November 2014 Blog with Durk and Sandy

APPETIZERS

Fools need Advice most, but only wise Men are the better for it.

— Benjamin Franklin, Poor Richard’s Almanack

Writing is the best way to talk without being interrupted.

— Jules Renard

It is perfectly okay to write garbage— as long as you edit brilliantly.

— C. J. Cherryh

Ah, you miserable creatures! You who think that you are so great! You who judge humanity to be so small! Why don’t you reform your-selves? That task would be sufficient enough.

— Frederic Bastiat, The Law in a rare display of anger, 
directed at do-gooders and would-be rulers of mankind.

Life, liberty, and property do not exist because men have made laws. On the contrary, it was the fact that life, liberty, and property existed beforehand that caused men to make laws in the first place.

— Frederic Bastiat, The Law

Every new tribunal, erected for the decision of facts, without the intervention of a jury … is a step towards establishing aristocracy, the most oppressive of absolute governments.

— Sir William Blackstone (1723–1780) 
Commentaries On the Laws of England 1765–1769

Every thing secret degenerates, even the administration of justice; nothing is safe that does not show how it can bear discussion and publicity.

— Lord Acton

I cannot accept your canon that we are to judge Pope and King unlike other men with a favorable presumption that they did no wrong. If there is any presumption it is the other way against holders of power, increasing as the power increases. Historic responsibility has to make up for the want of legal responsibility. Power tends to corrupt, and absolute power corrupts absolutely.

— Lord Acton

For all individuals, secrecy carries some risk of corruption and of irrationality; if they dispose of greater than ordinary powers over others, and if this power is exercised in secret, with no accountability to those whom it affects, the invitation to abuse is great.

— Sissela Bok, Secrets (1983)

When a Friend deals with a Friend 
Let the bargain be clear and well penn’d 
That they may continue Friends to the end.

— Benjamin Franklin, Poor Richard’s Almanack

Any increase in the FDA’s authority over anything is a clear and present danger to the nation’s health.

— Milton Friedman, Nobel laureate in 
Economics (in a letter to us, July 1993)

 

FDA = First Amendment Destroying Agency 
FDA = Freedom Destroying Agency 
FDA = Federal Death Agency

Official FDA Dictionary Announcement

The word “anti-inflammatory” is hereby CANCELLED. No one can use the scientific word “anti-inflammatory” in a label or an advertisement for a dietary supplement. “Anti-inflammatory” is now OFFICIALLY a term reserved for the use of pharmaceutical companies in relation to FDA-approved drugs. (NOTE: This is an example of a Government preferred speaker, in violation of the First Amendment per numerous U.S. Supreme Court decisions.*) We have indicated the word “anti-inflammatory” as “[CENSORED BY THE FDA]” in all labels or adverts for supplement ingredients described in the scientific literature as “anti-inflammatory” along with links to the National Library of Medicine.

The government choice of only certain speakers to be allowed to use the scientific word “anti-inflammatory” is another example of the same exact transgression. It goes on and on, folks. These people pay no attention to anybody’s Constitutional rights or to the Constitutional limits on their own powers. Oh, yes, they can be stopped but it will require more members of Congress willing to take the necessary steps to withdraw power and money from the FDA and face the loss of campaign donations from pharmaceutical companies who benefit from the present system, who won’t like losing their special privileges at all.

We suggest, as a start that doesn’t require Congressional action, that disfavored speakers prohibited from using the scientific word “anti-inflammatory” make a point of indicating that their label or advertisement on a supplement supported by scientific evidence of having anti-inflammatory properties is [CENSORED BY THE FDA] in violation of the First Amendment.

* See, for example, the U.S. Supreme Court decision in U.S. v. C&P (Bell Atlantic), 830 F. Supp. 909 (E. D. Va. 1993), off’d No. 93-2340, 93-2341 (4th Cir. 1994), where the Court ruled that Section 533(b) of the Cable Act that prohibited a telephone company from providing video programming to its service area subscribers that was not prohibited to others was a violation of the First Amendment as an example of unconstitutional government favoring of certain speakers.

 

Another GREAT IDEA From the FDA

According to the 7 August 2014 Nature (pg. 11), the FDA announced on 31 July of this year that it will regulate the development of diagnostic tests and genetic tests by hospitals and laboratories in the United States. The regulations, to be phased in over 10 years, will bring “scientific rigour to a field that has become unruly,” according to the Nature editorial on pg. 5 of that issue. We think it would have been more appropriate to say the regulations will usher in a new era of “scientific rigor mortis.”

We are seriously alarmed at the welcome offered by the ignoramuses at Nature to the FDA’s acquisition (by self-proclamation independently of Congressional authorization) to be the sole authority on diagnostic and genetic tests. “Such guidance should be welcomed,” the editorial exhorts, “not resisted.” Oh, really? The historical record of the FDA offers no support for such confidence in the FDA’s scientific expertise. Rather than the “unruly” nature of freedom to innovate that fosters a diversity of ideas for diagnostic testing and for genetic testing (some of which will be good ideas, some will not be so good), we will have the dead hand of the FDA determining (with all the scientific authority of a loaded gun pointed at your head) what test you may use. This is what the federalies have done to 23andME — and it is resulting in poor health planning that could have been avoided if 23andMe could have supplied truthful information about current understanding of genetic risks to their customers.

(Incidentally, the email message sent to customers by 23andMe celebrating their “progress” in “negotiating” with the FDA to receive the agency’s approval to offer genetic information is simply pathetic — no progress was in evidence — they might as well celebrate the fact that the loaded gun pointed at their head had not been used to shoot them so far, so there’s some real progress there! What the company seems to fail to realize is that by the time years have gone by and they have not gotten the FDA’s approval to offer genetic information, competitors outside FDA’s authority (such as those located in other countries) will be cleaning up selling the information. 23andMe would be better off, in our judgment, to hire Jonathan Emord and vigorously sue the agency for violating their First Amendment rights. They might be very surprised at the speed with which the agency decides to reconsider their current censorship of 23andMe.

Just another good reason to seek medical services such as individual testing kits from outside the U.S. This is good news for Hong Kong and India, though. Just mail a bit of your spit to Hong Kong or Mumbai …

Another good reason to RESIST FDA tyranny!

PLATELETS CRUCIAL FOR EARLY METASTASIS IN CANCER

Taurine Regulates the Sensitivity of Platelets to Aggregation 

Taurine May Help Protect Against Metastasis

As we wrote in the last issue of this newsletter, taurine was found in a human study to increase the resistance of platelets to aggregation by 30% or 70% in response to supplementation with extra taurine (beyond ordinary adequate dietary amounts) of 1400 mg/day or 1600 mg/day, respectively.¹ We have followed up that intriguing result and have found out more on taurine’s effects on platelets, as well as the latest research findings on the crucial role of platelets in establishing early metastatic niches for circulating cancer cells.

Inflammation and Coagulation May Be Parts of the Same Process

As we further noted in our article in the last Durk & Sandy newsletter, increased inflammation has been proposed to be derived from increasing activation of the coagulation system with age, as both inflammation and coagulation share many components and have strong interactions. “The increased hypercoagulable state observed with aging may account for the higher incidence of arterial and venous thrombosis in the elderly persons.”² Moreover, the increased coagulability may also be a factor in the increasing susceptibility of elderly persons to develop cancer.

Platelet Sensitivity to Aggregation in Cats and Humans: Stabilized by Taurine

The paper mentioned in paragraph #1 above reported that taurine had a significant effect in decreasing the sensitivity of platelets to aggregation in both cats and humans. The taurine-deficiency condition in cats, a form of heart failure, is often complicated by systemic arterial thromboembolism. Platelets in vitro treated with taurine are stabilized against a variety of aggregating agents. The human study showed taurine supplementation increased the threshold level of collagen required to stimulate platelet aggregation and that the platelets released less TXB2 (thromboxane).¹

Resistance to Clot Formation in Hibernating Animals May Be Due to Taurine

A study^2B on the unusual subject of how taurine acts to prevent clots from forming under conditions of very slow blood flow and increased blood viscosity brought about by low body temperature contributes to our understanding of taurine’s effects on platelets. First, hibernating animals were reported to accumulate by 2.25-fold their amino acid pool, with taurine accounting for 52% of that. Taurine was shown to prolong coagulation time in donor plasma with taurine increasing platelet aggregation to thrombin at taurine’s highest concentration (25 mM) by 9%. The result was significant yet maintained the thrombin time within normal limits. At 5 mM, taurine inhibited platelet aggregation by 10%. There was essentially no difference in the ability of taurine to prevent excessive platelet aggregation (without preventing normal platelet aggregation) over a 500% serum concentration range. This is very different from prescription anti-platelet drugs, which typically have a very narrow therapeutic window. If you took five times the prescribed dose of these anticoagulation drugs you would be in serious danger of bleeding to death.

Taurine Chloramine and Taurine Bromamine Are Also Anticoagulants

As reported in another paper,^2C taurine chloramine, the reaction product of taurine and hypochlorous acid (the latter released by the enzyme myeloperoxidase in the presence of chloride ion) is able to kill a variety of pathogens, including bacteria, fungi, viruses, protozoa, as well as degrading biofilms and also is anti-inflammatory and anticoagulant. Taurine bromamine, the reaction product of taurine and hypobromous acid (released by myeloperoxidase in the presence of bromide ion) has similar effects to taurine chloramine.

Platelets’ Important Involvement in Establishing Early Metastatic Niches

A new paper³ reports on a close relationship between platelets and tumor cells, including the early establishment of metastatic niches. As the paper explains, there are a number of mechanisms involved. For example, direct contact between tumor cells and platelets is reported to induce signaling through the transforming growth factor beta (TGFbeta1) and NFkappaB signaling pathways in tumor cells that induces a process called the epithelial-­mesenchymal transition, which is important in carcinogenesis and promoting metastasis. In early metastasis, platelets “recruit” granulocytes in the bloodstream via the release by the platelets of certain chemokines.

The researchers used a very clever technique for following metastasis from its inception: injecting tumor cells into the lungs of mice and examining in detail what took place during the first few minutes to hours of the ensuing process. Platelet aggregates surrounding tumor cells were observed after only one minute following the injection of the tumor cells. Granulocytes were recruited to the platelet-tumor cell aggregates over the next 30 minutes. Granulocyte-depleting antibodies could, in a single dose, result in fewer metastases. Similarly, platelet depletion was even more potent in inhibiting tumor cell seeding, almost completely eliminating it after 48 hours. The researchers report that recent clinical studies have shown that high levels of CXCL5, a chemokine released by platelets, and elevated numbers of circulating granulocytes are independent predictors of disease progression and poor prognosis for patients.

Taurine Content of Platelets Is Extraordinarily High

According to an early paper,⁴ normal human blood platelets contain more taurine than any other amino acid and, remarkably, increase taurine uptake against a concentration gradient of 440:1 (!) Unsurprisingly, taurine is actively transported (the process requires the expenditure of energy), as it would hardly do so otherwise against such a high concentration gradient. Clearly, taurine is important for platelet function to justify this metabolically expensive process.

CONCLUSION: Taurine May Help Combat Metastasis 
CONCLUSION: Taurine May Be Useful In Preventing Blood Clots in Those At Risk

We conclude that taurine may act to reduce the likelihood of early metastatic processes established by the activity of platelets and that taurine may, therefore, be useful as part of cancer prevention and even as part of cancer therapy. We conclude, as well, that taurine may be a useful therapy for people who are at risk of abnormal blood clots. For those with such a problem who have been prescribed Coumadin, an anticoagulant, note that Coumadin has a very small therapeutic index (the ratio between the therapeutic dose and the toxic dose). You might want to talk to your physician about increasing your intake of taurine and possibly decreasing your dose of Coumadin, but be sure to get your physician’s advice before doing this. He or she will have a far better understanding of the specifics of your case (because he or she can measure your platelet aggregation and coagulation) than we can have (since we are scientists, not physicians, and don’t know about your medical situation at all).

Suggested Daily Dose of OUR Taurine and Bromine Formulation Supplies 3,000 mg Taurine (as Two Divided Doses)

We are both taking the suggested daily dose of our new Taurine and Bromine formulation. As we had noted previously, Sandy has noticed significant improvement in her painful knee osteoarthritis with it. (This effect probably has nothing to do with platelet aggregation but may be due to the powerful anti-inflammatory effects of taurine chloramine and taurine bromamine, which are naturally formed in your body.) For even more information on our Taurine and Bromine Formulation, see the last issue of this newsletter for much more data and additional references.

Antiplatelet Effects of Allyl Isothiocyanate, a Major Component of Mustard

A new paper⁵ claims to be the first attempt to evaluate the effect of allyl isothiocyanate (AITC), a major constituent of mustard, on platelet aggregation. AITC is the source of the pungent flavor of mustard and studies have reported anti-inflammatory and antitumor effects of the compound. The effect of AITC on platelet aggregation and on thromboembolism in mice, rats, and humans were investigated. Platelet aggregation on rat platelets in vitro as induced by collagen, thrombin, adenosine diphosphate (ADP), and arachidonic acid (AA) were significantly inhibited by either 100 or 300 μM AITC, indicating that allyl isothiocyanate can suppress platelet aggregation by a number of different aggregation-inducing stimuli. The researchers also used the acute pulmonary thromboembolism mouse model to evaluate the protective effect of AITC in this commonly used model. Oral administration of 3 mg/kg AITC had a protective effect against pulmonary thrombo­embolism mortality, reducing it by 63%. AITC was also effective in inhibiting platelet aggregation in human PRP (platelet rich plasma) induced by collagen, thrombin, ADP, and AA, reducing the release by platelets of thromboxane2. The authors conclude that their data suggest that AITC has “remarkable antiplatelet effects and maybe a therapeutic potential for the prevention of aberrant platelet activation-related disorders.”⁵ So, slather mustard on your reduced fat hot dog and enjoy!

References

1. Hayes, Pronczuk, et al. Taurine modulates platelet aggregation in cats and humans. Am J Clin Nutr. 49:1211–6 (1989).
   2. Xu, Ameja, Tappia, et al. The potential health benefits of taurine in cardiovascular disease. Exp Clin Cardiol. 13(2):57–65 (2008).
   2B. Miglis, Wilder, et al. Effect of taurine on platelets and the plasma coagulation system. Platelets.13:5–10 (2002).
   2C. Gottardi et al. N-chloramines, a promising class of well-tolerated topical anti-infectives. Antimicrob Agents Chemother. 57(3):1107–14 (2013).
   3. Labelle et al. Platelets guide the formation of early metastatic niches. Proc Natl Acad Sci U S A.[publ. online July 14, 2014]:E3053–61.
   4. Ahtee et al. Transport of taurine by normal blood platelets. Br J Pharmacol. 52:245–51 (1974)
   5. Lee, Kim, Jung. Inhibitory effect of allyl isothiocyanate on platelet aggregation. J Agric Food Chem. 62:7131–9 (2014).

 

HYDROGEN GAS — FOR PREVENTION AND TREATMENT OF 
RHEUMATOID ARTHRITIS AND RELATED DISEASES

New Review Paper¹ Provides Update on Hydrogen for 
Hard to Treat Inflammatory Conditions

We continue here our series on trends in the use of hydrogen as a medical therapy as provided by inhalation, dissolved in water, or as generated by gut microbes that release hydrogen from fermentable dietary fibers (such as long chain oligofructose — inulin). For extensive background on the earlier research we described on hydrogen therapy, see [See “Hydrogen Therapy: The Emergence of A New Field of Medicine and How You Can Benefit From It Right Now” in the June 2012 issue of Life Enhancement].

Rheumatoid arthritis (RA) is a good example of a chronic inflammatory condition that is difficult to treat. About 1% of the population is thought to have this disease and its frequent accompaniment by rapidly progressive atherosclerosis makes it even more serious. Interestingly, this associated atherosclerosis is not necessarily linked to the usual risk factors, such as high serum cholesterol, high blood pressure, obesity, or diabetes. But what it is linked with is chronic inflammation, oxidative stress, and autoimmunity.

The chronic inflammation involved in RA is associated with ROS (reactive oxygen species) such as superoxide, hydrogen peroxide, hydroxyl radicals, and peroxynitrite (a powerful oxidant formed from the reaction of nitric oxide and superoxide). Hydrogen is particularly effective in scavenging hydroxyl radicals, the most damaging type of radical, and peroxynitrite.¹ Hydroxyl radicals may be responsible for a majority of toxicity associated with ROS because of its rapid reactivity and indiscriminate targeting of macromolecules² and is believed to be the source of most of the damage (to DNA and other macromolecules) resulting from radiation.

Whereas antioxidants can frequently react with radicals to reduce their toxicity, this often results in the creation of another radical, less toxic than the original radical but still able to cause some damage. A distinct advantage of hydrogen as an antioxidant is that it reacts with the hydroxyl radical and detoxifies it WITHOUT forming other potentially harmful radicals.¹

One study described in the review paper was the treatment of rheumatoid arthritis with a high concentration of hydrogen in water (4–5 ppm) in patients early in the course of the disease.³ Drinking 500 ml of this water daily for four weeks effectively reduced oxidative stress as well as improving patient disease condition.

In a gene expression array analysis,⁴ hydrogen caused an upregulation of 548 and downregulation of 695 genes in rat liver. The authors of the review paper¹ note that these results may indicate that a large number of small effects on gene function can have a large overall effect in a disease phenotype.

Hydrogen produced by fermentation of fiber in the colon is one of the reasons that a high fiber diet is healthful — it acts as an effective time-release source of hydrogen. One of the big — and undesirable — changes in our modern diet compared to that of our ancestors is a major reduction in fermentable fiber.

References

1. Molecular hydrogen: new antioxidant and anti-inflammatory therapy for rheumatoid arthritis and related diseases. Curr Pharm Des.19:6375–81 (2013).
2. Candeias, Patel, et al. Free hydroxyl radicals are formed on reaction between the neutrophil-derived species superoxide anion and hypochlorous acid. FEBS Lett.333:151–3 (1993).
3. Ishibashi, Sato, Rikitake, et al. Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis, an open-label pilot study. Med Gas Res.2:27 (2012).
4. Nakai, Sato, Ushiama, et al. Hepatic oxidoreduction-related genes are upregulated by administration of hydrogen-saturated drinking water. Biosci Biotechnol Biochem.75:774–6 (2011).

 

EPIGENETIC MECHANISMS IN CARDIOVASCULAR DISEASE — EXPLOSION OF NEW DATA

Boom! Bang! Blam! Epigenetic Mechanisms Being Uncovered in Many Diseases Explosion of New Data Reveals Important 

New Ways to Improve Health and Probably Live Longer 

Hot Off the Press — Greater Protection Against Cardiovascular Disease

Blam!! When an idea catches hold in science, you may see something akin to an explosion of important connections to that idea (as if, all of a sudden, “everything” is explained by the new idea) that bring together a huge amount of data, making it more understandable and more useful for doing the heavy lifting of living longer and better.

That is what is happening now in the field of epigenetics, the scientific area that explains how genetic expression can be controlled by regulatory mechanisms (for example methylation of DNA) that change how DNA is transcribed rather than changing the actual DNA code. These epigenetic mechanisms are being connected to a large variety of age-associated diseases and, indeed, to aging itself. It is important to note that, while aging is associated with increased DNA methylation overall (reducing genetic expression), there are areas where there is decreased DNA methylation (which increases genetic expression). Hence, once again this is a balancing act that gets out of kilter with the progression of aging.

Aspirin Reduces Methylation of ABCA1, Gene 
Important for Regulating Intracellular Cholesterol

Let’s look at a paper just published this year on epigenetics and disease. In this paper¹ researchers have identified DNA demethylation brought about by aspirin (acetylsalicylic acid) that corrects excessive methylation at the ABCA1 gene promoter locus (responsible for regulating intracellular cholesterol content by inducing its efflux). The scientists who published this paper¹ published a previous one² in which they showed that higher DNA methylation at the ABCA1 gene promoter locus was associated with lower levels of cardioprotective HDL-C and a previous history of coronary artery disease in those with familial hypercholesterolemia. Other papers (cited in reference #1) have reported lower expression of ABCA1 with higher DNA methylation levels. Another paper cited in reference #1 was of a Netherlands paper that found aging and prenatal famine exposure are associated with hypermethylation at the ABCA1 gene promoter locus. The researchers¹ note the proposal by another group³ that “aspirin use might reduce the methylation rate associated with aging, especially at cancer-related genes.” Hypermethylation at certain DNA locations causes the silencing (suppression of genetic expression) of cancer protective genes, thereby increasing the risk of cancer.

The study¹ relating methylation at the ABCA1 gene promoter locus and coronary artery disease susceptibility and the effect of aspirin on DNA methylation at that DNA locus provides evidence for a mechanism that explains at least part of the protective effect of low-dose aspirin against the development of cardiovascular disease. The researchers found that aspirin therapy was associated with a 3.6% lower ABCA1 methylation level, independent of aging or coronary artery disease status.

Another recent paper⁴ found that ABCA1 in arterial macrophages not only promotes cholesterol removal to apo-lipoprotein A-1, the major protein in HDL, but is also “a direct molecular link between the cardioprotective effects of cholesterol export from arterial macrophages and [via the activation of JAK2/STAT3] suppressed inflammation.”^3B This raises the possibility, the authors suggest, that “ABCA1 has a direct anti-inflammatory function in addition to its lipid export activity.” They note further that loss-of-function mutations in ABCA1 results in the acceleration of atherosclerosis.

Natural Demethylating Agents That Affect Epigenetic Processes

As we have written before, natural demthylating agents include EGCG (found at particularly high levels in green tea)⁵ and curcumin (a component of turmeric root),⁶ as well as others. Used at safe physiological doses (as would be found in a diet of those drinking green tea and/or eating foods (such as Indian curry dishes) enriched in turmeric spice), these may provide protection against increasing DNA methylation as occurs in aging and some age-associated diseases. The demethylating drug 5-aza-2’-deoxycytidine is currently used in the treatment of myelodysplastic syndromes and related demethylating drugs are in Phase II and III cancer trials. DNA hypermethylation can silence cancer suppressor genes; by restoring their expression, these genes can help combat the cancer.⁷

IMPORTANT NOTICE: The FDA has now declared the scientific word “anti-inflammatory” to be prohibited if used within sight of a dietary supplement (e.g., on a label or in an advertisement). The word may be used in commercial speech without risk of FDA thuggery (agency legal action against you) only in association with FDA-approved drugs. So much for the many U.S. Supreme Court decisions declaring it unconstitutional for the government to discriminate between different speakers in the communication of the same truthful speech. If it is protected speech for a scientific journal to report on the anti-inflammatory effects of a certain natural product, then it is unconstitutional for the government to prohibit certain other speakers from communicating that same information.

References

1. Guay, Legare, Houde, et al. Acetylsalicylic acid, aging, and coronary artery disease are associated with ABCA1 DNA methylation in men. Clin Epigenetics.6:14 (2014).
2. Guay et al. ABCA1 gene promoter DNA methylation is associated with HDL particle profile and coronary artery disease in familial hypercholesterolemia. 7:464-72 (2012).
3. Noreen et al. Modulation of age- and cancer-associated DNA methylation change in the healthy colon by aspirin and lifestyle. J Natl Cancer Inst.106(7). pii: dju161. doi: 10.1093/jnci/dju161. Print 2014 Jul.
4. Tang, Liu, Kessler, et al. The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor. J Biol Chem.284(47):32336-43 (2009).
5. Fang, Wang, Ai, et al. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res.63:7563-70 (2003).
6. Liu, Xie, Jones, et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett.19:706-9 (2009).
7. Du, Xie, Wu, et al. Reactivation of RASSF1A in breast cancer cells by curcumin. Nutr Canc.64(8):1228-1235 (2012).

 

IMPORTANT NEW DISCOVERY! 
NEW WAY TO PREVENT ATHEROSCLEROSIS

Answer to Question of Why Atherosclerotic Plaques 
Tend to Form in Areas of Disturbed 

Blood Flow Points to Way to Prevent Formation of 
Plaques in Those Areas

What could be an immense advance in the prevention of atherosclerosis was the discovery, reported in July 2014 The Journal of Clinical Investigation,¹ of the underlying cause of plaque formation in areas of disturbed blood flow, such as where arteries bifurcate. It has long been known that laminar (shear) flow in arteries is atheroprotective whereas turbulent blood flow in arteries induces the initiation and development of atherosclerotic plaques, leading to increased rate of formation of plaques in areas with disturbed blood flow. But why?

The new paper¹ reports that changes in gene expression take place in endothelial cells in response to exposure to laminar (shear) flow as compared to disturbed (turbulent) blood flow. These gene expression changes were found to be under the control of epigenetic mechanisms — hypermethylation within the promoter regions of 11 genes sensitive to mechanical stimulation in endothelial cells occurred when exposed to turbulent blood flow. The hypermethylation, acting as a sort of mechanosensitive master switch, altered the expression of these arterial genes (without changing the DNA sequence) to promote atherosclerosis rather than to protect against it.

The researchers were able to restore methylation status to normal (correcting the hypermethylation) by treating cells from C57BL/6 mice exposed to partial carotid ligation surgery (to induce turbulent flow) with the demethylating drug 5-aza-2’-deoxycytidine, FDA approved and currently used for the treatment of certain types of cancer, such as leukemia.

Not discussed in this paper but very relevant to its findings, however, there are natural products that also act as demethylating agents, including curcumin (found in turmeric root) and EGCG (epigallocatechin-gallate, found in particularly high concentrations in green tea).^2,3 We have written about the potential medical applications of these naturally occurring demethylating agents in earlier newsletters. See, for example, in our Nov. 2013 newsletter [“Epigenetic Changes in Expression of Genes via DNA Methylation” in Life Extension News, Volume 16, Number 10], our article on how demethylating agents can restore the sensitivity of diffuse B-cell lymphoma to chemotherapy.⁴ We are on the lookout for data on how potently the natural demethylating agents work in comparison to the drug 5-aza-2’-deoxycytidine.

The researchers found that subjecting the mouse carotid arteries to partial carotid ligation resulted (as detected by mRNA array) an increase in the expression of DNA methyltransferase (DNMT) by about 2.4 fold higher in the left carotid artery as compared to the right carotid artery that was exposed to shear (not disturbed) flow. They also reported that the increased DNMT expression took place in both endothelial and smooth muscle cells. These effects were confirmed using cultured human endothelial cells (HUVECs) exposed to oscillatory shear stress to mimic disturbed flow. DNMT1, but not DNMT3a or DNMT3b, were regulated in this flow-dependent manner in the above studies.

Surprisingly, the emergence of DNA methylation as a field of scientific research took place 35 years ago.⁵ For those interested in the technical details, here’s how it (methylation) takes place: DNA methyltransferases add (write) a methyl group to the 5 position of the cytosine pyrimidine ring.⁵ Cytosine is one of the four bases of DNA. Epigenetic modulation of gene expression (via methylation or acetylation of DNA) is being discovered to importantly regulate how the exact same DNA code gets translated. For example, neuronal activity has been reported to modify DNA methylation in the adult brain.⁶

Extracellular superoxide dismutase in human monocytes/macrophages is an important protective mechanism against atherosclerosis by inhibiting the oxidation of LDL via the acceleration of superoxide dismutation.^6B Here, researchers used the DNA methyltransferase inhibitor 5-azacytidine to demethylate genes whose expression was suppressed by hypermethylation, providing another example of how epigenetic mechanisms have been revealed to play a major role in atherosclerosis.

References

1. Dunn, Qiu, Kim, et al. Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis. FASEB J.124(7):3187–3199 (2014). 
   2. Fang, Wang, Ai, et al. Tea polyphenol (-)-epigallocatehin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res.63:7563–70 (2003). 
   3. Liu Z, Liu S, Xie Z, et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett. 19:706–709 (2009); Du, Xie, Wu, et al. Reactivation of RASSF1A in breast cancer cells by curcumin. Nutr Canc. 64(8):1228–35 (2012). 
   4. Clozel et al. Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma. Cancer Discov. 3(9):1–18 (2013). 
   5. Ladd. Epigenetic factors in neurodegeneration. Curr Tran Geriatr Gerontol Rep.1:206–13 (2012). 
   6. Guo, Ma, Mo, et al. Neuronal activity modifies the DNA methylation landscape in the adult brain. Nature Neurosci. 14(10):1345–51 (2011). 
   6B. Kamiya, Machiura, Makino, et al. Epigenetic regulation of extracellular superoxide dismutase in human monocytes. Free Rad Biol Med. 61:197–205 (2013).

 

EPIGENETIC MECHANISM IN DEPRESSION 
Rapid Antidepressant Effects Elicited By 
L-Acetylcarnitine Treatment in Rats and Mice

Another example of a recent discovery of genetic expression modified by epigenetic mechanisms was reported in a recent paper.⁷ In this study, rats with a genetic defect that results in reduced expression of certain glutamate receptors (mGlu2/3) and a spontaneous depressive state were treated with L-acetylcarnitine, a natural acetylating agent with antidepressant, antianxiety, and anti-pain effects (gene expression is modified by the addition of an acetyl group to DNA in certain brain regions). The activation of mGlu2/3 glutamate receptors shortens the time required for the therapeutic efficacy of conventional antidepressants in rats with this genetic defect. The results showed that treatment with L-acetylcarnitine, a naturally occurring molecule, caused a “rapid, robust, and long-lasting antidepressant effect” in the genetic model of depression in rats as well as (another part of the same study) the depression induced in mice by chronic unpredictable stress. Antidepressive effects were assessed by sucrose preference (depressed rodents ingest less sucrose) and the forced swim test, but the treatment also resulted in correction of the reduced BDNF (brain derived neurotrophic factor) in the hypothalamus of the rats with the genetic defect.

Reference

7. Nasca, Xenos, Barone et al. L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proc Natl Acad Sci U S A. 110(12):4804-9 (2013).

 

OLD AGE DEODORIZED!

The Human Body Odor of the Elderly Easily 
Suppressed — Smell of Aging Prevented, Not 
Covered Up With Perfumes

The distinct odor you perceive in the vicinity of many el­derly people is the result of unsaturated aldehydes such as 2-nonenal and 2-octenal that are produced by the degradation of unsaturated fatty acids, such as palmitoleic acid, in the aged person’s skin. In a study of people 55 years and older,¹ the subjects first took a shower, following which they were sprayed over their bodies with a 2% trehalose solution. Then, as the authors explain, the subjects put on clean underwear. Twenty hours later, samples of the unsaturated aldehydes were obtained from the used underwear and analyzed. The researchers report about a 70% reduction in the odor-causing unsaturated aldehydes from the subjects as a result of the 2% trehalose spray. Testing for oxidized unsaturated fats gave similar results. Here is a simple answer to a common problem — the smell that tells everybody your age! The above is a perhaps mundane application of trehalose that also applies to a more serious underlying problem — the degradation of fatty acids by lipid oxidation. We have written before about the properties of natural osmolytes such as trehalose that act as chaperones to help proteins to fold properly and to help prevent unfolding.² [See “The Origami of Aging” in the September 2008 issue.] They have other effects as well. Here¹ the researchers report that trehalose suppresses the formation of volatile aldehydes such as propanal, butanal, hexanal from alpha-linolenic acid (an omega-3 fatty acid) by 10–30% of the control. These aldehydes are not only a marker for lipid peroxidation, but cause damage themselves. For example, acetaldehyde, the aldehyde formed in the metabolism of alcohol (rather than fatty acids), produces the symptoms that reflect tissue damage when you experience a hangover. In one paper,³ the authors explained that an aldehyde lipid peroxidation product, 4-hydroxy-2-nonenal, is one of the most reactive and cytotoxic products of lipid peroxidation; the molecule can react with biomolecules, especially those containing sulfhydryl and amino groups, and cause cell death. Moreover, the authors¹ found that the formation of 3,4-decadienal from linoleic acid by boiling while exposed to air, was also significantly reduced by trehalose thus, as they reported, stabilizing linoleic acid. Interestingly, mushrooms contain 10–25% trehalose by dry weight.¹ Mushrooms don’t need social media to let us know they “like” trehalose.

Protection Against Lipid Oxidation —  
an Antiaging Mechanism

As lipid oxidation is a ubiquitous process and especially so in older individuals, whose antioxidant protective mechanisms are generally decreased as compared to the young, the prevention of lipid oxidation can be considered an anti-aging mechanism and, as explained, can be simply achieved by taking trehalose orally or (for off-odors emanating from the skin) by spraying the surface of the body.

The subjects were actually employees at the Japanese company where these studies were done. They may have been a bit taken aback to discover that they stank! (Of course, they also learned how to deal with it.)

Reference

1. Novel functions and applications of trehalose. Pure Appl Chem.74(7):1263–9 (2002).
2. Davies et al. Trehalose reduces aggregate formation and delays pathology in a transgenic mouse model of oculopharyngeal muscular dystrophy. Hum Mol Genet. 15(1):23–31 (2006).
3. Pappa, Chen, et al. ALDH3A1 protects human corneal epithelial cells from ultraviolet and 4-hydroxy-2-nonenal-induced oxidative damage. Free Rad Biol Med.34(9):1178–89 (2003).
4. THE RETURN OF INEFFABLE ESSENCE
5. Well, Actually, It Never Went Away But Here It Is With 
   GREAT NEWS for People Who Enjoy Eating 
   
   UMAMI Flavor Molecules ENHANCE APPETITE, But Also INCREASE SATIETY
6. Ineffable Essenceis a source of molecules delivering the highly popular natural UMAMI flavor — popular that is until some people get nervous when they find out that their taste buds crave the savory UMAMI flavor without realizing that that natural flavor is — uh oh — monosodium glutamate and disodium inosinate (the sodium salt of inosine 5-monophosphate), two flavor molecules found in foods like meat, cheese, and vegetables. Some people have a serious phobia about these natural flavor molecules probably due to years of misleading claims that MSG is hazardous to your health. Well, sure, anything is hazardous at a high enough dose. But at the “dose” you get in fresh foods naturally containing them, they are not at all hazardous to your health.
7. And now a new scientific report¹shows that in human subjects eating a soup preload containing the UMAMI flavor molecules monosodium glutamate and inosine 5’-monophosphate, these flavor molecules significantly reduced energy intake of a subsequent ad libitum lunch regardless of whether the UMAMI supplement was added to a low energy or a high energy preload. The researchers reported that when the subjects ate the soup, the addition of MSG/IMP “stimulated hunger on the first tasting of the soup, but when combined with high energy carbohydrate and protein, it resulted in a faster decrease in appetite during the subsequent test meal.” The researchers state that “[t]o our knowledge, this is the first study to report a biphasic action of MSG/IMP and implies that the increased liking at one eating occasion can lead to better regulation at the next eating occasion.”
8. Restoring the levels of MSG/IMP to those found in fresh food has a really profound effect on flavor. If you haven’t tried it, you don’t know what you are missing. We’ve been using Ineffable Essence for about 30 years and wouldn’t leave home without it.
9. FOOD SOURCES OF NATURAL GLUTAMATE Many foods naturally contain considerable quantities of glutamate. Fresh foods contain the most, as the glutamate is degraded by natural processes, as the food ages. That’s one reason why you get a more pleasurable burst of umami flavor from fresh food. Here are some foods with their natural content of glutamate (mg/100 g):

Parmesan cheese	8,210
Chedder cheese	6,090
Salmon	3,840
Steak	> 2,000
Broccoli	950
Beans	880
Walnuts	658
White mushrooms	400
Fresh tomato	310
These data from Ajinomoto Co., Inc.

 

Western Civilization Nearly Brought to Its 
Knees by the Chinese Restaurant Syndrome 

FACT or FICTION?

It is important to know that the amounts of monosodium glutamate used in foods at some Chinese restaurants are at much higher levels than the natural amounts normally found in food. Amounts as high as 25 grams of MSG in a bowl of wonton soup have supposedly been measured. This is far beyond a reasonable dose and actually you have to wonder why everyone eating soup containing this much MSG is not experiencing Chinese Restaurant Syndrome (CRS). Moreover, at such high doses, MSG would actually decrease the palatability of food (the threshold for this effect is > 60 mg/kg^A). In an early study of human subjects ingesting 5 grams of pure MSG, 32% of 77 subjects reported symptoms that included one or more of the following: feelings of warmth or burning, stiffness or tightness, weakness in the limbs, pressure, tingling, headache, lightheadedness, heartburn, or gastric discomfort.² As of 1979, 28,000 tons per year of MSG (presumably as the pure material) was said to be consumed in the U.S.^B

The researchers² conducted a double blind, placebo controlled trial with 27 students receiving 125 mg/kg of MSG or placebo. Of those, 12/27 showed symptoms and 15/27 failed to show symptoms in response to MSG. The 12 students showing symptoms were then treated double blind with 9 receiving pyridoxine (vitamin B6) — 50 mg daily — and 3 receiving placebo. Of the nine students that showed symptoms and received pyridoxine, 8/9 showed no symptoms in response to MSG after pretreatment with pyridoxine, while one subject did show symptoms. The authors propose that B6 is involved in the metabolism of glutamate and that a deficiency of B6 may, therefore, allow unprocessed glutamate to accumulate which may be the cause of the CRS symptoms. There appears to have been little followup on this research seeking a possible vitamin B6 deficiency in the etiology of CRS. (Talieferro. Monosodium glutamate and the Chinese Restaurant Syndrome: a review of food additive safety. J Environ Health. June 1, 1995)

No Explanation Forthcoming for Why Glutamate 
Found Naturally in Foods Does Not Provoke a 
Chinese Restaurant Syndrome

Noting the rather large amounts of glutamate found naturally in parmesan cheese, could there be an Italian Restaurant Syndrome that nobody is talking about. Not so far as we know. It appears that no such thing has ever been reported. (We’re just joking, of course. Our point is that glutamate is safe to consume at amounts naturally found in foods or that are added to supermarket-purchased food by consumers to increase its content of glutamate to that naturally found in very fresh food.)

References

331. Airoldi, et al. (1979) Attempts to establish the safety margin for neurotoxicity of monosodium glutamate. In: Glutamic Acid: Advances in Biochemistry (Filer LJ, et al, eds.), pp. 321–331. Raven Press, New York, NY (1979). 
     B. Giacometti. Free and bound glutamate in natural products. In: Glutamic Acid: Advances in Biochemistry and Physiology(Filer LJ, et al, eds.), pp. 25–33, Raven Press, New York (1979). 
     1. Masic and Yeomans. Umami flavor enhances appetite but also increases satiety. Am J Clin Nutr.100:532–8 (2014). 
     2. Folkers et al. Biochemical evidence for a deficiency of vitamin B-6 in subjects reacting to monosodium L-glutamate by the Chinese Restaurant Syndrome. Biochem Biophys Res Commun. 100(3):972–7 (1981).

QUICK QUIZ

1. If you want to avoid Chinese Restaurant Syndrome, you should:
   1. Avoid going to Chinese restaurants
   2. Eat large quantities of parmesan cheese
   3. Order only “no MSG added” food at a Chinese restaurant and sprinkle on Ineffable Essence to restore glutamate and inosine to their natural levels found in fresh meats, cheeses, eggs, and vegetables.

2. Umami is a flavor distinct from sour, salt, sweet, and bitter. Sources of umami include:
   1. Glutamate and inosinate
   2. Powdered mushrooms
   3. Soy sauce
   4. All of the above

1215 The Year of Magna Carta

2015 800 Years Later, We’re Way 
Overdue for the Next Magna Carta

Historical facts and direct quotes that follow are from Danny Danziger & John Gillingham’s “1215: the Year of Magna Carta” (Touchstone, 2003). [Buy at http://tinyurl.com/l7ekrzf].

THE RISE AND FALL OF THE MAGNA CARTA

“Magna Carta, Clause 47: All forests which have been afforrested in our time shall be disafforested at once.” During King John’s lifetime, a third of England was said to be forest, though that word didn’t mean what we mean by “forest” today. “Forest” as the word was used then was to a large extent ordinary inhabited countryside that was declared to be “forest” by the King, which then established for the King “a royal monopoly over the management and distribution of resources previously enjoyed by local lords and tenant farmers.” (This is much like “our” nationalized forests today, all of which were in use by Americans before they were nationalized.)

Not surprisingly, the huge profits the King could obtain by way of declaring lands to be “forests” meant that conversion of inhabited countryside to the King’s “forests” was taking place at a rapid rate, with rules and regulations (primarily aiming to extort money from those living in those areas) covering most uses of the “forest.” Penalties for unauthorized hunting included blinding (hart or hind) and (for large game animals) death or mutilation (such as removal of the offender’s eyes or testicles). But nearly every other use actually permitted, such as farming, was conditional based on regulations subject to change without notice. “When one woman had an unauthorized ditch dug around her own land, it was confiscated, and it cost her a hundred marks to buy it back.” (A mark was worth about 2⁄3 of a pound.) The right of farmers to graze livestock on the “forests” was strictly controlled and permission to do so could be withdrawn at any time.* Just like today’s federalie bureaucrats!

In 1217 and following King John’s death, further reforms were added in the Forest Charter of 1217 to disafforest larger sections of land. “Every freeman was to have the right to develop his own land within the forest so long as this did not cause damage to a neighbor; in future no man was to lose life or limb for taking the king’s venison.”

It is said that a practice preceding the reforms of the Magna Carta and the Forest Charter was the disafforestation by various Kings, such as Richard I in 1190, in exchange for money payment. “This could only have happened because people in those counties raised funds and petitioned for something they regarded as being of benefit to them all; such action helped to create county communities and was of great importance in paving the way for Magna Carta. It gave people experience of cooperative political action, of demanding reform and being prepared to pay for it. The Crown accepted that the extent of the forest could be a matter for negotiation — and this too would be a feature of Magna Carta.”

Eight hundred years later …

Eight hundred years later, we are back to square one. About one third of the land area of the United States is declared “federal lands,” which are not public lands in any sense but are lands claimed by and controlled by the Federal government, with use strictly limited and subject to change without notice. Hunting on these lands is no longer punishable by death or mutilation, but for many “endangered” species and even for some non-endangered species such as crows, to do so can result in potentially long prison sentences and large fines. The woman who was punished for digging a ditch around her own land (see above) would encounter a similar fate if she did so today. (A rancher friend of ours was sent to federal prison for doing this.) Forest reforms instituted by Magna Carta can be seen no more, with the creation of a permanent Federal land estate (the federal lands) having taken place, at first slowly, during the last 120 years and then rapidly with the passage of the Federal Land Policy and Management Act of 1976 which established by Congressional statute the permanent Federal land estate. No longer does a freeman have the right to develop his land provided it does not cause damage to a neighbor.

R.I.P. Magna Carta

* See the July 2014 issue of this newsletter for our article [See “A True Story — Durk’s Participation In The Negotiations With The Bureau Of Land Management and Two Rancher Friends for Grazing Rights”] on how the Bureau of Land Management regulates livestock grazing today (what an eyewitness, a close friend of ours, reports really happened when heavily armed federal forces invaded the ranch of Cliven Bundy and what Durk Pearson saw and heard as an eyewitness to negotiations between two ranchers and the Bureau of Land Management on a contract for livestock grazing). King John would have approved.

 

RESTORING FREEDOM — A GOOD START

Most “Laws” These Days Are “Rules” Decreed By Regulatory Agencies, Frequently Without Any Legal Authority Provided in Congressional Statute — AND VOID OF CONSTITUTIONAL PROTECTIONS, SUCH AS THE RIGHT TO A JURY TRIAL 

BELOW: A GOOD START TO GETTING THE ADMINISTRATIVE STATE UNDER CONSTITUTIONAL CONTROL

The concern of many is that of an administrative state running amok, generating immense and unlimited numbers of rules and regulations purporting to be “laws” despite the fact that the Constitution in Article I Section 1 specifies that “all legislative [lawmaking] Powers herein granted are to be vested in a Congress of the United States, which shall consist of a Senate and a House of Representatives.” In 2013, 72 bills were passed by Congress, while over 5,000 rules and regulations were issued — over 80,000 pages in the FEDERAL REGISTER — by regulatory agencies. In the process, the Constitutional rights as recognized in the Bill of Rights have been jettisoned in administrative “courts” (not to be confused with Constitutionally authorized courts — see Article III) that includes the right of jury trial (the administrative “court” is judge, jury, and executioner, that even controls what evidence you may enter in your own defense), the Fifth Amendment right not to testify against oneself (they can seize your papers and use them against you), the Fourth Amendment right to be free of unreasonable searches and seizures of persons, houses, and effects and no warrants shall issue but upon probable cause, supported by Oath or affirmation, and describing the place to be searched and the person or things to be seized (warrantless searches by regulatory agencies are common, or the agency simply issues it’s own “administrative business records demands” that are not authorized in the Constitution.

Increasingly, however, it is the search for a solution to this problem that is appearing in public discussions.

We suggest that a bill such as HR3396 that was written by Constitutional attorney Jonathan W. Emord for then-Representative Ron Paul (the bill was introduced) would be an excellent start. We publish it in its entirety here for those who might like to follow up on it. The bill would require that any regulatory agency rule or regulation that imposes a cost above a certain specified amount (for example, costs of $5,000 or more to an individual in a year) would have to notify those regulated within a year and would have to discontinue enforcing the rule until a bill was passed by the Congress and signed by the President that provided for the requirements of those rules. This would help restore the Constitutional requirement that all laws emanate from Congress, thereby stemming the destructive force of proliferating regulatory rules and regulations.

Text of the Congressional Responsibility and Accountability Act

This bill was introduced on July 29, 2009, in a previous session of Congress, but was not enacted. The text of the bill below is as of Jul 29, 2009 (Introduced).

111th CONGRESS 1st Session H. R. 3396 

IN THE HOUSE OF REPRESENTATIVES 

July 29, 2009

Mr. Paul introduced the following bill; which 
was referred to the Committee on the Judiciary

A BILL

To amend title 5, United States Code, to prohibit agencies from enforcing rules that result in a specified economic impact until the requirements of those rules are enacted into law by an Act of Congress, and for other purposes.

1. Short title

This Act may be cited as the “Congressional Responsibility and Accountability Act.”

2. Rules that result in a specified economic impact

Section 553 of title 5, United States Code, is amended by adding at the end the following:

(f)

(1) Before adoption of a rule, each agency shall determine whether compliance with the rule will result in a specified economic impact. If an agency determines that a rule will result in a specified economic impact, the agency shall provide notification and shall not enforce the rule until the requirements of the rule are enacted into law by an Act of Congress.

(2) Not later than 180 days after the date of the enactment of this Act, and annually thereafter, each agency shall determine whether any rule of that agency has resulted in a specified economic impact in the preceding year. If an agency determines that a rule has resulted in a specified economic impact in the preceding year, the agency shall provide notification and, not later than 365 days after making such determination, shall no longer enforce the rule until the requirements of the rule are enacted into law by an Act of Congress.

(3) In this subsection:

(A) The term “provide notification” means transmit the rule determined to result in a specified economic impact and the findings supporting such a determination, including relevant public comments in the case of a proposed rule, to the Federal Register for publication and to the Committees on Appropriations of the House of Representatives and the Senate, not later than 30 days after a determination is made in the case of a proposed rule and not later than 60 days after a determination is made in the case of an existing rule.

(B) The term “a specified economic impact” means any of the following:

(i) Costs to any individual of $5,000 or more in a year.

(ii) Costs to any partnership, corporation, association, or public or private organization, but not including the Federal Government or a State government, of $10,000 or more in a year.

(iii) Costs to all persons in the aggregate, but not including the Federal Government or a State government, of $25,000 or more in a year.

(iv) The loss by 1 or more United States citizens of existing employment in a year.

The Declaration of Independence declared the un­acceptability of rules and regulations imposed without representation by the British Crown on the colonists in its famous list of grievances that includes: “He has erected a Multitude of new Offices, and sent hither Swarms of Officers to harrass our People, and eat out their Substance.” This is an excellent description of the Swarm of regulatory agencies and their Officers that are currently eating out our Substance.