January 2013 Blog with Durk and Sandy

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 The old principle: who does not work shall not eat, has been replaced by a new one: who does not obey shall not eat.— Leon Trotsky (1937)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).

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