THE PRICE OF DISOBEDIENCE
...dissent is transformed into a threat that the subject will refuse to carry out the authority’s orders. Finally ... he disobeys. Inner doubt, externalization of doubt, dissent, threat, disobedience: it is a difficult path, which only a minority of subjects are able to pursue to its conclusion. Yet it is not a negative conclusion, but has the character of an affirmative act, a deliberate bucking of the tide.
The price of disobedience is a gnawing sense that one has been faithless. Even though he has chosen the morally correct action, the subject remains troubled by the disruption of the social order he brought about, and cannot fully dispel the feeling that he deserted a cause to which he had pledged support. It is he, and not the obedient subject, who experiences the burden of his action.
—Stanley Milgram, Obedience to Authority (Harper & Row, 1975)
He said that they needed in all countries natural leaders like myself; I had only to sign, and bygones would be bygones, and I should be given every chance to satisfy my will to power. I didn’t tell him that natural leaders don’t have any will to power. He wouldn’t have understood what I meant.
—Geoffrey Household, Rogue Male (Orion Books, 2002)
In writing a novel, when in doubt, have two guys come through the door with guns.
In diabetes, nephropathy (kidney failure) is a common and life-threatening complication. The loss of the kidney’s ability to filter plasma so that it retains some constituents and passes others on for excretion in the urine is reflected in albuminuria, where albumin, the protective blood protein, is excessively excreted in the urine; albuminuria is used as a measure of kidney failure.
BUT IT ALSO OCCURS IN AGING...
The loss of albumin is a serious complication of diabetes, but it also occurs in aging, though less severely, as the kidneys lose their ability to filter blood. Epidemiological data have consistently shown an increased mortality rate with lower levels of serum albumin. “In diseased populations as well as in the general population, it has been estimated that the odds of death increase by about 50% for each 2.5 g/l decrement in the initial albumin level. This association holds also for cardiovascular disease...” “It has been reported that serum albumin decreases with age...” (Bourdon, 1999) “A recent meta-analysis of studies in human subjects concluded that moderate consumption of GT [green tea] reduces the risk of cardiovascular events and stroke by enhancing endothelial-dependent vasodilation.” (Borges, 2016)
GREEN TEA RE-ESTABLISHES TETRAHYDROBIOPTERIN LEVELS IN HUMAN DIABETICS
A recent paper (Borges, 2016) reports that tetrahydrobiopterin levels were significantly increased by green tea in a small study. This suggests an exciting potential benefit of green tea that has not been widely discussed or appreciated.
Patients were randomly assigned to two groups, 21 of which received GTP (green tea polyphenols) containing 800 mg of epigallocatechin gallate (EGCG), while 21 received placebo. Of the 21 receiving green tea, 17 had type 2 diabetes and 4 had type 1 diabetes; the 21 that received placebo had type 2 diabetes. “The beneficial effect of GTP [green tea polyphenols] on albuminuria was maintained even when we included only patients with diabetes mellitus (DM) type 2 in the analyses, resulting in a 37% reduction vs. a 4% increase (p=0.03) for the GTP and placebo groups, respectively [after 12 weeks of treatment].” (Borges, 2016)
GREEN TEA MAY HAVE LIFE-EXTENDING PROPERTIES
By protecting tetrahydrobiopterin from oxidation, green tea may have indirect life extending effects because tetrahydrobiopterin is an important cofactor for the production of nitric oxide from endothelial nitric oxide synthase (eNOS). “That NO [nitric oxide] may extend lifespan has been supported by the relevant observations by Li and colleagues (Li et al, 2011).” Moreover, “it has been reported that eNOS expression is induced, and NO-dependent mitochondrial biogenesis [creation of new mitochondria] is augmented, in the every-other-day feeding model of caloric restriction (CR) in mice.” A 2015 review paper (Valerio, 2015) describes these and some of the other recent research suggesting the possible life-extending effects of nitric oxide.
Tetrahydrobiopterin, the Oxidative Stress Regulator You Probably Never Heard of...And Why You Should
TETRAHYDROBIOPTERIN (BH4) is a key to the regulation of the mitochondrial electron transport chain that produces the cellular energy carrier in the form of ATP. One reason that you probably haven’t heard of tetrahydrobiopterin is that it is not available as a dietary supplement. It cannot be taken orally (check!). In animal experiments, it is administered by injection.
Yet, increasing tetrahydrobiopterin may offer important health benefits. It is great to know, then, that the bioavailability of tetrahydrobiopterin can be significantly increased with EGCG, a common inexpensive dietary supplement.
What are the benefits of tetrahydrobiopterin? A recent paper reports that it “may be useful in treating DN [diabetic nephropathy, the kidney damage that is a frequent complication of diabetes and is also a common cause of death from diabetes], a disease characterized by endothelial dysfunction.” (Faria, 2012, Borges, 2016) (Interestingly, kidneys are not very good at self-repair and their function declines with age. If you live long enough, kidney failure is likely to get you.) But tetrahydrobiopterin does much more than provide protection against kidney damage.
ACCELERATED AGING AND TETRAHYDROBIOPTERIN
Diabetes is considered a good model of accelerated aging. It is an age-associated disease and the mechanisms that cause it are the same as those causing other age-associated diseases. For example, the endothelial dysfunction that characterizes diabetes also characterizes cardiovascular disease (CVD) and, like diabetes, CVD is the result of the uncoupling of nitric oxide synthase, the enzyme that produces nitric oxide, a gas that regulates the dilation of blood vessels. This uncoupling is what causes nitric oxide synthase to produce superoxide radicals rather than nitric oxide.
A study (Verma, 2002) of the effects of tetrahydrobiopterin administered intravenously in a rat experimental ischemia/reperfusion model restored impaired endothelial function. The authors suggest that “this cofactor [tetrahydrobiopterin, a cofactor for nitric oxide synthase] might exert myocardial protection through prevention of endothelial dysfunction, lipid peroxidation, and direct cardiomyocyte injury.” They note that tetrahydrobiopterin has very low toxicity and can be administered intravenously in high doses. In conclusion, the authors say: “These data underscore the importance of BH4 [tetrahydrobiopterin]...”
CRITICAL ROLE IN THE MAINTENANCE OF NO BIOAVAILABILITY
“...enzymatic coupling of eNOS by BH4 [tetrahydrobiopterin] plays a critical role in the maintenance of NO bioavailability...” (Faria, 2012)
And here is where TETRAHYDROBIOPTERIN comes in. The uncoupling of nitric oxide synthase is “characterized by a reduction in tetrahydrobiopterin (BH4) levels” and increasing BH4 levels could reverse that uncoupling. (Faria, 2012) One reason for the reduction in tetrahydrobiopterin levels is that it is very sensitive to oxidation. “BH4 [tetrahydrobiopterin] is one of the most potent naturally occurring reducing agents. It is therefore reasonable to hypothesize that oxidative stress may lead to excessive oxidation and depletion of BH4. As oxidative stress occurs in cardiovascular pathophysiology...oxidation of BH4 may be the common cause of eNOS [endothelial nitric oxide synthase] dysfunction...” (Forstermann, 2011) The authors (Forstermann, 2011) note: “Administration of BH4 restored endothelial function in animal models of diabetes and insulin-resistance, as well as in patients with hypercholesterolaemia, diabetes mellitus, essential hypertension, and in chronic smokers.”
WHY WE TAKE EGCG:
IT’S MUCH MORE THAN JUST AN ANTIOXIDANT
We consider EGCG one of the most cost-effective supplements we include in our regimen. In addition to all of the above, EGCG has been found to reactivate methylation-silenced cancer suppressing genes in cancer cell lines (Fang, 2003). Also, vitamin D3 conversion to the biologically active form by certain genes (primarily CYP24A1) is decreased by downregulation of CYP24A1 expression by DNA methylation in prostate cancer cells, resulting in less active vitamin D3. (Deeb, 2011) EGCG may, we believe, reactivate CYP24A1 as has been found in methylation-silenced genes in cancer cells. This might be part of EGCG’s anti-cancer protection.
We get our EGCG from Life Enhancement’s Green Tea Booster EGCG capsules and take one capsule with each meal. Each capsule contains 330 mg of EGCG.
Monetary Incentive Induced Greater Reward Learning, Decreased Depressive Symptoms in Human Pilot Study
The results of a recent randomized, double-blind, placebo-controlled study involving 74 human subjects suggest that it might be a good idea to offer your employees (if you have them) free green tea to enhance their response to incentives such as raises or bonuses. The study (Zhang, 2013) found that participants receiving green tea for 5 weeks had improved reward learning (decreasing the reaction time in a monetary incentive delay task) compared to those receiving a placebo. Plus, the subjects showed improved mood scores on a measure of depressive symptoms.
Impairment of reward learning is associated with depression. Receiving a raise or bonus or similar incentive is not going to provide a rewarding boost to mood when depression has reduced your ability to respond to rewards (a state called anhedonia). Thus, the results of this study might be of particular interest to entrepreneurs trying to find ways to increase the rewarding effect of monetary incentives. The incentive trials allowed participants to earn money or to avoid losing money by pressing a button during the presentation of a cue (shown for a period of 4.5 to 9.5 seconds). The reaction time (time to push the button following the presentation of the cue) was taken as a measure of depression when response time was retarded.
The results showed significantly enhanced reward learning (faster response to the cue indicating an available reward) in those receiving the green tea. The tea was administered as 400 mg of green tea powder dissolved in hot water three times a day (one serving 30 minutes after each of three meals) and contained 45.6% of polyphenols as EGCG.
In discussing the mechanisms that might be responsible for the improvement in reward learning, the authors note that dopamine deficiency has been proposed as an important cause of anhedonia, an individual’s loss of response to rewarding stimuli in depression. “The mesolimbic and nigrostriatal DA [dopamine] system appears to be related primarily to reward system function and responsiveness to the environment.” ( Zhang, 2013) “It has been reported that the active component of green tea, EGCG, inhibited psychostimulants-induced hyperactivity in part by modulating dopaminergic transmission.” (Zhang, 2013) “A recent study showed that green tea extract treatment can reduce hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in response to stress in mice.” (Zhang, 2013)
Another recent paper (Scholey, 2012) reports on potential benefits of the green tea polyphenol EGCG on brain activity and mood. They refer to an earlier study showing a modest but significant association between green tea consumption and lower psychological distress. Green tea, of course, contains considerable amounts of EGCG but also other components that could have effects on psychological distress, such as theanine and caffeine.
In this human study, there were 31 volunteers (mean age 27.74 years, SD (standard deviation) 9.28, with 12 males and 19 females). This was, therefore, a small study but the researchers measured a number of interesting parameters that are not generally included in studies of mood, specifically EEG data that included theta, alpha, and beta activity. The treatment (with placebo controls) consisted of 300 mg of Teavigo,® a caffeine-free purified and refined extract of Camelia sinensis (tea) that consisted of approximately 94% EGCG and 6% vitamin C (in the form of ascorbyl palmitate). The researchers note that the results of testing for cognitive and cardiovascular functioning was to be published elsewhere, while this paper reports on mood and resting state EEG.
The EGCG treatment was reported to significantly increase calmness and reduce stress as assessed by the Bond-Lader mood scale. More interestingly, compared with placebo, “EGCG administration was associated with a significant overall increase in alpha, beta, and theta activity (data not shown) more dominant in midline frontal and central regions.” (Scholey, 2012) The data were summarized in Figure 1b of the paper.
The researchers state that: “Previously an increase in both alpha and theta activity has been observed during non-directed meditation...” and they speculate that “the changes in these same waveforms in the EGCG condition may reflect a relaxed yet attentive state due to the intervention.” (Keep in mind that this is speculative.) Moreover, the EGCG was combined with ascorbyl palmitate and it has been reported that vitamin C increases the bioavailability of EGCG. (Green, 2007))
Note that our Double-C™ contains both ascorbyl palmitate (a fat soluble form of vitamin C) and calcium ascorbate (a non-acidic, water soluble form of vitamin C.
Mechanisms Identified for Protective Effect of EGCG Against Cognitive Dysfunction Resulting from Amyloid Beta Buildup as Occurs in Alzheimer’s
A recent study of a mouse model of Alzheimer’s disease (Lee, 2009) reports that mice pretreated with EGCG for three weeks before receiving intracerebroventricular administration of amyloid beta had reduced toxic effects as compared to animals receiving the amyloid beta but not being pretreated with EGCG. The authors suggest, on the basis of their data, that “EGCG may be a beneficial agent in the prevention of development or progression of AD [Alzheimer’s disease].” (Lee, 2009)
The mice receiving EGCG were given doses of 1.5 or 3 mg/kg body weight in their drinking water. (This is roughly equivalent to a dose of 18 mg to 36 mg for a 100 kg human—these are very small doses compared to the usual human supplementation of EGCG.)
One of the measures of cognition used by the authors was the Morris water maze test, where treatment with amyloid beta resulted in significantly slower arrival times at the platform location (where the mice escaped the need to continually tread water), whereas pretreatment with EGCG (either dose) significantly inhibited the effects of amyloid beta on escape latencies (the delay in reaching the platform).
The apoptotic death of neurons induced by amyloid beta was reported to be prevented by pretreatment with EGCG. The researchers explain that activation of MAP kinase and NFkappaB as well as the activation of alpha, beta, and gamma-secretase are implicated as causes of amyloid beta-induced neuronal cell apoptosis and that pretreatment with EGCG significantly inhibited the expression of these molecules. Other mechanisms were discussed in the paper.
Failure of feedback mechanisms to inhibit gluconeogenesis (the conversion of amino acids to glucose) in the liver is a major reason for excess blood sugar in type 2 diabetes. (Eating is supposed to shut down gluconeogenesis, with glucose derived from food acting as a negative feedback signal.) The release of GLP-1 (glucagon like peptide 1) is involved in the feedback inhibition of eating to tell liver cells to stop gluconeogenesis. In a fairly recent paper (Collins, 2007), researchers were able to show in mouse liver cells that EGCG suppressed gluconeogenesis by activating 5’-AMP-activated protein kinase (AMPK), an important regulator of energy metabolism that responds to eating by (for one thing) suppressing gluconeogenesis. (The authors point out that the activation of AMPK is associated with EGCG-induced apoptosis in cancer cells, but that is another story.)
The results of this study suggest that EGCG could, as the authors note in their summary (last paragraph in the paper), point to a new therapeutic approach for the management of diabetes. (Collins, 2007)
Hydrogen gas is produced in your body and permeates through your tissues, including your brain, as well as important cellular organs, such as the energy-producing mitochondria. Yet there is little awareness of hydrogen gas as a biological player and what it is doing for you. It might be termed a silent guardian of your health. Here is a selection of disorders in which hydrogen gas is currently being used and some of the many other uses to which it could be put. We start with what the hydrogen molecule is doing—without your awareness—and what you can do to turn it to your benefit.
UNPAIRED ELECTRONS LOOKING FOR A CONNECTION
We start with the ubiquitous FREE RADICALS, molecules with an unpaired electron (the cause of OXIDATIVE STRESS), that have become common with the well-read public as dangerous entities that are causative in many diseases, such as cardiovascular disease, cancer, arthritis, diabetes, and a host of others. When a free radical meets a hydrogen molecule, it can be converted to far less dangerous forms. A group of multisystem diseases share the properties of attack by these radicals (called oxidative stress), the basic factor in the causes of many diseases other than those mentioned above, including tinnitus, chronic fatigue syndrome, multiple chemical sensitivity, and posttraumatic stress disorder (PTSD).
WE HYPOTHESIZE THAT HYDROGEN MAY REDUCE PAIN
Interestingly, peroxynitrite, a potent oxidant derived from the chemical reaction of superoxide radicals with nitric oxide, has been linked to PAIN. (Ndengele, 2008) Hence, reducing peroxynitrite may be an effective way to decrease pain in diseases such as arthritis that are associated with oxidative stress/inflammation and in which peroxynitrite is generated.
Since HYDROGEN is a powerful scavenger of peroxynitrite, we hypothesize that it may be an effective treatment for pain.
WHAT SOME LEADING EXPERTS SAY ABOUT HYDROGEN AND ITS TARGETS
“All these basic properties are shared by a group of multisystem illnesses, including chronic fatigue syndrome (CFS), multiple chemical sensitivity (MCS), fibromyalgia (FM), and posttraumatic stress disorder (PTSD), which are now thought to be caused by a vicious cycle mechanism known as the NO/ONOO- (‘no, oh no!’) cycle mechanism.” The authors propose that the vicious cycle mechanism NO/ONOO- may be causative in these diseases.
—Pall and Bedient. The NO/ONOO- cycle as the etiological mechanism of tinnitus. Int Tinnitus J. 13(2):99-104 (2007), pp. 99-100.
“There is a clear need for more effective and safer antioxidants.” “Ohsawa et al studied the antioxidant properties of molecular H2 and reported that it selectively reduces OH- and ONOO- [‘oh no’] but does not affect physiological ROS [reactive oxygen species].”
—Hong, Chen, Zhang. Hydrogen as a selective antioxidant: a review of clinical and experimental studies. J Int Med Res. 38(6):1893-903 (2010).
“H2 selectively reduces OH- and ONOO- [‘no, oh no’] in cell-free systems.”
—Ohsawa, Ishikawa, Takahashi, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 13(6):688-94 (2007), pg. 689
“The interactions between nitric oxide and superoxide leading to the formation of peroxynitrite represent a novel molecular mechanism accounting for free-radical dependent damage in biological systems.”
— Radi R. Oxidative reactions of peroxynitrite in biological systems: direct attack versus the hydroxyl radical-like pathway, in chapter 4 of The Oxygen Paradox (Davies, KJA* and Ursini F, eds. (CLEUP University Press, 1995).
* Note: Kelvin J. A. Davies, co-editor of The Oxygen Paradox, is an expert in the biology of free radicals (now generally called oxidative stress) and the long-time Editor-in-Chief of Free Radical Biology and Medicine, arguably (or, at least, we argue) the leading scientific journal on free radical science.
“We propose that increased superoxide production in the vasculature may not only interfere with the regulation of vascular tone (by reaction with nitric oxide) but may also remove an antioxidant and generate the powerful pro-oxidant peroxynitrite.”
— Hogg NB. Kalyanaraman B, Darley-Usmar V. Oxidant and antioxidant effects of nitric oxide and superoxide in the vasculature, in The Oxygen Paradox (Davies KJA and Ursini F, eds) pp. 317-324. (CLEUP University Press, 1995).
“Recent evidence indicates that most of the cytotoxicity attributed to NO [nitric oxide] is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion.”
—Pacher, Beckman, Liaudet. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 87(1):315-424 (2007), pg. 315
“Interestingly, peroxynitrite, a potent oxidant derived from the chemical reaction of superoxide radicals with nitric oxide, has been linked with pain; hence, reducing peroxynitrite may be an effective way to decrease pain...” “Since hydrogen preferentially scavenges hydroxyl radicals and peroxynitrite over that of superoxide and hydrogen peroxide, it may be beneficial in pain relief...”
—Durk Pearson & Sandy Shaw, from the April 2012 Durk Pearson & Sandy Shaw’s®Life Extension Newsletter, authors of the #1 best-seller Life Extension, A Practical Scientific Approach (Warner Books, 1982)
(continuation of the series by Sandy Shaw)
Sometimes old papers contain important information that has become forgotten or ignored over time. These “oldie but goodies” are sometimes worth spending some time with—they can act like a time machine for recalling past discoveries that may point the way to new thinking about an old subject.
So it goes with a paper from 1981 (Klein, 1981) that investigated the loss of nicotinamide enzymes (including NAD+) in the ischemic-infarcted hearts of dogs. What these researchers found was that loss of NAD+, MADH, and NADPH, nicotinamide adenine dinucleotides, “may be responsible for the transition from reversibly ischemic to irreversibly infarcted cell damage.”
As the authors explain, “Ischemic myocardium undergoes a sequence of biochemical changes until it becomes irreversibly damaged.” What this means is that initial damage may be reversible if conditions are right and prevent irreversible damage which leaves the heart permanently weakened. At that time (1981), the biochemical mechanism that led to this permanent damage had not been worked out. The authors thought that the loss of NAD+ might account for this.
Under the conditions of their study, the researchers found a loss of total NAD+ of about 60-70% when they diagnosed irreversible cell injury by electron microscopy. Total NAD, the sum of NAD+ and NADH, “started to decrease significantly in the ischemic subendocardium 1 hour after onset of ischemia” and “... started ... to become significant after two hours of ischemia.” The researchers summed up their results: “We conclude from our data that the loss of the nicotinamide coenzymes is crucial for the irreversibly ischemic injury.” They note that in rat hearts a loss of 60% of NAD could theoretically mean that either the mitochondria or the cytoplasm is totally without NAD, with the result being a severe decrease in the ability to produce ATP.
RESTORES SILENCED GENE BY MODIFYING DNA METHYLATION
An important new trick performed by sodium selenite is reported in two fairly recent papers. It adds to the data we’ve already written about showing that sodium selenite is a powerful protectant against cancer.
Here, the papers describe how sodium selenite is able to reactivate a major tumor suppressor gene that has been silenced by methylation of DNA, preventing it from carrying out its important anticancer function. The silencing of tumor suppressor genes and, indeed, many other genes, are “turned off” during aging. Scientists have learned recently how some of this works and how to restore silenced genes.
The silencing of PTEN is an important mechanism in many forms of cancer, such as prostate cancer (Berggren, 2009). In one study (Berggren, 2009), the authors showed that selenite increased the activity of a kinase, casein kinase-2 (CK2), involved in PTEN phosphorylation and the regulation of the tumor suppressor’s activity in these cells. DU-145 prostate cancer cells were reported to express PTEN and had decreased activity of the kinase CK2. The researchers found that sodium selenite upregulated CK2 activity, thus increasing the stability and activity of PTEN. “...the novel finding that Se [selenite] increases CK2 activity, which in turn can affect PTEN activity, is of interest for the treatment of prostate cancer.” (Berggren, 2009)
A second paper (Xiang, 2008) provides data on how selenite reactivates silenced genes by modifying DNA methylation and histones in prostate cancer cells. Hypermethylation of DNA prevents genes from being expressed, which silences them. Methylation or demethylation is an important way that genes are turned off or turned on, the epigenetic process. It is a way that DNA can be made to function in a different way without having to alter the DNA code (create a mutation).
“Cancer is a disease associated with both genetic and epigenetic changes. Epigenetic gene regulation has been recognized to play a role in the etiology of cancer.” This paper describes how selenium “may have epigenetic effects on gene expression involved in prostate carcinogenesis.” (Xiang, 2008) Here, the authors explain how selenium “can restore the expression of the hypermethylation-silenced genes ... in human prostate cancer cells ...”
When you buy one and get one free, it is the same as getting 50% off when you buy two. So, why is it that consumers have a marked preference for the first option?
The difference may be because “when prices are mentioned, people apply market norms, but when prices are not mentioned (i.e., the price effectively is zero), they apply social norms to determine their choices and effort.” (Shampan’er, Working Paper, MIT) There is a switch to seeing the item being offered as being outside of a market where qualities other than price are what determines value. Because those qualities add value to the product, the consumer perceives it as being worth more than “zero.” Thus, “they overreact to the free product as if zero price meant not only a low cost of buying the product but also its increased valuation.” (Shampan’er, Working Paper, MIT)
Thus, offering an item for “free” (e.g., having a price of zero) increases its attractiveness much more than if it were offered for a penny. It makes sense, therefore, to offer two items for “buy one and get one free” rather than getting 50% off when you buy two.
The paper (Shampan’er, Working Paper, MIT) we’ve been discussing here shows that a price of zero increases the value of an item beyond what it would be if it were priced at a penny. Another paper (Murayama, 2010) found that a monetary reward had an undermining effect on intrinsic motivation. The zero price increased the intrinsic value of the product by removing its purchase from the market. The other paper, looking on the transaction in the opposite direction, showed that the zero price would prevent the undermining effect that a monetary price would have imposed.
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