interferon-gamma-stimulated murine dendritic cells. Jnbsp;Biol Chem.284(6):3700-8 (2009).
4. Wirleitner et al. Resveratrol suppresses interferon-gamma-induced biochemical pathways in human peripheral blood mononuclear cells in vitro. Immunol Lett.100:159-63 (2005).
5. Zunszain et al. Interleukin-1beta: A new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. 37:939-49 (2012).
6. Dobos et al. The role of indoleamine 2,3-dioxygenase in a mouse model of neuroinflammation-induced depression. J Alzheimers Dis.28:905-15 (2012).

KILLING PROSTATE CANCER CELLS

INHIBITION OF LOX-5 TRIGGERS MASSIVE DYING OFF OF HUMAN PROSTATE CANCER CELLS

An early (1998) paper¹ described how arachidonic acid, an omega-6 fatty acid, stimulates proliferation of prostate cancer cells through its metabolite 5-HETE, produced by the action of 5-lipoxygenase. They refer to multiple studies that have suggested a role for arachidonic acid and its precursor, linoleic acid, in prostate cancer growth and metastasis. In their paper,¹ the authors show that 5-HETE is also a potent survival factor for human prostate cancer cells. They showed that, by inhibiting 5-lipoxygenase, 5-HETE production was completely prevented and that this resulted in massive apoptosis (programmed cell death) in both hormone-responsive (LNCaP) and -nonresponsive (PC3) human prostate cancer cells. The apoptosis was blocked by the thiol antioxidant N-acetylcysteine. These results, the authors state, identifies a possible mechanism by which high dietary fat can promote the progression of prostate cancer.

A more recent (2007) paper² follows up on these earlier findings by reporting on the use of 5-LOX inhibitors to block the conversion of arachidonic acid to 5-LOX products associated with various disorders, including osteoporosis and cancers (e.g., prostate, pancreas and breast), as well as atherosclerosis, heart attack, and stroke. The author describes many natural products that act as 5-LOX inhibitors or inhibitors of 5-LOX products, including nordihydroguaiaretic acid (NDGA), caffeic acid, quercetin, luteolin, silibinin, curcumin, gingerols (derived from ginger), rosmarinic acid, and resveratrol. Also, see article (below) on benfotiamine.

Boswellic acids have also been reported as inhibitors of 5-LOX, have potent anti-inflammatory activity, and have been extensively investigated for their activity against tumor cells and in cancer chemoprevention.³

References

1. Ghosh and Myers. Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells. Proc Nat Acad Sci USA.95:13182-7 (1998).
2. Inhibition of 5-lipoxygenase product synthesis by natural compounds of plant origin. Planta Med.73:1331-57 (2007).
3. Banno et al. Anti-inflammatory activities of the triterpene acids from the resin of Boswellia carteri.Jnbsp;Ethnopharmacol. 107:249-53 (2006).

SEROTONIN’S ROLE IN IMPULSIVITY

SEROTONIN IN CERTAIN BRAIN NEURONS IS NECESSARY FOR WAITING FOR DELAYED REWARDS

A recent study reveals a causal role for serotonin in the serotonin neurons in the midbrain dorsal raphe nucleus in the ability of rats to wait for a delayed reward. This is consistent with studies showing that reduced serotonin brain levels are associated with increased impulsivity, especially with respect to violent acts, including suicide.

In the new study,¹ the authors explain that the dorsal raphe nucleus (DRN) is the major origin of serotonergic projections to the forebrain. They had previously reported that “DRN serotonergic neurons increase tonic firing while rats wait for delayed rewards and cease firing before rats give up waiting for long delayed rewards.”¹ However, these results did not reveal whether the activation of serotonergic neurons is causal and necessary for waiting for delayed rewards. Hence, the researchers conducted this new study.

In the new study, the rats performed a task and could receive a prompt reward (waiting for 2 seconds) or a delayed reward (where they had to wait 7–11 seconds). The rats had to alternatively visit food and water sites to acquire rewards after either the rapid or delayed reward condition. The researchers found that “the suppression of 5-HT [serotonin] neural activity in the DRN increased premature exit from reward sites before the delivery of rewards, which indicated impaired patience for delayed rewards.”¹

Interestingly, selective serotonin reuptake inhibitors (SSRIs) can have inconsistent results on the ability to wait for delayed rewards. “For example, some studies showed the administration of SSRIs increased the selection rate of a large, delayed reward over a small, immediate reward, indicating a decrease in impulsive choice. By contrast, a lack of effect has also been reported. Furthermore, opposite effects of different doses of citalopram in a probabilistic reversal learning have been reported. These inconsistent results may be due to opposing effects of SSRI on 5-HT neuron firing and postsynaptic 5-HT concentrations.”¹ These inconsistencies may also relate to the occasional reports of impulsive violent acts carried out by adolescents treated with SSRIs, including schoolyard shootings and suicides. These unfortunate effects might be avoided by taking tryptophan or 5-hydroxytryptophan (5-HTP) supplements but the exact amounts needed will differ between individuals and require careful titration. Those individuals with lower levels of the enzyme required to convert tryptophan to 5-hydroxytryptophan (the first step in the conversion of tryptophan to serotonin) are likely to find taking 5-hydroxytryptophan rather than tryptophan a more effective way to increase their serotonin levels.

Reference

1. Miyazaki et al. Activation of dorsal raphe serotonin neurons is necessary for waiting for delayed rewards.J Neurosci. 32(31):10451-7 (2012).

GOING MOUNTAIN CLIMBING? QUERCETIN FOUND TO BE PROTECTIVE AGAINST HIGH ALTITUDE CEREBRAL EDEMA

Another mechanism described by the researchers is hypobaric hypoxia leading to low blood oxygen saturation that triggers the production of erythropoietin (to increase the number of red blood cells). They go on to explain that increases in red blood cells induce hypoxic inflammation by producing reactive oxygen species. The researchers carried out a study to identify “a potent therapeutic agent which can reduce hypobaric hypoxia-induced oxidative stress, as well as inflammation” as a possible way to reduce high altitude cerebral edema.¹ Quercetin has been found to have powerful antioxidant and antiinflammatory effects. Moreover, quercetin has been reported in several studies to reduce inflammation by attenuating the redox-sensitive transcription factor NFkappaB, as well as scavenging free radicals. The researchers compared the effects of quercetin with dexamethasone (a synthetic corticosteroid, which acts as an antiinflammatory) against high altitude cerebral edema in male Sprague Dawley rats.A new paper¹ starts by telling you about the dangers of traveling to high altitudes or mountain climbing without adequate acclimatization. You could end up like one of the millions of people who every year suffer from acute high altitude mountain sickness, from which 5% can develop life threatening high altitude cerebral edema. High altitude cerebral edema has been described as, “although uncommon, high altitude cerebral edema causes significant morbidity and occasionally death in otherwise perfectly healthy individuals.” The researchers¹ report that their recent study “proved that oxidative stress and inflammation play an important role in high altitude cerebral edema via the redox-sensitive transcription factor, NFkappaB activation.” NFkappaB is a major regulator of inflammation-associated genes.

In the study, rats were exposed to an altitude of 25,000 feet for 24 hours, as a result of which they showed a significant rise in various blood parameters including white blood cells, red blood cells, lymphocytes, monocytes, granulocytes, hemoglobin, platelets, MCV, and HCT (hematocrit). The authors hypothesize that increase in red blood cells, hemoglobin, and hematocrit might lead to increased blood viscosity and stasis of blood, increasing the risk of blood clots. However, administration of quercetin or dexamethasone prior to hypoxia exposure resulted in a reduction in many of these changes. Quercetin was more effective than dexamethasone as an antioxidant (decreasing reactive oxygen species and increasing superoxide dismutase) as well as an antiinflammatory by downregulating NFkappaB. Unlike dexamethasone, quercetin does not have the many side effects commonly observed in corticosteroid therapy (such as severe allergic reactions, loss of appetite, depression, diarrhea, dizziness, fever, muscle weakness, severe nausea or vomiting, swelling of feet or legs, and others).

According to the authors, the MSD (material safety data sheet) for quercetin in the rat for LD50 (dose that kills 50% of the animals) is 161 mg/kg of body weight. For a human of 70 kg, this would be equivalent to about 11,270 mg. The basic multinutrient formulation we both take daily contains in the recommended 12 capsules a day 128 mg of quercetin or nearly two orders of magnitude lower than the LD50 for rats.

Anti-inflammatory Effects of Benfotiamine Mediated By Regulation of Arachidonic Acid Pathway in Macrophages

As noted in the article (above), arachidonic acid stimulates the proliferation of prostate cancer cells through its metabolite HETE, produced by 5-lipoxygenase. Interestingly, a 2012 paper² reports that benfotiamine, a lipid soluble form of vitamin B1 (thiamine) inhibits the formation of arachidonic acid metabolites by preventing the LPS-induced metabolizing of arachidonic acid via 5-lipoxygenase and other arachidonic acid metabolizing enzymes such as COX-2 (cyclooxygenase 2), TXB (thromboxane) synthase, and PG12 (prostacyclin) synthase. Moreover, benfotiamine has been found to be a potent blocker of AGEs (advanced glycation end products) as well as antiinflammatory against LPS (lipopolysaccharide). “Bacterial lipopolysaccharide (LPS), the structural component of the Gram-negative bacterial outer cell wall, is a potent initiator of the inflammatory response during most commonly seen bacterial infections.”²

References

1. Patir et al. Quercetin as a prophylactic measure against high altitude cerebral edema. Free Radic Biol Med.53:659-68 (2012).
   2. Shoeb and Ramana. Anti-inflammatory effects of benfotiamine are mediated through the regulation of the arachidonic acid pathway in macrophages. Free Radic Biol Med.52:182-90 (2012).

UNDERSTANDING THE MECHANISM: WHY BLEEDING MIGHT BE BENEFICIAL IN OBESITY OR DIABETES

Going back even a couple hundred years, bleeding was a popular therapy for a wide variety of disorders, but the mechanism(s) was (were) not understood so that the likelihood of doing harm (recall the case of George Washington, for example) was probably in most cases greater than the likelihood of benefit. As reported in a paper in the latest issue of The Journal of Clinical Investigation,¹ “phlebotomy [bleeding] of humans with impaired glucose tolerance and ferritin values in the highest quartile of normal increased adiponectin and improved glucose tolerance. These findings demonstrate a causal role for iron as a risk factor for metabolic syndrome and a role of adipocytes in modulating metabolism through adiponectin in response to iron stores.”

Ferritin is the commonly used marker for total body iron stores. Phlebotomy improves blood glucose levels and aspects of the “metabolic syndrome” associated with obesity and diabetes (e.g., insulin resistance). The latter suggests that excess iron, which can be decreased by bleeding, may be a causal factor in these disorders.¹ The authors note that recent studies have found a negative correlation between serum ferritin and the insulin-sensitizing adipokine, adiponectin. Moreover, obesity and diabetes are associated with lower levels of adiponectin, with the latter being causally related to insulin resistance. “Studies in cell culture, mouse models, and humans demonstrate that iron plays a direct and causal role in determining adiponectin levels and diabetes risk.”¹

One of the findings of this paper was that mice on a high-iron diet had a significant decrease in their maximal glucose disposal rate per gram of lean tissue, indicating impaired glucose tolerance.

The researchers found that when ferroportin, an iron channel and exporter in adipocytes, was deleted (knocked out) in mice, they had increased adipocyte iron levels, decreased serum adiponectin, and increased insulin resistance. In the ferroportin knockout mice, there was an increased level of adipocyte iron accompanied with a 58% decrease in adipocyte adiponectin RNA, which was reflected in decreased serum adiponectin. The researchers also studied human subjects with impaired glucose tolerance that had serum ferritin levels in the highest quartile of the normal range. By about six months after phlebotomy, there was a fall in serum ferritin to the lowest quartile of normal, with the average blood donation being 3.7 units.

These findings suggest that frequent blood donations could help reduce the risk of diabetes and could even be therapeutic for those who already had the disease, although we do not know whether blood from diabetics taking drugs for their medical condition would be suitable for transfusion to normal subjects.

Another 2012 paper² reports finding similar results in an epidemiological study of 27,548 people (16,644 women mainly aged 35–65 years and 10,904 men mainly aged 40–65 years) as part of the multicentre European Prospective Investigation into Cancer and Nutrition (EPIC). High ferritin levels were associated with higher risk of type 2 diabetes independently of established diabetic risk factors and a range of diabetes biomarkers. The authors conclude that “[t]hese results support the hypothesis that higher iron stores below the level of haemochromatosis [iron overload disorder] are associated with risk of type 2 diabetes.” In order to reduce the possibility of including individuals with undiagnosed haemochromatosis, the researchers excluded subjects in whom serum ferritin was elevated beyond three times the SD (standard deviation) from the mean (25 women with ferritin over 37.3 mg/l, 21 men with ferritin over 100.0 mg/l).²

A third 2012 paper³ also reported an association between iron metabolism and adipocyte insulin resistance and plasma adiponectin, suggesting (per the authors) that “factors related to iron and iron metabolism may contribute to adipocyte IR [insulin resistance] early in the pathogenesis of T2DM [type 2 diabetes mellitus].”

References

1. Gabrielsen et al. Adipocyte iron regulates adiponectin and insulin sensitivity.Jnbsp;Clin Invest.122(10):3529-40 (2012). doi:10.1172/JCI144421.
2. Montonen et al. Body iron stores and risk of type 2 diabetes: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. 55:2613-21 (2012).
3. Wlazio et al. Iron metabolism is associated with adipocyte insulin resistance and plasma adiponectin: the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Diabetes Care.36(2):309-15 (2013 Feb).

MILD EXERCISE INCREASES DIHYDROTESTOSTERONE
EVIDENCE FOR ANDROGENIC MEDIATION OF NEUROGENESIS

A 2012 paper¹ reports that, in male animals, mild exercise enhances hippocampal synthesis of dihydrotestosterone and increases adult hippocampal neurogenesis as a result of androgenic action.

The paper begins its introduction by explaining that testosterone (T) and dihydrotestosterone (DHT) exert neuroprotective effect via androgen receptors in the hippocampus. Interestingly, current studies have shown that androgens can be synthesized in the hippocampus, not only be (as generally understood previously) androgen production in the testes and distribution to the brain by the bloodstream. Moreover, the beneficial effects of exercise on cognition and mood (such as results from mild exercise on wheel and treadmill running exercise) may be mediated by exercise-induced neurogenesis in adults. The authors developed a mild exercise using a treadmill that didn’t result in lactate production and produced minimal stress. They further showed that that amount of mild exercise was able to induce hippocampal neuronal activity and neurogenesis.¹

The researchers then examined the effects of 2 weeks of this mild exercise on androgen levels in hippocampus and adult hippocampal neurogenesis. They found that treatment with an androgen receptor antagonist resulted in suppression of the exercise-induced neurogenesis, indicating a causal involvement of androgens in the neurogenesis resulting from the mild exercise. The researchers discussing the results, speculated “[b]ecause the injection of testosterone has been shown to reduce deposits of beta-amyloid protein in vitro through the enhanced effects of neprilysin, it might be that mild exercise, in mediating paracrine effects through androgens and/or DHT [dihydrotestosterone] may, in turn, also reduce the deposits of beta-amyloid protein and protect cognitive functions.”¹

Reference

1. Okamoto et al. Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis. Proc Nat Acad Sci USA.109(32):13100-5 (2012).

NEW DISCOVERY OF CAUSE OF PANCREATIC BETA CELL
FAILURE IN DIABETES MAY POINT THE WAY TO A CURE

It has long been thought that the loss of insulin release by pancreatic beta cells in diabetes is the result of the death (apoptosis) of these cells. In a new paper,¹researchers have discovered that the reason the beta cells (in a FOXO1 knockout mouse model of diabetes) stopped producing insulin is not because the cells died but because they dedifferentiated to an earlier stage of development in which they cannot produce insulin. “Dedifferentiated beta cells reverted to progenitor-like cells expressing Neurogenin3, Oct4, Nanog, and L-Myc.”¹ These markers indicate that these beta cells are endocrine pre-beta cells.¹

The scientists studied FOXO1 immunoreactivity in beta cells of mice with insulin-resistance diabetes, including mice with mild fasting hyperglycemia and severe hyperglycemia. “As hyperglycemia increased, loss of FOXO1 immunoreactivity paralleled loss of insulin content. To determine whether the loss of FOXO1 was a cause or effect of the beta cell failure and what happened to the “missing” beta cells, e.g., did they die or what, the researchers then studied mice with the FOXO1 gene knocked out in their beta cells. They were surprised to find that the beta cells without FOXO1 stopped producing insulin but nearly all of the cells remained alive. “The findings indicate that ‘empty’ beta cells in IKO [knockout] mice are not degranulated beta cells, but represent a distinctive pre-beta cell differentiation stage.”¹

The authors point out, however: “While the metabolic abnormalities in mice with beta cell-specific FOXO1 specific knockout are not as marked as those seen in the other diabetic models, this might be due to compensatory increases in other FOXOs. Nevertheless, the impairment of beta cell mass and function caused by lack of FOXO1 is consistently observed in other models of diabetes.” “Importantly, we show that beta cell dedifferentiation is a regression to an endocrine progenitor-like stage rather than a degenerative stage.” “The model arising from our observations can help explain why decreases in beta cell mass occur slowly as a function of diabetes duration. It is consistent with and provides an explanation for the slow progression and temporary reversibility of beta cell dysfunction, vindicating the concept of ‘beta cell rest’ as a diabetes treatment.”

This mechanism (if reproduced) suggests that beta cell function might be restored in diabetes during a “window of opportunity” by redifferentiating the dedifferentiated beta cells, providing for a potential cure for diabetes. We offer our congratulations to the researchers who performed this work.

Reference

1. Talchai et al. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. 150:1223-34 (2012).

LDLR (LDL RECEPTOR) OVEREXPRESSION ENHANCES THE RATE OF AMYLOID BETA CLEARANCE

AMYLOID BETA CLEARANCE FROM THE BRAIN IN A MOUSE MODEL OF BETA-AMYLOIDOSIS

A new paper¹ reports that amyloid-beta is removed from the brain via apoE and that the apoE4 form, which is associated with an increased risk for Alzheimer’s disease as compared to other forms of apoE, exhibited the slowest rate of amyloid beta clearance from the brain as compared to the other forms of apoE. LDLR is known to play an important role in the periphery in mediating removal of cholesterol and cholesterol esters, but the authors note that little is known about its function in the brain. In this paper, the authors explain that recent work has identified LDLR as a major apoE receptor in the CNS that “profoundly affects the accumulation of amyloid beta.” In this new paper,¹ the authors found that LDLR regulates clearance from the brain of exogenously administered amyloid beta across the blood-brain barrier.

The researchers created a mouse that overexpresses LDLR in the setting of CNS expression of human amyloid beta and the PDAPP mouse model of beta-amyloidosis. “We found that LDLR overexpression in young PDAPP mice markedly decreases apoE and decreases amyloid beta deposition in aged PDAPP mice.”¹ They found, moreover, that LDLR overexpression significantly increased the appearance rate of endogenously produced human amyloid beta from brain to blood, suggesting, the authors stated, that this is a mechanism whereby LDLR regulates brain amyloid beta accumulation by eliminating it from brain to blood.

The researchers say, in their final paragraph, that LDLR has very few identified ligands for modulating the expression of LDLR and that affords an opportunity for discovery to identify innovative avenues for Alzheimer’s disease prevention and treatment.

Natural Products That Upregulate LDLR in the Periphery

Some natural products are known to upregulate LDLR in the periphery, thus acting as a mechanism to remove cholesterol from the circulation. That includes a green tea catechin extract that upregulates the LDLR in the rat liver,² Mulberry extracts that were shown to exhibit a hypolipidemic effect on liver cells,³ and the medicinal plant goldenseal that is a natural LDL-lowering agent.⁴ However, whether these peripheral forms of LDLR would also have an effect in the brain of removing amyloid beta was not discussed in these papers.

References

1. Castellano et al. Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Amyloid beta clearance in a mouse model of beta-amyloidosis. Proc Nat Acad Sci USA.109(38):15502-7 (2012).
2. Bursill and Roach. A green tea catechin extract upregulates the hepatic low-density lipoprotein receptor in rats. 42:621-7 (2007).
3. Liu et al. Effects of mulberry (Morus alba) extract on lipid homeostasis in vitro and in vivo. J Agric Food Chem.57:7605-11 (2009).
4. Abidi et al. The medicinal plant goldenseal is a natural LDL-lowering agent with multiple bioactive components and new action mechanisms. J Lipid Res.47:2134-47 (2006).

REVENGE OF THE FLY: THE RELATIONSHIP BETWEEN INTESTINAL HEALTH, AGING, AND DEATH

In setting the scene for the important health information that follows, please note: If you have recently entered a box looking like a weird telephone booth (but not a Tardis) and ended up with your head on a fly’s body (or, worse yet, your body with a fly’s head), the following health information may apply to you. On the other hand, even if you haven’t done anything remotely like this (and we certainly hope you haven’t), it still might apply to you. This silly introduction is just for fun, but the research is real.Note: If you have not seen the movie The Fly, skip the introductory paragraph below.

A new paper¹ in the December 26, 2012 Proceedings of the National Academy of Sciences USA reports that intestinal barrier dysfunction links metabolic and inflammatory markers to aging in Drosophila (“the fly”). Most remarkably, however, the paper provides evidence that “[r]egardless of chronological age, intestinal barrier dysfunction predicts impending death in individual flies.” “Thus, intestinal barrier dysfunction appears to be a better predictor of this marker of aging [increased expression of antimicrobial peptides, AMP] than chronological age.” Elie Metchnikoff, a very early investigator of the causes of aging, thought that intestinal health was an important factor in aging and recommended yogurt consumption.²

The researchers reported in an earlier paper of theirs that the loss of intestinal barrier function could be detected by the presence of a nonabsorbable blue food dye (FD&C blue dye no. 1) outside of the intestinal tract. As they¹ report, “[b]oth male and female flies showed a significant age-dependent increase in the number of flies exhibiting blue dye throughout the body after feeding.” The researchers named these blue flies Smurfs. Although the blue dye itself had no effect on mortality, “all flies in the population exhibited the Smurf phenotype before death.”¹ The presence of the blue dye throughout the body (indicating loss of intestinal barrier function) was found to be a predictor of age-onset mortality.

The authors found intestinal barrier dysfunction in Drosophila to be linked to a variety of markers of aging, including systemic metabolic dysfunction, increased expression of immunity-related genes, and reduced spontaneous physical activity.¹

The “revenge” of the fly, mentioned above, would be manifest if the blue dye experiments were replicated in humans with similar results. In the meantime, the authors report that several age-related changes take place in the intestinal epithelium of rodents, including barrier dysfunction. Defects in intestinal barrier function have been associated in humans with intestinal or extraintestinal inflammatory disorders, multiple sclerosis, chronic heart failure, cancer, and Parkinson’s disease, as well as being a common event in critically ill patients.¹ In a recent paper,³ researchers noted that increased intestinal permeability allowing the abnormal passage of substances from inside the intestines to enter the general circulation may be responsible for food allergies and even metabolic syndrome.

The researchers suggest that, on the basis of prior research, a key structure in maintaining the intestinal barrier is the tight junction lining the gut. In what the authors term a “leaky gut” dietary AGEs (advanced glycation endproducts) can enter the general circulation, where they induce inflammation³ and, hence, may contribute to diseases such as diabetes and cardiovascular disease. These authors suggest supplementation with the amino acid glutamine, which is an important nutrient for preventing increased intestinal permeability (four papers are cited in support), and possibly curcumin because of its effects in reducing colonic inflammation and experimental colitis in animal models.

Interestingly, “intestines from aged flies contain higher counts of indigenous bacteria than their younger counterparts and this has been reported to influence epithelium renewal during aging.”¹

References

1. Rera et al. Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila. Proc Nat Acad Sci USA.109(52):21528-33 (2012).
2. Elie Metchnikoff. The Prolongation of Life (G. P. Putnam’s Sons, 1908) We have an original copy of this book. They are available remarkably inexpensively from sellers of antiquarian books (or were as of several years ago) if you would like a copy yourself. It is also available from Amazon.com as a reprint.
3. Rapin and Wiernsperger. Possible links between intestinal permeability and food processing: a potential therapeutic niche for glutamine.65(6):635-43 (2010) This is an Open Access article. doi: 10.1590/S1807-59322010000600012

 IMPORTANT COURT DECISION

APPEALS COURT RULES THAT NLRB DID NOT HAVE QUORUM IN RECENT CASE AND HAD NO AUTHORITY TO ISSUE ORDER

PRESIDENTIAL APPOINTMENTS WERE UNCONSTITUTIONAL

THE DECISION

A very recent decision by a three-judge panel of the Court of Appeals for the DC District (Jan. 25, 2013) found that an order of the NLRB (Nat’l Labor Relations Board) was void because the Board did not have a quorum. This may sound like a minor matter, but in fact was a very important ruling on how Presidents can avoid getting the advice and consent of the Senate when making appointments by using a Constitutional alternative called Recess Appointments. The painstakingly argued decision of the Court revolved around whether the appointment of three new NLRB Board members conformed to Constitutional requirements for Recess appointments and, hence, did not need to get Senate approval. The Court ruled that these appointments were unconstitutional for convincing reasons we describe below and, hence, the NLRB order that was the proximate reason for the lawsuit was void. The NLRB was ruled not to have a quorum and, hence, had no authority to issue an order.

As you ought to know by now if you have been paying attention, Constitutional limits on government powers have been failing to limit government actions and much of the blame is the failure of courts to enforce these limits. The Constitutional design for the “checks and balances” to prevent usurpation by one branch of the powers delegated by the Constitution to another branch is in its provisions establishing the separation of powers. The requirement that Presidents get the advice and consent of the Senate to make appointments (to high level policymakers at regulatory agencies and cabinet secretaries, for example) is one of these checks and balances. The Constitution does provide for when the Senate is out of session (“The Recess”) and, hence, cannot provide advice and consent, that an appointment can be made unilaterally by the President.

The requirements for making these Recess appointments are spelled out in the Constitution. The Judges followed the Constitutional wording in great detail to show that the recent appointment of three members of the NLRB Board were not made between sessions of the Senate but within a session that was in a short break in Senate business during that session. The Constitutional language as cited in the court decision is very clear on this matter. As the court noted, “[t]he Framers emphasized that the recess appointment served only as a stopgap for times when the Senate was unable to provide advice and consent.” The court further explained that when the Constitution was written, senators did not have the luxury of catching the next flight to Washington so as to be available for considering appointments. Hence, “the Framers established the ‘auxiliary’ method of recess appointments. But they put strict limits on this method, requiring that the relevant vacancies happen during ‘The Recess.’”

The court continued, “[i]t would have made little sense to extend this ‘auxiliary’ method to any intrasession break, for the ‘auxiliary’ ability to make recess appointments could easily swallow the ‘general’ route of advice and consent. The President could simply wait until the Senate took an intrasession break to make appointments, and thus ‘advice and consent’ would hardly restrain his appointment choices at all.” Moreover, the court noted, in the case of Freytag v. Commissioner of Internal Revenue (501 U.S. 868, 883 (1991)), the court had explained that “[t]he manipulation of official appointments had long been one of the American revolutionary generation’s greatest grievances against executive power, because the power of appointment to offices was deemed the most insidious and powerful weapon of eighteenth century despotism.”

In arguing against an attorney general’s support for the use of a vague definition for the length of time required to be necessary for a “Recess” in an earlier case, the court noted that the Supreme Court has observed, “when interpreting ‘major features’ of the Constitution’s separation of powers, we must ‘establish[] high walls and clear distinctions because low walls and vague distinctions will not be judicially defensible in the heat of interbranch conflict.”

A final argument (we haven’t discussed them all) for a possible interpretation of “The Recess” as advocated by the government’s Office of Legal Counsel in this case, is that the President should have discretion to determine that the Senate is in recess. To which the court replied in part, “This will not do. Allowing the President to define the scope of his own appointments power would eviscerate the Constitution’s separation of powers.” We keep wondering when Chevron deference whereby courts simply accept without investigation the findings of regulatory agencies on the basis of their supposed superior technical knowledge, will be thrown out on the basis that there is no Constitutional authorization for freedom from court review of purported facts when you are accused of crimes and may be subject to a prison sentence. Deference is just another word for lazy. Courts don’t have to bother protecting the public from the lies of regulatory agencies if they just “defer.” But, back to the decision:

And finally the court concludes as to whether the Board had a quorum: “Because the Board lacked a quorum of three members when it issued its decision in this case on February 8, 2012, its decision must be vacated.” Most importantly, the court resets the standard for Presidential appointments back to the Constitutional one.

The decision was 46 pages long and argued very convincingly, in our view, in great detail with extensive consideration of the Constitutional language. It is about time some of the limits on Federal power are enforced.

THE AFTERMATH: NLRB RESPONDS TO THE DECISION

The NLRB requested an en banc hearing before the entire DC Circuit Court of Appeals and was turned down.

The NLRB has issued a statement concerning the above decision (see The Wall Street Journal editorial section, Jan. 29, 2013) that is consistent with the criminality running amok in the current Administration. The Board has declared, the WSJ reports, that “it doesn’t like the D.C. Circuit Court of Appeals Friday ruling that three board members were illegally appointed so it plans to ignore it.” (this is how their response is described by the Journal) The Board’s Chairman Mark Pearce is quoted as saying: The Board respectfully disagrees with today’s decision and believes that the President’s position in the matter will ultimately be upheld.” Moreover, he notes, “It should be noted that this order applies to only one specific case, Noel Canning, and that similar questions have been raised in more than a dozen cases pending in other courts of appeals. “In the meantime, the Board has important work to do. The parties who come to us seek and expect careful consideration and resolution of their cases, and for that reason, we will continue to perform our statutory duties and issue decisions.” Clearly, the NLRB plans to continue doing business as usual, as if nothing had happened, as if the Constitution doesn’t apply to them.* In fact, there are some 200 rulings issued by the NLRB, according to the WSJ, that took place during this period in which there was no quorum and, hence, no authority to issue orders. How can anybody still believe that we have a rule of law in this country? Or is the Administration counting on a lot of people who don’t give a damn as long as they get their government handout? This is a scary situation, folks.

* One of the lawyers that represented the FDA in the landmark case of Pearson v. Shalala was actually heard to say that he didn’t think the First Amendment applied to the FDA!

We applaud Tina Turner, thirty-year resident of Switzerland (but forced to continue paying U.S. income taxes despite that) for her courageous action in giving up her American citizenship. The Land of the Free and the Home of the Brave is one of the very few countries that continues to tax citizens that live and work outside of their borders. In fact, many countries have extradiction treaties so that the IRS can have you forcibly returned to the U.S. and imprisoned if you don’t keep paying despite not living in the U.S.

The opinions expressed in the editorial sections of this newsletter are those of Durk Pearson and Sandy Shaw and do not necessarily represent the views of Life Enhancement Products, its owners, officers, and its employees.

GERMANY WANTS THEIR GOLD BACK AND WHY THEY ARE UNLIKELY TO GET IT

The Germans sent auditors to the Federal Reserve of New York City in 2007 and again in 2011 and were refused the right to examine, let alone audit, their own gold. In 2011 they were allowed a glimpse of some gold and to weigh a few bars, but that was all. According to the latest deal with the Fed, Germany will be able to get their gold in 7 years (!).If the U.S. wanted another war with Germany (or, at least to risk retaliatory seizures of U.S. property in Germany) they are doing the “right” things to get it. The news as of this morning (Feb. 1, 2013) is that the Germans are becoming downright belligerent in demanding the return of their gold, about half of which is stored in the U.S. Federal Reserve building in New York, after earlier attempts to repatriate their gold—or even to see it—from the U.S. failed. The German Central Bank is required to count and weigh the gold it owns every year, but the German gold reserves kept in the U.S. have not been weighed or counted once in three decades.

If this sounds ominous, it also suggests that an audit should be immediately conducted of the U.S.’s store of gold supposedly under the Federal Reserve’s control.

The news has gotten around and stimulated similar demands. The Dutch, for example, have asked for an audit and full transparency. A question of concern is why it would take 7 years for Germany to get its gold. Keith Barron, a geologist and consultant responsible for one of the largest gold discoveries in 25 years, has been quoted in King World News: “I believe that most of the Western world’s gold, which is supposed to be in central bank vaults, has been leased out. Much of it is now in private hands in India, and what remains continues going East to China and other Asian vaults. So most of the Western gold has vanished from the vaults and it’s now just a book entry … Obviously the trust is breaking down in the system.”

The story concluded with a warning that we may be seeing the start of a run by other nations on central-bank (importantly including the Federal Reserve) stored gold. (The pie graph in the story showed the U.S.’s central bank as storing about one third of the world’s store of gold.)

The story suggests that the price of gold may skyrocket in response to a panic stemming from fears over where one’s gold has gone and how to get it back. The morale of this story is to hold your gold in your physical possession, not stored in the dungeons (er, vaults) of central banks.

The above is from a report of LewRockwell.com (written by Peter Krauth, Feb. 1, 2013)

REDUCING FEDERAL DEFICIT THE FEDERAL RESERVE WAY

The Jan. 31, 2013 Wall Street Journal reports that the Federal Reserve has announced (after their first policy meeting of 2013) that they plan to continue purchasing $85 billion a month of mortgage-backed and Treasury securities. Meanwhile, the fourth quarter of 2012 showed the economy contracting by 0.1%, despite the massive amounts of Federal Reserve funny money flooding the economy.

“Many Fed officials want the two sides [Republicans and Democrats] to come up with a plan that reduces federal budget deficits over several decades [!!], without pulling back so fast that it crushes economic growth.” As if economic growth is doing fine with the federal budget deficit as it is … One can easily see that a “plan” to reduce the deficit over several decades is a way of ensuring that it will never happen.

REJECTION OF “UNFAIR” OFFERS MAY NOT
REPRESENT A PREFERENCE FOR “FAIRNESS” (EQUALITY)

The ultimatum game has become a highly studied model for human behavior that has been widely interpreted to mean that humans prefer “fairness” (roughly close to a 50:50 division of money between the two players), so much so that they are willing to forego some money if the division deviates from a roughly 50:50 split.*

* The ultimatum game is an economic game played by two players. The proposer has a sum of money (supplied by the researchers) which he/she can divide as he/she chooses into two shares, one he/she proposes to keep while the other share is offered to the second player, the responder. If the responder accepts the offer, they split the money as agreed. If the responder rejects the offer as too low (or “unfair”), neither the proposer nor responder get to keep any of the money.

Now, a new paper¹ has appeared that comes to a different interpretation of the rejection of “unfair” offers that occur in the ultimatum game. The new interpretation involved running some other games with slightly different rules to see whether the results are consistent with the view that the ultimatum game supports a strong reciprocity model of cooperation where individuals punish noncooperators (those who keep an “unfairly” large share of the money for themselves), even though it means giving up the share offered to them (less than 50% of the divided sum of money).

As the authors explain, “a strong reciprocator is defined as an individual who is willing to ‘sacrifice resources for rewarding fair and punishing unfair behavior EVEN IF THIS IS COSTLY [TO THEM] AND PROVIDES NEITHER PRESENT NOR FUTURE MATERIAL REWARDS FOR THE RECIPROCATOR.” “In other words, strong reciprocators reciprocate both positively AND negatively — positive reciprocity promotes cooperation, and negative reciprocity stabilizes it.”¹ “The rejection of unfair offers that is frequently observed in UG [ultimatum game] experiments has been regarded as evidence of strong reciprocity that is driven by a preference for reciprocal fairness and inequity aversion on the part of the responder.”¹

The researchers tested this hypothesis by comparing the results of the UG to other social preference games. For example, the impunity game is similar to the UG, but a responder who rejects an offer as “unfair” gets to keep no part of the offered split (eg., the responder gets $0 if he/she rejects the offer as unfair, same as in the UG) but the proposer gets to keep the entire amount of money he proposed as his/her share. The decision of the responder has no effect on how much money the proposer gets, unlike in the UG, where the rejection of the offer as unfair by the responder means that neither the responder nor the proposer get anything. Yet, responders in the impunity game still rejected 30–40% of the “unfair” offers (about half of the responders reject offers in which they would receive less than 30% of the total sum). This is not consistent with the usual interpretation that the rejection of “unfair” offers represents a form of negative reciprocity, since rejection of the “unfair” offer does not “punish” the proposer who makes the “unfair” offer. The responder loses by rejecting a possible share of the divided money but gets no reward by punishing the proposer.

Instead, the researchers propose that the rejection of unfair offers in the ultimatum game is the responder’s way of rejecting the imposition of an inferior status or a “wounded pride hypothesis” as it has been described in an earlier paper.

We note that the proposed interpretation may or may not be the correct one, but there can be no doubt that the widely held belief that the rejection of “unfair” offers represents a form of strong reciprocity cannot be correct.

Perhaps what is needed is a game designed to test whether the rejection of “unfair” offers represents a negative emotional response to reduced status. How about a game with the same rules as the ultimatum game and when the offer is accepted, both parties get their agreed upon split, but the proposer has to pay a “tax” of 15% to a third party, while the responder has to pay a “tax” of 5% to that third party. The offer began as a “fair” offer (since it was accepted by both proposer and responder), but does it remain “fair” with the split altered by the imposed (and unequal) taxes? Could a new rule of the game be added to allow the proposer and responder an option to “punish” the tax collector that would restore “fairness” to the arrangement?

Reference

1. Yamagishi et al. Rejection of unfair offers in the ultimatum game is no evidence of strong reciprocity. Proc Nat Acad Sci USA. 109(50):20364-8 (2012).

APPETIZERS

The main difference for the history of the world if I had been shot rather than Kennedy is that Onassis probably wouldn’t have married Mrs. Khrushchev.

— Nikita Khrushchev

After The Wizard of Oz I was typecast as a lion, and there aren’t all that many parts for lions.

— Bert Lahr

A lady came up to me on the street and pointed at my suede jacket. “You know a cow was murdered for that jacket?” she sneered. I replied in a psychotic tone, “I didn’t know there were any witnesses. Now I’ll have to kill you, too.”

— Jake Johannsen

Never go to a doctor whose office plants have died.

— Erma Bombeck

How small of all that human hearts endure That part which laws or kings can cause or cure!

— Samuel Johnson

FEELING BURNED OUT?

REDUCED SENSITIVITY TO GLUCOCORTICOID FEEDBACK REGULATION OF INFLAMMATORY CYTOKINES IN VITALLY EXHAUSTED MEN

In our article on leptin and increased body fat (Durk & Sandy Life Extension Newsletter,Oct. 2012), we noted that leptin, a negative feedback adiposity signal, is less effective in the presence of inflammatory conditions.A One source of inflammation is stress.^1,2Researchers found that male industrial employees suffering from vital exhaustion (a combination of unusual fatigue, loss of energy, and irritability) have high levels of inflammatory cytokines such as IL-1beta, TNF-alpha, IL-6, and C-reactive protein (CRP).¹ In another study,² researchers reported that daily social interactions that are negative and competitive are associated with increased proinflammatory cytokine activity. Under these inflammatory conditions, one would expect leptin signaling to be impaired, resulting in weight gain and reduced satiety.

The authors of the paper on vital exhaustion in men¹ report that the increased inflammatory responses of activated monocytes are generally normalized by glucocorticoid feedback regulation, but there is a reduced release of endogenous cortisol in individuals with vital exhaustion. Hence, these individuals, because of inadequate glucorticoids, do not adequately downregulate inflammatory responses and, thus, have increased plasma levels of inflammatory cytokines, such as those listed in the paragraph just above. As the authors of paper #1 explained, “… more dexamethasone [a glucocorticoid] was required to suppress IL-6 release in response to the same LPS stimulus in highly exhausted subjects as compared with nonexhausted individuals.” Inadequate shutting down of monocyte release of proinflammatory cytokines in response to LPS (lipopolysaccharide, a bacterial cell wall component that strongly stimulates immune system activation) can result in a chronic inflammatory state such as is associated with obesity and an increased risk of cardio­vascular disease.

CONSUMPTION OF HYDROGEN (IN WATER) PREVENTS STRESS-INDUCED IMPAIRMENTS IN HIPPOCAMPUS-DEPENDENT LEARNING IN MICE

We continue our Hydrogen Therapy Series here with a paper that found protection by hydrogen against stress-induced learning impairments in mice.

A recent paper³ reports that mice subjected to 4 to 8 weeks of chronic physical restraint stress had a variety of cognitive impairments and significantly increased oxidative stress in the brain, which is a known inducer of inflammation. Consistently with increased inflammation, there was a decline in the proliferation of neural progenitors (neurogenesis) in the stressed mice.

Treating the stressed mice with hydrogen-saturated water was able to restore neurogenesis and improve their performance in passive avoidance learning, novel recognition test, and in the Morris Water Maize test (where the mice have to find a hidden platform in a tank of water to avoid having to continually tread water).

Supplementation with long chain oligosaccharides (a form of inulin) is one way to provide a food that humans cannot digest for consumption by resident bacteria in the lower intestine that they can use to produce hydrogen. Data indicate that hydrogen is produced and released over a longer period of time than when hydrogen is ingested in water or saline or when hydrogen is inhaled as a gas. Some of the hydrogen is consumed by other resident bacteria, but most diffuses out of the lower intestine and throughout the body, passing through the blood-brain barrier and even reaching into mitochondria, before being exhaled out from the lungs.

We are particularly impressed by the ability of hydrogen to reach into cellular compartments (especially mitochondria, subject to considerable oxidative stress) that many antioxidants are unable to do. Many other supplements have been reported to have potent antiinflammatory effects, though not necessarily including data on the ability to pass into mitochondria; a few examples are foods such as fruits,⁴ berries,⁴ whole grains,⁴ and fatty fish,⁴ as well as nutrients such as choline⁵ and betaine,⁵ and herb/spice constituents including curcumin,⁶ epigallocatechin gallate (EGCG),⁷ and cinnamon.⁸

References

1. Chen et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med. 12(4):425 (2006).
   1. Wirtz et al. Reduced glucorticoid sensitivity of monocyte interleukin-6 production in male industrial employees who are vitally exhausted. Psychosomatic Medicine.65:672-8 (2003).
   2. Chiang et al. Negative and competitive social interactions are related to heightened proinflammatory cytokine activity.Proc Natl Acad Sci USA. 109(6):1878-82 (2012).
   3. Nagata et al. Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice. Neuropsychopharmacology. 34:501-8 (2009).
   4. Wu and Schauss. Mitigation of inflammation with foods. J Agric Food Chem. 60:6703-17 (2012).
   5. Detopoulou et al. Dietary choline and betaine intakes in relation to concentration of inflammatory markers in healthy adults: the ATTICA study. Am J Clin Nutr. 87:424-30 (2008).
   6. Shehzad et al. New mechanisms and the anti-inflammatory riule of curcumin in obesity and obesity-related metabolic diseases. Eur J Nutr. 50:151-61 (2011).
   7. Kumaran et al. Attenuation of the inflammatory changes and lipid anomalies by epigallocatechin-3-gallate in hypercholesterolemic diet fed aged rats. Exp Gerontol.44:745-51 (2009).
   8. Kim et al. Suppression of age-related inflammatory NF-kappaB activation by cinnamaldehyde. Biogerontology. 8:545-54 (2007).

RESTORATION OF GLUCOCORTICOID SENSITIVITY TO DOWNREGULATION OF MONOCYTE RELEASE OF PRO-INFLAMMATORY CYTOKINES IN PATIENTS WITH COPD AND ASTHMA

As explained above, in vitally exhausted men, monocytes are insensitive to glucorticoid-induced downregulation of proinflammatory cytokine secretion. Interestingly, histone deacetylase-2 (HDAC2), “a critical component of corticosteroid anti-inflammatory action, is impaired in lungs of patients with COPD and correlates with disease severity.”⁹ “… curcumin acts at a post-translational level by maintaining both HDAC2 activity and expression, thereby reversing steroid insensitivity by either CSE [cigarette smoke extract] or oxidative stress in monocytes. Curcumin may therefore have potential to reverse steroid resistance, which is common in patients with COPD and asthma.”⁹ The similarity of this mechanism to the glucorticoid insensitivity to suppressing proinflammatory cytokine release in monocytes of men with vital exhaustion hints (but does not prove) that HDAC2 may be involved in the glucocorticoid insensitivity that was found in vital exhaustion and, therefore, curcumin may be able to restore glucocorticoid sensitivity in that disorder as was found in COPD patients.

Another activator of HDAC2 is sulforaphane (found in cruciferous vegetables, such as broccoli). It has been reported to reactivate HDAC2 in alveolar macrophages via activation of Nrf2 (a major regulator of antioxidant genes) and thus restore sensitivity to corticosteroid downregulation of proinflammatory cytokine release.¹⁰

Another paper¹¹ reports that “[l]ow subbronchodilator doses of theophylline can also act as corticosteroid-sparing drugs in asthmatics.” The authors note that although curcumin and low-dose theophylline “appear to restore corticosteroid [antiinflamatory] function and may initially provide therapeutic potential, they lack specificity [e.g., they affect other chemical pathways] and the mechanism of their action is unknown.”

9. Mela et al. Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol. 39(3):312-23 (2008).
   10. Malhotra et al. Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticoid sensitivity in macrophages from COPD patients. J Clin Invest. 121:4289-302 (2011).
   11. Marwick et al. Oxidative stress and steroid resistance in asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy. Expert Opin Ther Targets.11(6):745-55 (2007).

ACUTE PSYCHOLOGICAL STRESS IN MEN: HIGHER BODY MASS INDEX ASSOCIATED WITH REDUCED GLUCOCORTICOID INHIBITION OF INFLAMMATORY CYTOKINES

“Our data suggest that with increasing BMI, glucocorticoids are less able to inhibit TNF-alpha [tumor necrosis factor-alpha, a proinflammatory cytokine] production following stress. This might suggest a new mechanism linking BMI with elevated risk for adverse cardiovascular outcomes following stress.”¹²

A recent paper reports on reduced ability of glucocorticoid feedback signaling to inhibit inflammation (as assessed by monocyte TNF-alpha production) following experimental stresses (the Trier Social Stress Test, which is a combination of a mock job interview and mental arithmetic task) in 42 male subjects aged 21-65.¹² This is a lot less stress than vital exhaustion (as discussed above), but the decrease in glucocorticoid feedback signaling against inflammation (as indicated by reduction of monocyte TNF-alpha production) was similar. Although increased BMI was associated with reduced effectiveness of glucocorticoid suppression of TNF-alpha production under conditions of stress, baseline gluco­corticoid sensitivity was not associated with BMI.¹² “… mental stress might increase cardiovascular risk in overweight persons by lowering the capacity of GCs [glucocorticoids] to down-regulate monocyte cytokine release.”¹² A likely mechanism is leptin resistance, which, as noted above, is increased under proinflammatory conditions and also in obesity, which would link inflammation with increased adiposity and BMI. However, leptin was not discussed in this paper.¹²

12. Wirtz et al. Higher body mass index (BMI) is associated with reduced gluco­corticoid inhibition of inflammatory cytokine production following acute psychosocial stress in men. Psychoneuroendocrinology. 33:1102-10 (2008).

To trace something unknown back to something known is alleviating, soothing, gratifying, and gives moreover a feeling of power. Danger, disquiet, anxiety attend the unknown —the first instinct is to eliminate these distressing states. First principle: any explanation is better than none … The cause-creating drive is thus conditioned and excited by the feeling of fear.

— Friedrich Nietzsche

ANTHOCYANINS TO PREVENT OBESITY AND DIABETES ANTHOCYANINS ENHANCE SECRETION OF THE ADIPOCYTOKINES LEPTIN AND ADIPONECTIN WITHOUT ACTIVATING PPARGAMMA-INDUCED LIPOGENESIS

Thiazolidinedione drugs used to treat diabetes (example: pioglitazone) are powerful activators of PPARgamma, which can potently increase insulin sensitivity, but unfortunately also activate PPARgamma target genes that increase lipogenesis (fat synthesis), thereby inducing weight gain as an undesirable side effect. A 2004 paper¹reported that anthocyanins (colored molecules such as cyanidin or cyanidin 3-glucoside found in blueberries and many other blue or purple fruits and vegetables but not beets) are able to increase the release of adipocytokines (specifically adiponectin and leptin) from rat adipocytes (fat cells) that enhance insulin sensitivity without activating PPARgamma induced lipogenesis, by a mechanism that may be different from that of thiazolidinediones. As the authors summarize: “[t]hese data suggest that anthocyanins have a potency of unique therapeutic advantage and also have important implications for preventing obesity and diabetes.”¹

The researchers also report that in another study, the gene expression of adiponectin was upregulated in white adipose tissue in mice fed an anthocyanin supplemented diet. As we mentioned in the article just above, leptin acts as a signal that reduces food intake and increases energy expenditure. In an earlier study,² some of the same researchers that published paper #1 found that purple corn color, enriched with the anthocyanin cyanidin 3-O-beta-D-glucoside, prevented obesity and ameliorated hyperglycemia in mice fed a high fat diet. In that paper, the scientists also reported that dietary anthocyanin normalized hypertrophy of the adipocytes in the epididymal white adipose tissues. Hypertrophy of adipocytes, an increase in the size of fat cells, results in larger, more insulin resistant cells.

Anthocyanins Effective at Nanomolar Quantities

In a different paper,³ scientists found that anthocyanins were protective against oxidative stress induced by high doses of glucose in pancreatic mouse beta-cells despite their very low bioavailability because they are bioactive at NANOMOLAR quantities. Thus, very small amounts were required and could be effective intracellularly even at their low bioavailability. “Mouse pancreatic beta-cells (TC-3) were treated with chokeberry anthocyanins [chokeberries are purple/dark blue colored like blueberries or bilberries] at concentrations between 0 and 3 nM, expressed as cyanidin 3-galactoside. … the viability and proliferation of TC-3 cells is stimulated by all tested anthocyanin concentrations.” “Our data shows that the oxidative stress induced by 100 mM glucose determined a significant decrease (50%) of GSH [glutathione]. The intracellular GSH level increased significantly (25%) in cells preincubated with 0.2 nM chokeberry anthocyanins compared to glucose (100 mM) treated cells, but remain under the normal GSH levels in untreated pancreatic beta-cells. The GSH level in cells treated with the highest concentration of chokeberry anthocyanins (1.0 nM) and 100 mM glucose was restored, being even HIGHER than for untreated cells.”³ (emphasis added)

These protective effects of chokeberry anthocyanins at such low concentrations are remarkable and, although this paper did not report changes induced by the anthocyanins in inflammatory cytokines, oxidative stress induced by high levels of glucose is known to be associated with increased inflammation. Hence, anthocyanins would likely have anti-diabetic effects, as has been reported in other studies (cited in paper #3).

In paper #1, the researchers explain that “[a]nthocyanins are the largest group of water-soluble pigments in the plant kingdom. They are widely distributed in the human diet through crops, beans, fruits, vegetables, and red wine, suggesting that we ingest significant amounts of anthocyanins from plant-based daily diets.” The authors reported that in four of their earlier papers (citations provided in paper #1), they showed that in addition to antioxidant properties, cyanidin 3-O-beta-D-glucoside, a typical anthocyanin, also had anti-inflammatory properties based on in vitro and in vivo studies.

References

1. Tsuda et al. Anthocyanin enhances adipocytokine secretion and adipocyte-specific gene expression in isolated rat adipocytes. Biochem Biophys Res Commun. 316:149-157 (2004).
   2. Tsuda et al. Dietary cyanidin 3-O-beta-D-glucoside-rich purple corn color prevents obesity and ameliorates hyperglycemia in mice. J Nutr.133:2125-30 (2003).
   3. Rugina et al. Protective effect of chokeberry anthocyanin-rich fraction at nanomolar concentrations against oxidative stress induced by high doses of glucose in pancreatic beta-cells. Bul UASVM, Vet Med. 68(1):313-9 (2011).

CHRONIC INFLAMMATION AND SUPEROXIDE RADICALS PRODUCED BY NADPH OXIDASE ARE REPORTED TO BE THE MAIN DETERMINANTS OF PHYSICAL FRAILTY IN OLDER ADULTS

A new study¹ reports that physical frailty (assessed on the basis of gait speed) in 280 ambulatory elderly (over 60 years of age) is associated with superoxide anion overproduction by NADPH oxidase and low-grade chronic inflammation.

In the studied group, 64% of patients had a walking speed less than 0.8 meter/second. The higher prevalence of slow walkers in the subjects studied here as compared to some other studies is, the authors explain, probably due to the fact that 37% of the subjects were more than 83 years old. “Our group had already shown that inflammation and oxidative stress are linked in older people by reciprocal activations. Indeed, inflammation is accompanied by activation of NADPH oxidase, particularly through TNF-alpha, leading to overproduction of superoxide anion in stressful situations.”¹

References

1. Baptista et al. Low-grade chronic inflammation and superoxide anion production by NADPH oxidase are the main determinants of physical frailty in older adults. Free Radic Res.46(9):1108-14 (2012).

PROCYANIDINS FROM GRAPES SHOWN TO BE INHIBITORS OF HUMAN ENDOTHELIAL NADPH OXIDASE

A very useful new paper² reports that procyanidin-rich grape pomace, a commonly available by-product of the wine industry processing of grapes, was found to be a natural inhibitor of NADPH oxidase.

As explained by the authors,² NADPH oxidase expression and superoxide anion production were shown to correlate with the severity of atherosclerosis, plaque stability, oxidative stress in coronary artery disease, and plasma metalloproteinase-9 levels, suggesting that NADPH oxidase could be a target for reducing the risk of atherosclerosis. The authors, however, state that there are no inhibitors of this enzyme that can be used in therapeutics, nor are there any specific inhibitors of the enzyme isoforms. Thus, the researchers initiated this study hoping to identify a safe, natural inhibitor of NADPH oxidase; they focused on three different procyanidin-rich fractions from an aqueous extract of grape pomace that included skin, seeds, and a small number of stems. These were compared to the effects of two known NADPH oxidase inhibitors diphenylene iodonium (DPI) and apocynin.

Interestingly, there was a differential effect of the grape procyanidin-rich fractions on NADPH oxidase and on superoxide anion, in that the F4, F5, and F6 procyanidin fractions (10–100 ng/ml) inhibited NADPH oxidase activity in a concentration-dependent manner, yet only the highest concentrations of these fractions were effective as superoxide scavengers. Thus, the effects as superoxide scavengers and as inhibitors of NADPH oxidase were independent effects.

In addition, the researchers found that the three grape pomace procyanidin fractions were effective inhibitors of NADPH oxidase in living HUVEC (human umbilical vein endothelial cells), being active at both the extra- and intracellular level.

The authors claim that “[t]he NADPH oxidase inhibition activity described in our work for procyanidins from grape pomace has not been reported before, despite the inhibitor activity on this oxidase having been described for other components of grapes.” They cite, for example, a study in which polyphenols from grape extracts reduced NADPH oxidase subunit expression in human neutrophil mononuclear cells and in an endothelial cell line.

We are delighted that grape procyanidins were effective as NADPH oxidase inhibitors, as we have been on the lookout for a safe, effective and potent natural inhibitor of this enzyme for some time. The enzyme is hyperactive in the production of oxidative stress associated with many serious conditions, including cardiovascular disease and diabetes, and NADPH oxidase is the major source of superoxide anions in the vasculature.²

2. Alvarez et al. Procyanidins from grape pomace are suitable inhibitors of human endothelial NADPH oxidase.J Cell Biochem.

THE HYDROGEN THERAPY SERIES CONTINUED MEASUREMENT OF HYDROGEN GAS EMITTED FROM THE SKIN DURING INHALATION OF HYDROGEN-RICH AIR

As we have mentioned, after the production of hydrogen in the lower intestinal tract by resident microbes, the hydrogen diffuses throughout the body and is exhaled from the lungs. But the gas also leaves the body by being released from the skin, as discussed in a paper¹ presented in a poster session on May 15, 2011 at a scientific c-onference held at the Colorado Convention Center. The researchers propose that the measurement of this skin-emitted hydrogen is a convenient way to monitor the increase and then decrease of hydrogen following the inhalation of hydrogen gas. The “skin gases were obtained from perfusion gas passing through a chamber covered by the palm and the forearm skin gas in a Tedlar bag.”¹ This would also appear to be a useful way to monitor hydrogen gas production by the resident microbiota in the lower digestive tract.

The poster reported that “[t]o reach the equilibrium levels of skin H2 during H2inhalation, at least 30 min. was needed, whereas the skin H2 rapidly decreased after the cessation of H2 inhalation and recovered to the baseline level within 10 to 20 min.” The production by resident microbiota of hydrogen gas by processing of a meal containing indigestible carbohydrates that reach the lower digestive tract can result in increasing hydrogen gas for hours before decreasing to baseline levels. The ability to monitor this increase and the following decrease by skin-emitted hydrogen could be very convenient and likely to be relatively inexpensive. The hydrogen flow through the skin would also provide significant protection against exposure to the skin of environmental substances that increase oxidative stress and inflammation (particularly when it involves hydroxyl radicals and peroxynitrite) such as radiation, ultraviolet light, or ozone.

References

1. Shimouchi and Nose. Changes in Hydrogen Gas Release from the Skin During Inhalation of Hydrogen-rich Air. Am J Respir Crit Care Med.183:A1682 (2011).

HYDROGEN AND RADIATION PROTECTION

A new paper,² published Sept. 2012, reports (“for the first time”) the protective effect of hydrogen gas in irradiated cells and in mice. “A randomised, placebo-controlled investigation also showed consumption of H2 can improve the quality of life of patients treated with radiotherapy for liver tumours. These encouraging results suggested that H2 has a potential as a radioprotective agent with efficacy and non-toxicity.”

The researchers note that, as we have mentioned before, hydroxyl radical is the determinant species for reactions with biological molecules. “It was estimated that 60–70% of the IR [irradiation]-induced cellular damage was caused by hydroxyl radical.”² “Studies in the late damages in cardiac myocyte and pulmonary alveoli showed pretreatment of H2 significantly suppressed the radiation-induced fibrosis.”² For survivors of cancers treated with radiotherapy, late appearing damage can show up years or even decades after the radiation treatment, with serious life-shortening effects such as accelerated atherosclerosis or fibrosis. Hence, hydrogen could be a useful method of reducing these late effects.

2. Chuai et al. Molecular hydrogen and radiation protection. Free Radic Res.46(9):1061-7 (2012).

HEPATIC OXIDOREDUCTION-RELATED GENES ARE UPREGULATED IN RATS BY HYDROGEN-SATURATED DRINKING WATER

This recent paper³ reports on an experiment in which rats drank hydrogen-saturated water for four weeks and resulting gene changes in the liver were studied with DNA microarrays. “Our major finding in the present study was that drinking of hydrogen water altered the hepatic gene expression profile. Taken together with previous studies, the hepatic oxidoreduction-related gene uprregulation observed in this study appears to confirm the findings reported to date concerning the antioxidant effect of hydrogen water.”

Interestingly, the researchers observed upregulation of genes for cholesterol biosynthesis. However, they also observed that primary bile acid synthesis pathway and steroid hormone biosynthesis pathway-related genes such as Cyp27A1, Cyp3A2, and Hsd17b6 were upregulated in the hydrogen water-drinking group.

This suggests, they propose, that pathways of cholesterol catabolism (disposal) were promoted by the hydrogen water, which resulted (as a compensatory effect) in upregulation of the genes for cholesterol synthesis to normalize levels of cholesterol.

Another result was the decrease of liver TBARS (a measure of lipid peroxidation) detected by DNA microarray analysis, indicating reduction of oxidative stress by hydrogen water.

3. Nakai et al. Hepatic oxidoreduction-related genes are upregulated by administration of hydrogen-saturated drinking water. Biosci Biotechnol Biochem.75(4):774-6 (2011).

MEDIUM CHAIN TRIGLYCERIDES
WASH ’EM DOWN WITH NIACIN

Coconut Oil Increases Tomato Carotenoid Uptake as Compared to Safflower Oil in Mongolian Gerbils Fed Whole Tomato Powder

A new study¹ reports beneficial effects in accumulating carotenoids from a “salad” of powdered tomatoes for Mongolian gerbils eating a diet of 10% whole tomato powder along with a 20% safflower oil diet or an 18% coconut oil plus a 2% safflower oil diet (the latter was added to prevent essential fatty acid deficiency). The authors report that Mongolian gerbils are a good rodent model for humans ingesting tomatoes as “the lipoprotein profiles of the gerbil are more similar to humans than most other rodents, making carotenoid metabolism findings more relevant than those results in other species.” In addition, gerbils are reported to accumulate tomato carotenoids in levels proportionate to humans.¹ Coconut oil is a good source of medium chain triglyceride fats, while safflower oil is the most commonly used vegetable oil in commercial salad dressings. The purpose of the study was to determine how the coconut oil plus low-dose safflower oil compared to the high-safflower oil for the tissue uptake of carotenoids from the powdered tomatoes. The authors note that recent studies have suggested that the combination of carotenoids derived from whole tomato powder may be more effective in disease prevention than lycopene alone.¹ Tomatoes are known to contain the carotenoids phytoene, phytfluene, alpha-carotene, Z-carotene, and beta-carotene, as well as lycopene and lutein.

The results showed that “the coconut oil feeding resulted in significantly increased tomato carotenoid bioaccumulation compared to safflower oil in all tissues measured except the spleen and skin. Increased tissue accumulation may have been a result of increased solubility of tomato carotenoids in the intestinal lumen, portal absorption of medium-chain fatty acids, a cholesterol-mediated change in the flux of carotenoids between the liver and peripheral tissues, facilitated carotenoid cellular uptake by specific fatty acids, or the combination of the four.”¹

Also observed was that serum cholesterol in the coconut-oil fed animals was significantly higher than that of the safflower-fed animals. The safflower oil-fed gerbils, however, had significantly higher liver cholesterol than the coconut-oil fed animals. These findings are consistent with what is known of the fatty acid content of these oils. You can avoid the increase in serum or liver cholesterol levels by not adding vegetable oils at all to your salad or using a smaller quantity than fed to the gerbils, but then you might absorb smaller amounts of the carotenoids than the gerbils did in this study. We get around this by both using smaller amounts of oil and eating larger amounts of carotenoid containing veggies (as well as taking supplements that contain particular carotenoids of interest, such as lycopene, lutein, zeaxanthin, and astaxanthin). And, of course, we both take niacin.

Keeping Cholesterol Under Control with Niacin

Another solution to high cholesterol levels that doesn’t require you to meddle with your salad is niacin and, as we explain below, the mechanism(s) responsible for the remarkable effectiveness if niacin in lowering LDL and increasing HDL is, despite decades of research, still unknown.

Durk’s Familial Hypercholesterolemia Succumbs to Niacin

We both take niacin on a daily basis, but it has been even more important for Durk who, before finding out about niacin quite a few years ago, had always had a problem with hypercholesterolemia, which ran in his family.

But How Does Niacin Work?

The mystery of how niacin works is under intensive investigation (even by pharmaceutical companies, hoping to find out mechanisms that it can use to design patentable drugs for the treatment of hypercholesterolemia in the many patients who are not treated effectively by statin drugs). Yet, as the years go by, one mechanism after another that is thought to explain how niacin works ends up explaining something but not how niacin works. A paper published two months ago² explains that the GPR109A receptor that is activated by niacin (the “niacin receptor”) and was thought to be the reason for niacin’s decrease in triglycerides and LDL cholesterol and the increase in HDL cholesterol was found to be responsible for niacin’s antilipolytic effect but not for it’s effects on triglycerides or LDL or HDL. Hence, as reported in a commentary on the new niacin GPR109A findings,³ “[b]ecause the increase in HDL-C is regarded as the most important beneficial effect of nicotinic acid [niacin], the finding that it does not involve GPR109A questions the rationale for the development of synthetic GRP109A agonists; accordingly, most drug companies have stopped their GPR109A agonist programs.” However, the commentary also explains that there is reason to believe that the “increases in HDL-C may not be responsible for the long-term effects of nicotinic acid on the development of cardiovascular diseases.”

As the commentary explains, nicotinic acid has anti-inflammatory effects which do not involve GPR109A and has been shown to release adiponectin, the antiinflammatory cytokine released by fat cells. Moreover, the paper² that was the subject of the commentary found that most effects of niacin on plasma lipid levels are not mediated by the GPR109A receptor. New data, the commentary³ suggests, points to the possibility that GPR109A may be of use in the treatment of diseases involving inflammation and immunological processes.

The niacin mystery lingers, tantalizingly. The title of the commentary paper,³appropriately points out “It Ain’t Over ’Til the Fat Lady Sings.”

References

1. Conlon et al. Coconut oil enhances tomato carotenoid tissue accumulation compared to safflower oil in the mongolian gerbil. J. Agric. Food Chem.60:8386-94 (2012).
   2. Lauring et al. Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression. ­www.ScienceTranslationalMedicine.org4(148):148ra115 (22 Aug. 2012).
   3. Offermanns. It Ain’t Over ’Til the Fat Lady Sings. ­www.ScienceTranslationalMedicine.org4(148):148fs30 (22 Aug. 2012).

Transported to a surreal landscape, a young girl kills the first woman she meets and then teams up with three complete strangers to kill again. 
— Marin County (Calif.) newspaper’s TV listing for The Wizard of Oz

WHY WE RECOMMEND
SUPPLEMENTATION WITH L-ARGININE
(AND ALSO HISTIDINE)

Serum Levels of Histidine and Arginine Significantly
Lower in Obese as Compared to Non-Obese Women:
These Amino Acids Are Negatively Associated
With Inflammation and Oxidative Stress in Obese Women

A recent paper¹ reports that, in a study of 235 obese women compared to 217 non-obese women controls, six amino acids (but especially histidine and arginine) were found to be significantly lower in the obese women. Importantly, both histidine and arginine were negatively associated with inflammation and oxidative stress in the obese women, while in the non-obese controls, histidine was negatively associated with oxidative stress.

We both take histidine (250 mg. three or four times a day) as an ingredient in a formulation we designed for reducing the formation of AGEs (advanced glycation endproducts).^2,3 Inhibiting the formation of AGEs is a mechanism which we consider a very likely part of histidine’s anti-inflammatory and anti-oxidative stress effects. We also take arginine, 6–12 grams/day. Arginine can also provide protection against inflammation and oxidative stress via its conversion to nitric oxide, a critical factor in regulating vasodilation and blood pressure,⁴ as well as protecting against AGE formation.⁵

References

1. Niu et al. Histidine and arginine are associated with inflammation and oxidative stress in obese women. Brit J Nutr.108:57-61 (2012).
   2. Lee et al. Histidine and carnosine dellay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur J Pharmacol.513:145-50 (2005).
   3. Hobart et al. Anti-crosslinking properties of carnosine: significance of histidine. Life Sci.75:1379-89 (2004).
   4. Giugliano et al. Vascular effects of acute hyperglycemia in humans are reversed by L-arginine: evidence for reduced availability of nitric oxide during hyperglycemia. Circulation. 95:1783-90 (1997).
   5. Radner et al. L-arginine reduces kidney collagen accumulation and N-epsilon-(carboxymethyl)lysine in the aging NMRI-mouse. J Gerontol. 49(2):M44-6 (1994).

LOW PLASMA LEVELS OF L-ARGININE IN PATIENTS WITH MAJOR DEPRESSION

This recent paper⁶ reports on an investigation of the mechanisms that might explain why major depression (MD) is an independent cardiovascular risk factor. It was a small study involving 19 subjects with MD (34 ± 4 years) and 19 control subjects (34 ± 3 years). The researchers examined L-arginine influx, NO (nitric oxide) synthase activity and intracellular cGMP levels in platelets, as well as systemic factors including eNOS, iNOS, arginase, soluble guanylate cyclase, platelet aggregation and the systemic amino acid profile in both MD subjects and controls.

The results included: L-arginine influx in platelets was reduced in MD as compared to controls, from 46.2 ± 9.5 to 20.02 ± 2.12 pmol/10000000000 cells. NOS activity and intracellular cGMP were diminished in MD. The concentration of plasma L-arginine was reduced by 20% in the MD patients.

The reduced availability of arginine and reduced activity of the nitric oxide signaling pathway could be an important contributor to the increased risk of cardiovascular disease in MD patients. It is known that a deficiency of arginine can result in uncoupling of nitric oxide synthase and the subsequent production of superoxide radicals rather than nitric oxide.⁷ However, this was a small study and should, therefore, be interpreted with this limitation in mind.

6. Pinto et al. Low plasma levels of L-arginine, impaired intraplatelet nitric oxide and platelet hyperaggregability: implications for cardiovascular risk in depressive patients. J Affect Disord. 140(2):187-92 (2012).
   7. van der Zwan et al. Systemic inflammation is linked to low arginine and high ADMA plasma levels resulting in an unfavourable NOS substrate-to-inhibitor ratio: the Hoorn Study.Clin Sci (London). 121:71-8 (2011).

Plasma Arginine Concentrations Reduced in Cancer Patients

Another paper⁸ reports an association of low plasma concentrations of L-arginine with cancer. The researchers measured plasma arginine concentrations in patients with various types of tumors, hypothesizing that L-arginine concentrations would be lower than those in age- and sex-matched control subjects. Indeed, L-arginine concentrations were found to be significantly lower than in the controls in patients with the cancers they studied: breast cancer, colonic cancer, and pancreatic cancer.

The researchers propose that disturbances of L-arginine metabolism could “contribute to the cascade of metabolic events leading to cancer cachexia.”⁸ In addition, they explain, “[i]t was recently shown that the high arginase activity of tumors is a mechanism of tumor-induced immunosuppression through depletion of arginine concentrations in the microenvironment of the tumor.”⁸

8. Vissers et al. Plasma arginine concentrations are reduced in cancer patients: evidence for arginine deficiency? Am J Clin Nutr.81:1142-6 (2005).

In the economic sphere an act, a habit, an institution, a law produces not only one effect, but a series of effects. Of these effects, the first alone is immediate, it appears simultaneously with its cause; IT IS SEEN. The other effects emerge only subsequently; THEY ARE NOT SEEN; we are fortunate if we FORESEE them.

… it almost always happens that when the immediate consequence is favorable, the later consequences are disastrous, and vice versa. Whence it follows that the bad economist pursues a small present good that will be followed by a great evil to come, while the good economist pursues a great good to come, at the risk of a small present evil.

— From an essay by Frederic Bastiat in 1850,
“That Which is Seen and That Which is Unseen”

Ultra Easy Monetary Policy and the Law of Unintended Consequences

Stimulative monetary policies are commonly referred to as “Keynesian.” However it is important to note that Keynes himself was not convinced of the effectiveness of easy money in restoring real growth in the face of a Deep Slump. This is one of the principal insights of the General Theory.

… the Austrian school of [economic] thought, spearheaded by von Mises and Hayek, warned that credit driven expansions would eventually lead to a costly misallocation of real resources (‘malinvestments’) that would end in crisis. Based on his experience during the Japanese crisis of the 1990’s, Koo (2003) pointed out that an overhang of corporate investment and corporate debt could also lead to the same result (‘a balance sheet recession’).

— William R. White,
currently the chairman of the
Economic Development and Review Committee at the OECD in Paris
(http://dallasfed.org/assets/documents/institute/wpapers/2012/0126.pdf)

DIETARY HELP FOR STRESSED MICE AND HUMANS

ANTIDEPRESSANT EFFECTS OF WHEY PROTEIN ISOLATE IN MICE UNDER CHRONIC UNPREDICTABLE STRESS

A 2011 paper¹ reports significant effects of whey protein isolate in significantly reducing depressive behavior in mice subjected to the chronic unpredictable stress (CUS) model, where the mice (except for the controls) were exposed to various types of stress (one per day in random order for 24 days). One group of the mice were treated with the selective serotonin reuptake inhibitor drug fluoxetine (Prozac^®) (10 mg/kg po), while four other groups of mice received whey protein isolate (WPI) at dose levels of 75, 150, and 300 mg/kg po. The stress tests included commonly used tests such as the tail suspension test, the forced swimming test, and the open field test. Depression-like behavior included reductions in the activity of the mice (ambulation, rearing and grooming frequencies) and increased latency (“freezing”) in the open field test. Fluoxetine treatment restored the normal value of ambulation in the stressed mice, including the grooming frequency and and rearing frequency. WPI at both 75 mg/kg po and at 150 mg/kg po normalized the ambulation and grooming frequencies. “WPI, on the other hand, normalized all the four parameters and gave results that were comparable to those of fluoxetine (10 mg/kg).”¹

Chronic Unpredictable Stress Effects on Brain Serotonin, Norepinephrine, and Dopamine

The CUS model was reported to cause a significant decrease in the neurotransmitters serotonin, norepinephrine, and dopamine in the brains of the mice. There was a significant decrease of 44.83%, 36.13%, and 63.33%, respectively, as compared to the normal control levels. Fluoxetine elevated the levels of serotonin (117.24%), norepinephrine (94.45%), and dopamine (101.33%) compared to the normal controls. WPI (75, 150, and 300 mg/kg) significantly increased serotonin (130.77%, 138.46%, and 146.15%), and increased norepinephrine (146.91%, 156.74%, and 165.45%) and increased dopamine (172%, 172.67%, and 218.67%) compared to the normal control values.¹

Protection Against Oxidative Stress in the Brain by Whey Protein Isolate

The 75 and 150 mg/kg dose WPI did not have a significant effect on glutathione compared to the depressed group but both these doses did reduce the malondialdehyde (MDA) levels. The 300 mg/kg dose of WPI resulted in a significant increase in glutathione, with an effect similar to that of fluoxetine; it also significantly decreased the MDA level down to 47.64% as compared to the depressed group.

Alpha-lactalbumin, An Important Constituent of Whey, Benefitted Rats in Earlier Studies

Two earlier studies were reported to show that rats fed am alpha-lactalbumin rich diet showed elevated brain levels of tryptophan and serotonin levels after acute and chronic administration.^2,3 In an additional study⁴ rats on alpha-lactalbumin had enhanced serotonin release and also anxiolytic (reduced anxiety) and rewarding effects. As the authors of paper #1 explained, whey protein is rich in the amino acids tryptophan, glutamine, phenylalanine, and tyrosine. While tryptophan is precursor to the neurotransmitter serotonin, phenylalanine and tyrosine are precursors to both norepinephrine and dopamine.

… And Reduced Pain in Mice

An additional paper⁵ reported that alpha-lactalbumin derived from bovine milk reduced pain in mice in several commonly used pain models (such as the acetic acid-induced writhing test) and also reduced inflammation in mice by inhibiting COX2 and phospholipase A2. The authors of this paper conclude that “[t]hese results suggest that alpha-lactalbumin can be a safe and useful natural drug for patients with severe pain that requires anti-inflammatory drugs.”

References

1. Ahmed et al. Pharmacological study of the possible antidepressant activity of whey protein isolate in mice. Aust J Basic Appl Sci. 5(12):2649-59 (2011).
   2,3. Choi et al. Meal ingestion, amino acids and brain neurotransmitters: effects of dietary protein source on serotonin and catecholamine synthesis rates, Physiol Behav.98:156-62 (2009); Choi et al. The chronic ingestion of diets containing different proteins produces marked variations in brain tryptophan and serotonin synthesis in the rat. Neurochem Res.36:559-65 (2011).
   4. Orosco et al. Alphalactalbumin-enriched diets enhance serotonin release and induce anxiolytic and rewarding effects in the rat. Behav Brain Res.148:1-10 (2004).
   5. Yamaguchi et al. Novel functions of bovine milk-derived alpha-lactalbumin: anti-nociceptive and anti-inflammatory activity caused by inhibiting cyclooxygenase-2 and phospholipase A2. Biol Pharm Bull. 32(3):366-71 (2009).

ALPHA-LACTALBUMIN, A WHEY PROTEIN WITH HIGH TRYPTOPHAN CONTENT, IMPROVED COPING ABILITY IN STRESS-VULNERABLE HUMAN SUBJECTS

In the study described above, mice were protected against chronic unpredictable stress by whey protein isolate. Now, in a human study (10 men, 19 women) were subjected to experimental stress and received either a casein based diet or a alpha-lactalbumin-enriched whey protein diet.⁶ The diets were isoenergetic and contained equal amounts of protein, carbohydrate, and fat.

The human version of experimental stress included 18 successive 1 minute trials in which each subject had to do mental arithmetic under time constraints while at the same time receiving different levels of industrial noise (65, 70, or 80 dB) through headphones. Additional stress was added by changing the “criterion” (the specified number of calculations that had to be solved correctly in order to supposedly have the opportunity to control the noise level) so that all subjects continued to fail each trial and thus lost the “opportunity” to control the noise level. Perhaps they would have preferred the tail suspension test. …

One of the results of the experiment was that there was a significant 48% increase in the plasma ratio of tryptophan to other large neutral amino acids (which compete with tryptophan for transport into the brain) after the alpha-lactalbumin diet as compared to the casein diet. This meant that there was more tryptophan available for entry into the brain (for conversion to serotonin) with the alpha-lactalbumin diet. The latter diet also decreased the increased cortisol released in HS subjects during acute experimental stress.

Concerning mood, “we indeed found that only in HS subjects [high stress vulnerable subjects] did feelings of depression tend to be lower after experimental stress with consumption of the alpha-lactalbumin diet compared with the casein diet. In HS subjects who showed a physiologic stress response, this dietary effect on depression was significant (P=0.007). It is important, however, not to draw strong conclusions concerning the clinical implications of this observation because the dietary effects of mood seem to be small. We also found that HS subjects reported more depressive moods at baseline than did LS subjects. This seems to agree with the observation that experiences of chronic stress may lower mood and reflect a vulnerability to depression.”⁶

“… the present data show that an alpha-lactalbumin-enriched whey protein diet may reduce in stress-vulnerable subjects the negative consequences of experimental stress on cortisol secretion and mood, probably by enhancing brain serotonin mechanisms that are involved in adaptation to stress.” The authors propose, therefore, that a tryptophan-enriched whey protein diet in healthy but stress vulnerable subjects could improve ability to cope with stress.

6. Markus et al. The bovine protein alpha-lactalbumin increases the plasma ratio of tryptophan to the other large neutral amino acids, and in vulnerable subjects raises brain serotonin activity, reduces cortisol concentration, and improves mood under stress. Am J Clin Nutr. 71:1536-44 (2000).

APPETIZERS

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

NEW RESEARCH WITH HYDROGEN THERAPY

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.

References

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).

TREHALOSE INHIBITS AGGREGATION OF MUTANT ALPHA-SYNUCLEIN (THOUGHT TO BE A KEY FACTOR IN THE CAUSE OF PARKINSON’S DISEASE) AND DISAGGREGATES EXISTING FIBRILS

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.

Reference

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

EFFECT OF TREATING COCOA
WITH ALKALI: THE DUTCHING PROCESS

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.

References

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).

CHRONIC CAFFEINE CONSUMPTION FOR SIX MONTHS BY RATS FROM YOUNG ADULT TO MIDDLE AGED PREVENTS SOME ASPECTS OF COGNITIVE DECLINE AND IS ASSOCIATED WITH MORE YOUTHFUL MORPHOLOGY OF HIPPOCAMPAL NEURONS

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.

Reference

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).

TIMED HIGH FAT DIET RESETS CIRCADIAN METABOLISM AND PREVENTS OBESITY

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 J ² 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 addiction^2b 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.

References

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 REPORT ON HYDROGEN-LIMITED GROWTH OF METHANOGENS AT DEEP-SEA HYDROTHERMAL VENTS

BUT SO FAR NO NEW INSIGHTS ON THE INTERACTIONS OF HYDROGEN PRODUCING TO METHANE PRODUCING BUGS IN THE HUMAN COLON

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.)

References

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).

LITHIUM IDENTIFIED AS A PHY­SIOLOGICAL TRACE ELEMENT IN THE HUMAN NEOCORTEX

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.)

Reference

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.

JOHN STOSSEL ATTENDS OBAMA’S VICTORY PARTY IN CHICAGO
(FROM A COMMENTARY BY JOHN STOSSEL AS REPORTED IN RASMUSSEN REPORTS™)

“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.”

PREFERENCE FOR “FAIRNESS” IS HERITABLE:
POSSIBLE ROLE OF DOPAMINE D4 RECEPTOR GENE

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.”^1­

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.

References

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

UPDATE ON BOND V. UNITED STATES

RETURN TO FEDERALISM, BOND V. UNITED STATES AND THE TREATY POWER

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?)

LEPTIN AND WEIGHT CONTROL LEPTIN RESISTANCE INCREASED UNDER INFLAMMATORY CONDITIONS

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

References

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).

APPETIZERS

The trouble with borrowing money from China is that thirty minutes later you feel broke again.— Steve Bridges (as Barack Obama)Reality is what doesn’t go away when you stop believing in it.— Philip K. Dick (1928-1982)Depend on the rabbit’s foot if you wish, but remember that it didn’t work for the rabbit.— R. E. ShayIn a country where the sole employer is the State, opposition means death by slow starvation. The old principle: who does not work shall not eat, has been replaced by a new one: who does not obey shall not eat.— Leon Trotsky (1937)

(D&S: Grim but true. “Sole employer” has the same implications as “single payer” as in government as sole supplier of medical care. He who pays calls the tune. You obey their commands or you don’t get medical treatment from them and, as “sole supplier” nobody else can legally supply you.)

You may think you’re paranoid, but are you paranoid ENOUGH?— Pat Cadigan, Fool to Believe (1990)

HYDROGEN THERAPY

Hydrogen-rich Saline Treatment Ameliorates
Stress-associated Gastric Mucosa Damage in Rats

A new report¹ demonstrates that hydrogen-rich saline treatment was able to protect rats against restraint-cold-stress-induced gastric ulcers. Restraint-cold-stress caused increased oxidative stress, a decrease in superoxide dismutase (SOD) and glutathione (GSH) along with an accumulation of malondialdehyde (MDA, a lipid peroxidation product), protein carbonyl and 8-OHdG (a product of DNA damage) concentration. The results of the study (treating rats with or without hydrogen-rich saline to prevent the stress-induced gastric ulcers) showed that the hydrogen-rich saline prevented these changes (as listed above).

As the researchers explain, “there is a wealth of evidence to point out that mucosal hypoxia-ischemia is the major cause of cold immobilization stress-induced gastric injury. Under the hypoxic-ischemic condition, reactive oxygen species (ROS) such as superoxide anions, hydrogen peroxide, and hydroxyl radicals are rapidly and continuously produced, and the resulting oxidative stress is crucially responsible for the development and progression of epithelial necrosis and mucosal ulceration.” Hydroxyl radicals have been identified as a major causative factor in stress-induced gastric ulceration. Interestingly, the authors note that the hydroxyl radical is extremely short-lived at about a billionth part of a second and can only diffuse for approximately 4 nm before reacting. “Therefore, scavenging OH- [hydroxyl radical] has tremendous potential to control stress-induced gastric ulceration.”¹

Hydrogen has been discovered to be a selective antioxidant that is particularly effective in scavenging hydroxyl radicals. On that basis, the researchers of this study¹ decided to test the effectiveness of hydrogen in preventing stress-induced gastric ulcers in rats. [See our article “Hydrogen Therapy” in the June issue of Life Enhancement].

Moreover, the release of proinflammatory cytokines (TNF-alpha, IL-1beta, and CINC-1) found to be important determinants of mucosal inflammation and gastric injury following cold immobilization stress were linearly increased in rat gastric mucosa at 6 hours after the initiation of stress; these changes were prevented by hydrogen-rich saline.

“Caspase-3, a key mediator for execution of apoptosis [programmed cell death], is involved in apoptotic cell death in stress-induced ulcer. The cold restrained stress resulted in a dramatic activation of caspase-3. In our present study, the expression of cleaved caspase-3 was markedly decreased by the treatment of Hs [hydrogen-rich saline].”¹

The researchers also showed in this study that hydrogen up-regulated the expression of anti-apoptotic genes, Bcl-xl and inhibited the expression of apoptotic genes, Bax, thus providing protection against the death of gastric mucosa cells in response to the cold restrained stress.

This is a very interesting new therapeutic use for hydrogen therapy, which because of the extensive occurrence of stress-induced gastric ulcers, could be of value for many gastric ulcer patients. (Although many ulcers are caused by Helicobacter pyloriinfection, these bacteria aren’t the only cause of ulcers.)

Reference

1. Liu et al. The protective of hydrogen on stress-induced gastric ulceration. Int Immunopharmacol (2012) doi:10.1016/j.intimp.2012.04.004 [the authors are located at hospitals in China, hence, the somewhat weird English]

FILLING YOUR BRAIN’S FUEL TANK WITH MORE WILLPOWER

Willpower or self-control is an energy consuming process that allows the brain to override certain thoughts, impulses, urges, and emotions in order to promote the achievement of more highly desired goals. Not surprisingly, there is only a limited amount of energy available for the process and recent research shows that the use of willpower for one act of self-control impairs available willpower for a subsequent attempt at self-control.¹ Understanding how this works will help in economizing the use of willpower for more efficient use or, even better, increasing the amount of available willpower.

We describe here some experimental results reported in one paper¹ on the neurological basis of willpower, but there have been quite a number along the same line (see citations in paper #1). Included is proof of causation—that the brain’s glucose supply is the source of energy supporting the willpower program. You, too, can have more willpower when you need it—it could be as simple as drinking 140 calories of a glucose-laden glass of lemonade. Read on.

Limited Amount of Self-Control is Available

The researchers begin by supporting their contention that, consistent with evidence from many different scientists, self-control requires an energy source and that, under conditions where that energy has been depleted by prior effortful self-control, it becomes more difficult to generate more self-control. For instance, they cite¹ studies in which using self-control to resist the temptation to engage in a certain behavior results in an impairment in resisting a subsequent behavior, such as suppressing stereotypes and prejudice, coping with thoughts and fears of dying, controlling one’s monetary spending, resisting binge eating of palatable foods or drinking alcohol, restraining aggression, and others.

The brain depends upon glucose as its main fuel. The researchers¹ note that “most cognitive processes are relatively unaffected by subtle or minor fluctuations in glucose levels within the normal or healthy range” but that “[c]ontrolled, effortful processes that rely on executive functions, however, are unlike most other cognitive processes in that they seem highly susceptible to normal fluctuations of glucose.” For example, they note that one type of task requiring effortful cognition is the Stroop test, where a word naming a color is printed in a different color than that named by the word, so that when one is asked to name the color shown it requires effortful decision-making. Low glucose has been associated with impaired performance on the Stroop test, that is it takes more time to name the color and more errors are made in doing so than on an easy test such as looking at a blob of color and having to name the color. Another example of a difficult test that depletes glucose is a driving simulation task.

First, the researchers established that blood glucose levels are reduced from before to after performance of an initial self-control task and that this led to poorer performance in a subsequent self-control task. One such study involved requiring that participants watch a 6 minute video of a woman talking (without sound) and, to induce a need for self-control, requiring that those watching not look at captions at the bottom while she was talking. Another group of participants just watched the video without any constraints on where they looked. The result showed that, indeed, blood glucose was significantly reduced in those watching the video but having to avoid reading captions. Blood glucose did not differ between the before and after state in those just watching the video without constraints. “Thus, all participants watched the same video, but glucose levels dropped only among participants who had to exert self-control while watching.”¹

Another task performed by volunteers was the Stroop test. Glucose levels at the start of the experiment did not predict the performance (speed of identifying color and errors made), but lower glucose after having watched the video and not looked at captions (as described in the paragraph above) was associated with poorer Stroop performance; those subjects were significantly slower in identifying colors and they did make more errors, but the increased number of errors did not reach significance.

Enhanced Self-Control With Glucose

The most interesting part of the study occurred when the researchers tested their hypothesis that if depleting a source of energy (by reducing the level of blood glucose) results in impairment of self-control, then replacing the energy source should restore self-control at least in part back toward its initial level. Participants started out by performing 20 Stroop trials. Then half watched the video as mentioned above, having to avoid looking at the captions. The other half just watched the video without any constraints on where they looked. Following that, they were given 14 ounces of lemonade (containing either 0 calories because it was sweetened with Splenda or 140 calories because it was sweetened with 35 grams of glucose). The subjects were given some questionnaires to fill out but were not told that this was to allow time for the glucose to be absorbed and reach the brain from the bloodstream. Finally, they did 80 Stroop trials and were evaluated for speed and accuracy.

The results showed that those who watched the video with the self-control condition (don’t look at the captions) and received the glucose containing drink didn’t make additional errors like those who watched the video in the self-control condition but received the placebo drink. (In this part of the study, the number of errors made in the Stroop test was more sensitive to the effects of glucose than the speed of identifying colors.

In the researchers’ discussion of the results, they said, “At its core, self-regulatory change involves overriding one response in order to enable a different response. The stronger the initial response or impulse, the more difficult the self-control task will be—and, we would assume, the greater amount of energy in the form of blood glucose the system would have to expend in order to succeed.”¹ We agree with the researchers that glucose is likely to provide only a short-term help in counteracting the performance impairment resulting from prior effortful self-control because there will be counteracting metabolic factors (such as the need to release insulin in order to be able to use the glucose for energy) that prevent maintaining a high level of energy from a given amount of glucose for very long. It would be like trying to maintain the energy increasing effects of caffeine by drinking a cup of coffee again and again. That doesn’t work for very long because the factors that provide the lift from caffeine, such as the release of noradrenaline, are depleted after a while. In fact, you can extend the energy enhancing effect of caffeine by taking nutrients the brain can use to make more noradrenaline, such as the amino acids phenylalanine or tyrosine.^5,6 In the case of glucose, we would expect that taking nutrients along with glucose that improve insulin sensitivity, such as chocolate,² black tea,³ or cinnamon,⁴ might extend the length of time you could extract energy from a given amount of glucose.

References

1. Gaillot et al. Self-control relies on glucose as a limited energy source: willpower is more than a metaphor. J Pers Soc Psychol 92(2):325-36 (2007).
2. Grassi et al. Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons. Am J Clin Nutr 81:611-4 (2005).
3. Cameron et al. Black tea polyphenols mimic insulin/insulin-like growth factor-1 signalling to the longevity factor FOXO1a. Aging Cell 7:69-77 (2008).
4. Couturier et al. Cinnamon improves insulin sensitivity and alters the body composition in an animal model of the metabolic syndrome. Arch Biochem Biophys 501:158-61 (2010).
5. Borison et al. Metabolism of an antidepressant amino acid. presented in poster session at April 9-14 1978 FASEB, Atlantic City, NJ [l-phenylalanine in the treatment of depression].
6. Gelenberg et al. Tyrosine for the treatment of depression. Am J Psychiatry137(5):622-3 (1980).

INFLAMMATORY PAIN UPDATE

Choline Coadministered with Aspirin
Has Synergistic Effect on Pain Relief:
Higher Potency, Longer Duration, Fewer Side Effects

The results published in a new paper¹ will likely be of interest to anybody taking regular NSAID (nonsteroidal antiinflammatory drugs, such as aspirin, sodium naproxen (Aleve^®or ibuprofen) pain killers, particularly for chronic inflammatory conditions such as arthritis. The researchers report here¹ that choline, an alpha7 nicotinic cholinergic receptor agonist (a natural endogenous activator of this particular type of cholinergic receptor) has anti-nociceptive (anti-pain) effects of its own in a variety of pain models. They were, therefore, interested in a possible positive interaction between choline and aspirin in the treatment of pain and thus carried out experiments with two inflammatory pain models in mice.

One of the models they studied was the writhing test, where acetic acid is injected into the lower left quadrant of the abdomen of mice causing what must be excruciating pain as the pain behavior is manifest by writhing and evaluated by the number of writhes. We have chosen not to discuss this gruesome model as the results in terms of the observed pain relief to treatment with choline, aspirin, and a combination of the two were similar to the results of the inflamed paw test.

The other model of pain studied was that caused by subcutaneous carrageenan injection into the paw of a mouse, which caused pain behavior assessed by how long it took the mouse to withdraw its injected paw (the Pain Withdrawal Latency, or PWL) in response to the application of heat; the heat would cause pain to the inflamed paw. The results showed that the administration of a single dose of choline (48 mg/kg i.v., 1 hour after carrageenan injection) or a single dose of aspirin (30 mg/kg i.v., 1 hour after carrageenan injection) significantly suppressed the carrageenan-produced reduction in PWT only at 2 hours post carrageenan; thus, this time point was used as the test time in the remaining tests.

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

At low doses, choline (4 and 8 mg/kg i.v.) or aspirin (0.3125 and 0.625 mg/kg. i.v.) administered alone were reported to have no effect on the carageenan-produced reduction in PWT, but when choline (8 mg/kg) was coadministered with aspirin at 0.6125 mg./kg. or choline at 4 mg/kg + aspirin at 0.3125 mg/kg, the combination of drugs significantly reversed the carrageenan reduction of PWT. The effects were observed at 2 hours after carrageenan injection, but also at 3 hours and 4 hours after injection. Hence, the anti-pain effects of the coadministered choline and aspirin was prolonged.

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

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

Curiously, pretreatment with one alpha 7 nicotinic cholinergic antagonist, MLA, blocked the anti-pain effects of choline, while a different antagonist, alpha-bungarotoxin, enhanced the choline-induced anti-pain effect.¹ The researchers propose that the carrageenan-induced hindpaw edema in mice is a biphasic event, with an early phase of inflammation resulting from the release of histamine, serotonin, and similar substances, while a later phase is associated with the activation of kinin-like substances. This biphasic behavior may result in different responses to the two alpha 7 nicotinic cholinergic antagonists. Another complication they point out is that choline is a partial agonist of alpha9 alpha10 nicotinic cholinergic receptors. “Taken together, the antinociceptive effect of systemic choline seems to be dependent upon the presence of inflammation and its activity may be mainly via attenuating the release of inflammation cytokines through activation with peripheral macrophages and monocytes through alpha 7 nicotinic receptors, but this needs further studies in more pain models.”¹

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

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

Cholinergic Control of Inflammation

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

In a study of the antiinflammatory effects of choline (50 mg/kg, intraperitoneally (i.p.) in mice, this treatment prior to endotoxin (a bacterial cell wall constituent that activates the immune system) administration significantly reduced systemic TNF levels. In the same study, though, mice that did not have alpha7 nicotinic acetylcholine receptors (knockout mice) did not have a reduced systemic TNF levels in response to the same dose of choline, showing that these receptors were required for the reduced TNF (anti-inflammatory) effect of choline. In cells studied by the researchers,³ choline incubation prior to exposure to endotoxin suppressed both TNF and NFkappaB, another major regulatory molecule in inflammation. Choline also suppressed TNF production from endotoxin-stimulated human whole blood and cultured macrophages. As the researchers³ noted, “[t]he effective doses of choline used in the present study (25–50 mg/kg, i.p.) are within the dose range used in [] other studies. It is important to note that we did not observe any adverse neurobehavioral effects of these choline doses, which are comparable with the recommended tolerable upper limit of dietary choline intake in humans.”

Choline Synergy for Pain Relief Worked
for Sandy’s Severe Knee Osteoarthritis

An update on the ability of choline to enhance the pain-killing effects of naproxen (Advil^®): In recent months, Sandy had developed severe pain in her knees, making it difficult for her to walk uphill, to carry extra weight, etc. She has obtained very impressive relief by taking the following regimen:

1. Naproxen (one tablet in the morning and one in the evening). Each tablet contains 220 mg of naproxen sodium, an OTC non-prescription analgesic readily available in any supermarket or drugstore.
2. A serving (1 tsp.) of our sugar-free choline formulation containing 1,000 mg of choline dihydrogen citrate along with the morning tablet of naproxen and another serving with the evening tablet of naproxen.
3. A serving (1 heaping tablespoon) of our arginine, citrulline, choline plus other ingredients formulation that contains 6 grams of arginine along with each tablet of naproxen and the serving of our sugar-free choline formulation. The arginine provides protection against damage by NSAIDs (non-steroidal anti-inflammatory drugs) to the gastric mucosa and kidneys.

Using this regimen, Sandy’s knee pain has dramatically diminished. It has also improved the pain in her fingers, which are also affected by osteoarthritis.

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

Dietary Choline and Betaine Intakes in Relation to
Inflammatory Markers in the ATTICA study

A 2008 paper⁹ reported the relationship between dietary consumption of choline and betaine (a derivative of choline) and various markers of low-grade systemic inflammation in a survey of 1514 men and 1528 women with no history of cardiovascular disease. The dietary information was obtained via a validated food-frequency questionnaire, with the intakes of choline and betaine calculated from food-composition tables.

Compared with those in the lowest tertile of choline intake (less than 250 mg/day), participants who consumed greater than 310 mg/day had, on average, 22% lower concentrations of C-reactive protein (p<0.05), a widely used biomarker of inflammation, and 26% lower concentrations of IL-6 (p<0.05) and 6% lower concentrations of tumor necrosis factor (p<0.01), the latter two being proinflammatory cytokines. Also, those who ingested greater than 360 mg/d of betaine had, on average, 10% lower levels of homocysteine (p<0.01), 19% lower concentrations of C-reactive protein (not significant at p<0.1), and 12% lower concentrations of tumor necrosis factor (p<0.05) than those who consumed less than 260 mg/d.

These correlations do not prove causation (e.g., that choline or betaine REDUCED the levels of the inflammatory markers), but only show an association. However, together with other data (such as that discussed above), the anti­inflammatory effects of choline appear to be well supported.

References

1. Yong-Ping et al. Pharmacological action of choline and aspirin coadministration on acute inflammatory pain. Eur J Pain 15:858-65 (2011).
2. Rosas-Ballina and Tracey. Cholinergic control of inflammation. J Intern Med265:663-79 (2009).
3. Parrish et al. Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling. Mol Med 14(9-10):567-74 (2008).
4. Richter et al. Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats. Arthritis Rheum 62(12):3806-14 (2010).
5. Xu et al. The influence of p38 mitogen-activated protein kinase inhibitor on synthesis of inflammatory cytokine tumor necrosis factor alpha in spinal cord of rats with chronic constriction injury. Anesth Analg 105:1838-44 (2007).
6. Basbaum et al. Cellular and molecular mechanisms of pain. Cell 139(2):267-84 (2009).
7. Vaughan et al. How opioids inhibit GABA-mediated neurotransmission. Nature390:611-4 (1997).
8. Williams. The painless synergism of aspirin and opium. Nature 390:557-559 (1997).
9. Detopoulou et al. Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study. Am J Clin Nutr 87:424-30 (2008).

EPA ECONOMY RATINGS ON CARS

Based on Fraud —Another Government Lie

Columnist Jonathan Welsh, the The Wall Street Journal’s automobile expert, answered a question concerning how the EPA determines their gasoline mileage figures in the July 18, 2012 issue of The Wall Street Journal, P. D4:

Q: “I have always wondered if the EPA numbers shown on cars include the effect of ethanol. Articles have said that ethanol reduces gas mileage about 8% to 10%. I had a 2010 vehicle (Nissan Rogue) which never came close to the EPA numbers, so I traded it for a 2012 Jeep Patriot. After a limited number of miles, it had the same problem —about 8% to 10% below EPA number.”

A: “EPA fuel-economy ratings are based on non-ethanol gasoline, which leads to confusion since ethanol is mixed into fuel in so many regions that consumers tend to forget about it. In most cases that is the reason why so many drivers find their fuel economy disappointing.”

So, there you have it. Just another bum steer from the EPA, which not only lies about the fuel mileage to expect from your car but is the agency that mandates the addition of ethanol to gasoline in the first place. There’s an agency we’d like to fire. Getting rid of the EPA? Why … why … what would happen to polar bears if we did that? (The EPA wouldn’t lie about polar bears, right?)

IMPROVED COGNITION IN AGED ANIMALS

SIGMA-1 RECEPTOR CHAPERONES REGULATE THE SECRETION OF BDNF: DHEA AND PREGNENOLONE AS SIGMA-1 RECEPTOR AGONISTS

A 2012 paper¹ reports new data showing that the sigma-1 receptor chaperone (found in the endoplasmic reticulum where proteins are synthesized and folded) regulates the secretion of brain-derived neurotrophic factor, which has as one of its functions the promotion of adult neurogenesis. Other work described below identifies dehydroepiandrosterone (DHEA) as an agonist (activator) of the sigma-1 receptor, whereas progesterone was found to be a potent antagonist (inhibitor) of the receptor.

“The sigma-1 receptor (Sig-1R) is a novel endoplasmic reticulum (ER) molecular chaperone that regulates protein folding and degradation. The Sig-1R activation by agonists is known to improve memory, promote cell survival, and exert an antidepressant-like action in animals.”¹ Maintenance of proper protein folding is a critical form of quality control that is impaired with aging.

The Sig-1R is also reported to be involved in neuronal differentiation, neuroplasticity, and neuroprotection and to show therapeutic effects in animal models of depression, stroke, drug abuse, and neurodegenerative disorders. Its role in protein folding and degradation in the ER was reported in a 2007 paper.² Cutamesine, an experimental Sig-1R agonist drug that has completed phase II clinical trials in major depression and post stroke recovery has very recently been reported to regulate the secretion of brain-derived neurotrophic factor (BDNF), importantly involved in neurogenesis.¹ In a time and dose-dependent manner, the drug potentiated the secretion of BDNF without affecting mRNA levels of BDNF. The researchers of paper #1 found that cutamesine potentiates the post-translational processing of neurotrophins. It decreased the intracellular level of pro-BDNF and mature BDNF while increasing the extracellular level of mature BDNF which the authors report to be a different mechanism than that of clinically used antidepressants that promote the upregulation of BDNF.

The researchers explain that BDNF is secreted after a complex process starting with a pre-proBDNF in the endoplasmic reticulum (ER) and then undergoing a series of steps involving glycosylation, sorting, proteolytic cleavage, and finally secretion.

By serendipity, we found a 2011 paper³ in our files that reports finding sigma-1 receptor stimulation by dehydroepiandrosterone (DHEA). The researchers report that “[w]e here found that sigma-1 receptor stimulation by DHEA improves cognitive function through phosphorylation of synaptic proteins in olfactory bulbectomized (OBX) mouse hippocampus.”³ They didn’t assess DHEA effects on BDNF in this study. The olfactory bulbectomized mouse is an animal model of depression which, in a previous study by these authors, resulted in impaired signaling of calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) in the OBX mouse hippocampus. Significant improvement resulted after treatment of the OBX mice with DHEA (30 or 60 mg/kg p.o. once a day) for 7–8 daysafter the OBX operation. Spatial, cognitive and conditioned fear memories were significantly improved as assessed by Y-maze, novel object recognition, and passive avoidance task, respectively. DHEA also improved impaired hippocampal long-term potentiation (a mechanism of learning) in the OBX mice.

The authors also cite papers by other groups that report finding that DHEA interacts with sigma-1R.

Although the researchers in their latest¹ study did not evaluate changes in BDNF secretion in response to DHEA administration, it is interesting to note that the olfactory bulb is one of the two brain areas (in mice as well as in humans) that generates new neurons throughout life (via neurogenesis) in adult animals, a process in which BDNF is importantly involved.

Following up on this subject, we also found a 2001 paper⁴ that reported detailed studies of the interaction between neuroactive steroids, such as “pregnenolone, dehydroepiandrosterone, and their sulfate esters [that] behave as sigma-1 agonists, while progesterone is a potent antagonist.”⁴ More on sigma-1 receptor function was reported in this paper, including its modulation of intracellular calcium mobilization and extracellular calcium influx, NMDA-mediated responses, acetylcholine release, and effects on monoaminergic systems. “Selective agonists of this recently cloned receptor [sigma-1] have potent anti-amnesic, anti-depressant, and anti-stress effects, while selective antagonists have antipsychotic and anti-addictive property.”⁴Dehydroepiandrosterone is reported to exhibit anti-amnesic (memory enhancing) effects as a result of its interaction with the sigma-1 receptor.⁴ Higher levels of pregnenolone, another sigma-1 receptor agonist, was reported in two studies of aged rats to be correlated with learning ability and memory performances in a water maze and two-trial recognition task.

In another study described in the review paper⁴ a single systemic injection of DHEA sulfate immediately after training improved the impairment of memory in middle aged and old mice submitted to a footshock active avoidance test, “bringing it back to levels observed in young mice.” The authors of paper #4 also stated that “this neuroactive steroid [DHEA] plays a physiological role in preserving and/or enhancing cognitive abilities in old animals, possibly via an interaction with central cholinergic systems.”

References

1. Fujimoto et al. Sigma-1 receptor chaperones regulate the secretion of brain-derived neurotrophic factor. Synapse 66:630-9 (2012).
2. Hayashi and Su. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131:596-610 (2007).
3. Moriguchi et al. Sigma-1 receptor stimulation by dehydroepiandrosterone ameliorates cognitive impairment through activation of CaM kinase II, protein kinase C and extracellular signal-regulated kinase in olfactory bulbectomized mice. J Neurochem 117:879-91 (2011).
4. Maurice et al. The interaction between neuroactive steroids and the sigma-1 receptor function: behavioral consequences and therapeutic opportunities. Brain Res Brain Res Rev 37:116-32 (2001).

IMPROVED COGNITION IN AGED ANIMALS

INHIBITION OF NFKAPPAB, MASTER REGULATOR OF PRO-INFLAMMATORY SIGNALING PATHWAY, DELAYS DNA DAMAGE-INDUCED CELL SENESCENCE IN MOUSE MODEL OF ACCELERATED AGING

The evidence continues to accumulate that chronic inflammation is a major underlying factor in many age-related diseases, such as atherosclerosis, arthritis, cancer, diabetes, osteoporosis, dementia, vascular diseases, obesity, and metabolic syndrome disorders (eg., insulin resistance) and possibly in aging itself.^1–4 As a result, the investigation of anti-inflammatory effects of foods, nutrients, and food constituents (phytochemicals) has intensified. This is great news for those of us who would like to live as long as possible in as good condition as possible and also provides an important alternative to the FDA-controlled pathway to medical therapies and to the part of the American medical system that has become seriously dysfunctional as a result of extensive political micromanagement fostered by vested interests.

A new study¹ reports on the effects of NFkappaB inhibition in a mouse model of accelerated aging, the XFE progeroid syndrome, caused by a defect in DNA repair. As DNA repair is a major factor in aging and is known to decline with age, this is a good model to study for anti-aging treatments. NFkappaB is a transcription factor, controlling the expression of a large number of genes, that is activated by cellular damage, stress, and inflammation. The authors’ basic premise for the study was that the cellular response to damage may be the key driver to aging.¹

“NFkappaB was identified as the transcription factor most associated with mammalian aging, based on patterns of gene expression.” “Furthermore, chronic activation of NFkappaB is observed in numerous age-related diseases, including muscle atrophy, multiple sclerosis, atherosclerosis, heart disease, both type 1 and 2 diabetes, osteoarthritis, dementia, osteoporosis, and cancer. However these studies do not demonstrate a causal relationship between NFkappaB activation and aging.” (several citations were provided here)

As an example of some evidence in support of NFkappaB being causal in aging processes, the authors mention a study in which the depletion of NFkappaB in the skin of transgenic mice reversed age-related gene expression and histologic changes.

The researchers studied the XFE progeroid mice because the pattern of aging in these mice shows progressive degenerative changes that correlate strongly with natural aging. The overall results of the study showed that genetic or pharmacologic inhibition of NFkappaB activation delayed the onset of numerous aging-related symptoms and pathologies. “Inhibition of IKK/NF-kappaB activity reduced cellular senescence and oxidative damage, including DNA and protein damage, revealing that cellular stress responses promote further cellular damage. Our findings strongly suggest that inhibitors of the IKK/NF-kappaB pathway may delay damage and extend healthspan in patients with accelerated aging and chronic degenerative diseases of old age.”

Part of the study¹ involved examination of the activity of NFkappaB in aging wild type mice with normal DNA repair. The mice were genetically treated so that a “reporter” gene under the control of NFkappaB would indicate when NFkappaB was activated. The older wild type mice had more cells expressing the reporter than young wild type mice, indicating increased NFkappaB activity with age. Similar to natural aging, NFkappaB activity increased with age in the XPE progeroid syndrome mice. The increase in the progeroid mice was greater than the increase in the wild type mice, though, with 2.5 fold increase in kidney, 2.5 fold increase in pancreas, 1.7 fold increase in muscle, and 4-fold increase in liver as compared to the wild type mice. The researchers identified the p65 subunit of NFkappaB as the predominant subunit contributing to this increased activity.

Liver cells of progeroid mice showed “profound” cellular senescence. Inhibition of NFkappaB and reduced expression of the p65 subunit extended healthspan by “dramatically” reducing the numbers of senescent liver cells.

The authors conclude that “these studies demonstrate that spontaneous endogenous DNA damage can activate NFkappaB” and that “[c]hronic inhibition of IKK/NFkappaB activation is sufficient to delay the onset of aging symptoms and chronic aging-related diseases that arise spontaneously in DNA repair-deficient [] mice that model a human progeroid syndrome. Moreover, inhibiting NFkappaB activation reduces ROS production and oxidative damage to lipids and DNA. This demonstrates a direct causal role for NFkappaB in driving aging-related changes in response to cellular damage by promoting continued damage.”

Natural Products That Inhibit NFkappaB

We have written about NFkappaB inhibitors in previous newsletters. As interest in minimizing inflammation produced by disease-associated increased expression of NFkappaB with natural products is continuing unabated, here are a couple of 2012 papers on the subject.

In one of the new papers,⁵ turmeric (the yellow colored curry spice containing curcumin, curcuminoids, and other constituents) was reported to inhibit NFkappaB and NFkappaB regulated gene products as well as inducing death receptors leading to suppression of tumor cell proliferation.

The turmeric study was performed on tumor cell lines, including human myelogenous leukemia, human colon adenocarcinoma, pancreatic cancer, human breast cancer, and human multiple myeloma cells. As the authors of the paper noted, much more work has been published on curcumin, which is just one component of turmeric and a minor one at that, than on turmeric itself. They were interested in whether there were differences in the effects of curcumin and turmeric in their cell culture studies. In fact, they cited a study in which other researchers had found that curcumin-free turmeric extract inhibited DMBA-induced mammary tumorigenesis in rats, thus suggesting that other constituents of turmeric have anticancer activities.

NFkappaB is known to play an important role in the survival and proliferation of cancer cells, their resistance to chemotherapy, and bone loss associated with carcinogenesis.⁵The results showed that turmeric significantly inhibited the activation of both constitutive and inducible NFkappaB exhibited in breast, pancreas, and multiple myeloma cells, among others. Turmeric also suppressed the activation of STAT3, another pro-inflammatory transcription factor contributing to the development of various types of cancer, including (as observed in this study) multiple myeloma, pancreatic, colorectal, and breast. Turmeric also inhibited the expression of some STAT3- and NFkappaB-regulated proteins, including Bcl-2 and cIAP1, two proteins associated with increased survival of cancer cells, and cyclin D1 and c-Myc, two proteins associated with cancer cell proliferation. Turmeric also potentiated the cytotoxic effects of some chemotherapeutic chemicals.

Moreover, turmeric was found by these researchers⁵ to be more potent in inhibiting growth of various cell lines, such as breast cancer, than was curcumin. Turmeric is very inexpensive and has been used extensively and in large quantities as a cooking spice for thousands of years. The yellow color of curry is due to the contained turmeric. Because of its strong flavor, we take most of our supplemental turmeric in capsules.

A Natural Form of Boswellic Acid Inhibits NF-kappaB

Another natural NFkappaB inhibitor was tested for whether itcould affect the development of atherosclerosis in apoE-/- mice treated with bacterial lipopolysaccharide (LPS) to mimic a systemic infection.⁶ This NFkappaB inhibitor, acetyl-11-keto-beta-boswellic acid (AKbetaBA), was isolated from African frankincense and purified to >99.9% purity.

As reported here,⁶ extracts of Boswellia oleogum resins (also called frankincense) have been used in traditional medicine as anti-inflammatory remedies and in clinical pilot trials to treat patients with rheumatoid arthritis or inflammatory bowel diseases with what were described as “promising results.”⁶ In the mouse study, the AKbetaBA reduced atherosclerotic lesion size and inhibited NFkappaB in atherosclerotic lesions of the LPS-challenged ApoE-/- mice. It also inhibited plasma levels of prothrombotic and proinflammatory factors in the LPS treated ApoE-/- mice, but had no effect on plasma levels of triglycerides or cholesterol or on plasma levels of autoantibodies against oxidized LDL or cytokines produced by lymphocytes in the blood, liver, and spleen of the animals.

The authors⁶ conclude that “herbal therapies and plant resins from species of the Boswellia family might represent an alternative for classical medical treatments for chronic inflammatory diseases such as atherosclerosis.”

References

1. Tilstra et al. NFkappaB inhibition delays DNA damage-induced senescence and aging in mice. J Clin Invest 122(7):2601-12 (2012).
2. Chung et al. Molecular inflammation: Underpinnings of aging and age-related diseases. Ageing Res Rev 8:18-30 (2009).
3. Tilstra et al. NFkappaB in aging and disease. Aging Dis 2(6):449-65 (2011).
4. Franceschi et al. Inflamaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128:92-105 (2007).
5. Kim et al. Turmeric (Curcuma longa) inhibits inflammatory nuclear factor (NF)-kappaB and NF-kappaB-regulated gene products and induces death receptors leading to suppressed proliferation, induced chemosensitizaation, and suppressed osteoclastogenesis [which cause bone resorption]. Mol Nutr Food Res 56:454-65 (2012).
6. Cuaz-Perolin et al. Antiinflammatory and antiatherogenic effects of the NFkappaB inhibitor acetyl-11-keto-beta-boswellic acid in LPS-challenged apoE-/- mice. Arterioscler Thromb Vasc Biol 28:272-7 (2008).

For years astrophysicists have been racking their brains over the reason for the great difference in the amounts of cosmic dust in various galaxies. The answer, I think, is quite simple: the higher a civilization is, the more dust and refuse it produces. This is a problem more for janitors than for astrophysicists.— Stanislaw Lem, Let Us Save the Universe (an Open Letter from Ijon Tichy Space Traveller) (1966), translated by Joel Stern and Maria ­Swiecicka-Ziemianek (1981)

62% PUT ECONOMIC GROWTH AHEAD OF ECONOMIC FAIRNESS, SAYS RECENT RASMUSSEN POLL

Economic growth is far different from economic fairness. Economic fairness is what some call it when overall income is distributed over the population in the way they prefer. Many people believe that it is “unfair” for some people to earn more than certain amounts of money or more than other people. Economic growth, on the other hand, is an objective measure of increasing (or decreasing) economic activity leading to greater (or lesser) overall wealth in the economy.

Political differences often hinge on how people view economic fairness. Hence, it is interesting to note that a recent poll published by the Rasmussen Reports (July 19, 2012) found that in a telephone poll of 1,000 Likely U.S. voters, the participants prefer by 62% to 30% that the government encourage economic growth as a more important role for the government than ensuring economic fairness.

About 60 years ago, I said to my father, “Old Mr. Senex is showing his age; he sometimes talks quite stupidly.” My father replied, “That isn’t age. He’s always been stupid. He is just losing his ability to conceal it.”— Robertson Davies,
“You’re Not Getting Older, You’re Getting Nosier,”
in the New York Times Book Review

ASHWAGANDHA REVERSES ALZHEIMER’S PATHOLOGY IN A MOUSE MODEL BY UPREGULATING LIVER PROTEIN

A new paper¹ reports on a “remarkable therapeutic effect” (words of the authors) of W. somnifera (Withania somnifera, also known as Ashwagandha) that the researchers found to clear amyloid beta from the brain as well as reversing the behavioral deficits and pathology seen in a mouse Alzheimer’s disease model via the upregulation of LRP in the liver. LRP is “the major cell surface receptor for clearance of Abeta from brain interstitial fluid across the blood-brain barrier … [i]t is also involved in the endocytosis of APP [importing into cells of APP] and thereby influences Abeta production within neurons.”¹

As the authors explain, “influx and efflux of brain Abeta are regulated by receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein LRP [also called LDLR], respectively. The soluble form of LRP in plasma (sLRP) is a peripheral sink for Abeta that aids its sequestration. In AD [Alzheimer’s disease], plasma sLRP and LRP1 at the blood brain barrier are reduced, whereas RAGE expression is increased, resulting in accumulation of brain Abeta.” In their paper,¹ the researchers found that “a WS [W. somnifera] extract reverses behavioral deficits and plaque pathology and reduces the Abeta burden in middle-aged and old APP/PS1 mice through upregulation of liver LRP, leading to increased clearance of Abeta. The therapeutic effects of WS were reproducible in APPSwInd J20 mice, another model of AD, in which behavioral deficits were reversed and plaque load decreased significantly.” “Indeed, the ability of WS to induce liver LRP may be extremely important, given that cell surface LRP in liver is required for the rapid systemic clearance of the toxic Abeta peptide and subsequent degradation of this peptide by proteases in the liver.”¹

The authors note that a rather high dose of the withanolides and withanosides (major constituents of the WS extract) was used in this study.

Withanoside A and withanoside IV (which are, as noted above, major constituents of the roots of WS) have been reported in another study (cited in paper #1) to help promote neurite outgrowth in cultured neurons and in rodents injected with Abeta25–35. In a different paper,² WS root extract administered orally (at either 25 mg/kg or 50 mg/kg) significantly decreased the changes induced in adult Wistar rats (hyperglycemia, glucose intolerance, increase in plasma corticosterone levels, cognitive deficits, immunosuppression, mental depression, and others) by chronic stress (mild unpredictable footshock). The treatments (the two doses of WS extract or 100 mg/kg Panax ginseng) were compared to each other and to placebo and were administered 1 hour before footshock for 21 days.

Most of the effects of chronic stress were inhibited similarly by both doses of WS and by Panax ginseng at 100 mg/kg. Although WS at 50 mg/kg. was reported to have memory enhancing activity per se, PG did not, but both herbs could inhibit the adverse effects of chronic stress on the test for retention of learned tasks. In summing up, the authors state: “An overall activity indicated of WS anti-CS [chronic stress] effect of WS and PG showed that WS (25 and 50 mg/kg p.o.) was approximately equi-effective as PG (100 mg/kg p.o.) whereas WS (50 mg/kg p.o.) exhibited a higher antistress activity.”

References

1. Sehgaj et al. Withania somnifera reverses Alzheimer’s disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc Natl Acad Sci USA 109(9):3510-5 (2012).
2. Bhattacharya and Muruganandam. Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress. Pharmacol Biochem Behav 75:547-55 (2003).

A fruit is a vegetable with looks and money. Plus, if you let fruit rot, it turns into wine, something Brussels sprouts never do.— P. J. O’Rourke

YOU DON’T HAVE TO BUY BROCCOLI BUT IF YOU DO: HERE’S A TIP ON HOW TO COOK BROCCOLI TO MAXIMIZE SULFORAPHANE YIELD

It is not generally common knowledge concerning the best method for cooking and how long one should cook various vegetables in order to get optimal amounts of highly desirable phytonutrients. Of course one could eat vegetables raw, but cooking, rather than eating raw, is really the prudent course because of the ever present danger of getting food poisoning from bacterial contamination of vegetables, which is very common.

That’s why we were glad to see information in the latest issue of the Journal of Agricultural and Food Chemistry¹ on preparing broccoli in order to get the best yield of sulforaphane, the powerful anti-cancer component contained in it.

As the researchers explained, in broccoli the glucosinolate glucoraphanin is converted by the enzyme myrosinase into sulforaphane. But a myrosinase cofactor can direct the hydrolysis of glucoraphanin away from the production of sulforaphane to an inactive product sulforaphane nitrile. The cofactor is more heat sensitive than myrosinase, so by controlling the amount of heat and the length of time the food is heated it is possible to generate more of the sulforaphane, avoiding the undesired nitrile. The researchers processed four different broccoli cultivars and found that with boiling and microwave heating, there was an initial loss of nitrile with an increase in sulforaphane; this was then followed by loss of sulforaphane and all this took place within a minute. They then found that steaming the broccoli for between 1 and 3 minutes in three of the four cultivars led to an enhanced yield of sulforaphane with less nitrile as compared to the boiling and microwaving.

Hence, the maximum sulforaphane yield was reached following a much shorter heating period for microwave heating or boiling than for steaming. In fact, the researchers had to use an ice-water bath to rapidly stop the heating process after microwave or boiling. The authors of the study, therefore, recommend that “steaming for 1.0–3.0 min.enhanced SF [sulforaphane] levels in all but Brigadier [one of the broccoli cultivars] and therefore can be expected to enhance the health benefits of a broccoli meal.”¹ They recognize that broccoli sold at supermarkets does not identify the cultivar, but in the absence of that information suggest that their best recommendation is that steaming for 1–3 min. will provide the greatest SF availability.

This research was supported by a grant from the U.S. Dept. of Agriculture, which perhaps wants to encourage the eating of broccoli. Good idea. Another good idea would be to let the growers of broccoli pay for the research (rather than taxpayers via regulatory agencies) as the sellers of broccoli will profit directly from its sales—if the FDA would allow them to make truthful nonmisleading health claims …

Reference

1. Wang et al. Impact of thermal processing on sulforaphane yield from broccoli (Brassica oleracea L. ssp. italica). J Agric Food Chem 60:6743-8 (2012).

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.