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 EatingUMAMI 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.

APPETIZERS

Every time you spend money, you’re casting a vote for the kind of world you want.
— Anna Lappe

The hardest thing in the world to understand is income tax.
— Albert Einstein

No man ever listened himself out of a job.
— Calvin Coolidge

If you want a guarantee, buy a toaster.
— Clint Eastwood

YOUR PHYSICS LESSON FOR TODAY

Heisenberg and Schrodinger are driving, and get pulled over. Heisenberg, in the driver’s seat, is asked by the officer, “do you know how fast you were going?” Heisenberg replies, “No, but I know exactly where I am.” The officer looks at him confused and says, “you were going 108 miles per hour!” Heisenberg throws up his arms and cries, “Great! Now I’m lost.”

The officer, now more confused than ever, orders the two men out of the car, and proceeds to inspect the vehicle. He opens the trunk and yells at the two men, “Hey! Did you guys know you have a dead cat back here?” Schrodinger angrily yells back, “We do now, jerk!”

The Problem with Learning Physics from Jokes
Is That Unless You Already Know the Physics,
You Won’t Get the Punch LineOK. The Heisenberg uncertainty principle shows mathematically that you cannot know both your momentum AND your location at the same time. The police officer did not know that. The Schrodinger wave equation shows that, in order to determine whether, in your universe, the cat in your trunk is alive or dead, you have to take a look, otherwise you don’t know. The cop didn’t know that, either. The moral of this story is: Never expect a dumb cop to have a clue about physics. Your best bet is to fail to arrive at the pullout at the same time as the cop. You can blame it on Heisenberg. The cop will have you point blank on the speed violation but won’t have a clue whether you were in the speed zone at the time. In the meantime, the cat has died and the stench will act as a cop repellant as the Schrodinger equation waives the cop’s authority out of existence.

NOW DO YOU GET IT??

HYDROGEN THERAPY NOW APPEARING IN LEADING JOURNALS!

HYDROGEN-RICH WATER DECREASES LDL CHOLESTEROL AND IMPROVES HDL FUNCTION IN HUMAN TRIAL

Papers on hydrogen therapy are now appearing more frequently and in leading journals. A paper published this year¹ in the Journal of Lipid Research reports on the results of a small trial of human volunteers (12 men, 8 women equal to or older than 43 years), all of whom had one or more of the following conditions associated with metabolic syndrome: prehypertension (diastolic 80–89 mm Hg and systolic 139 mm Hg or lower; fasting serum glucose from 5.2 to 6.9 mmol/l (prediabetic), total cholesterol greater than 5.18 mmol/l and/or LDL cholesterol greater than 2.59 mmol/l; body mass index between 25.0 and 34.9 kg/m(squared); or waist circumference greater than or equal to 100 cm for men and greater than or equal to 88 cm for women. The subjects were considered to potentially have metabolic syndrome.

After 10 weeks of treatment with hydrogen-rich water, total cholesterol and LDL cholesterol levels were significantly decreased in 18, while 1 patient had increased total and LDL cholesterol and one other patient had no significant effects to either parameter. Interestingly, while 10 of the 20 patients were smokers and 10 were nonsmokers, treatment decreased serum total cholesterol and LDL cholesterol in both smokers (said to be occasional smokers) and nonsmokers.

We were particularly interested in the finding that the oxidative state and some functional properties of the HDL molecule were improved in the subjects treated with hydrogen-rich water. This is especially important because HDL can, especially under conditions of oxidative stress, lose its protective properties and actually become pro-atherogenic. One of the results, for instance, was that the ability of the isolated HDL particles to elicit efflux from cholesterol-loaded macrophages was dramatically higher after hydrogen treatment compared with the HDL particles isolated from the serum before hydrogen treatment. In addition, hydrogen was found to reduce the oxidation of LDL and LDL-mediated inflammation. Hydrogen also decreased apoB100, considered to be an antiatherogenic effect, while there was no change in ApoAI.

Although the criteria for having potential metabolic syndrome were relatively mild (only one of the above listed conditions needed to be present), this actually underlines the meaningful nature of these protective effects of hydrogen on HDL and LDL since it ought to be more difficult to demonstrate improvements in a less abnormal condition.

Reference

1. Song et al. Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome. J Lipid Res. 54:1884-93 (2013).

ONE OF THE MOST IMPRESSIVE EFFECTS OF HYDROGEN YET

Hydrogen Treatment Prevents Lipid Deposition in Descending Aorta in Rat Model of Periodontitis

As we have mentioned in this newsletter before (in the context of bacteria found in tooth decay being involved in the development of atherosclerotic plaques), the connection between periodontitis and atherosclerosis is becoming supported by more data (hypothesis under development). In this very interesting paper,¹ scientists have shown in a study of rats with induced periodontitis that lipid deposition occurred in the descending aorta, but when a similar group of rats with induced periodontitis was treated with hydrogen (as hydrogen-rich water), those rats had a significantly lower level of lipid deposition in their descending aortas. Hence, the results of this study if verified in people could be of major importance to a great many people with periodontitis, who may be unknowingly vulnerable to a silent source of atherosclerosis.

The researchers propose that the reduced lipid deposition was a result of decreased serum oxidized LDL and decreased aortic oxidative stress. The periodontal tissue examined showed infiltration by inflammatory cells, which was reduced in the group receiving hydrogen water therapy. Importantly, results showed that “[l]ipid deposition in the descending aorta was observed in all rats in the periodontitis group and in none of the rats in the control or periodontitis + HW [hydrogen water] groups.”¹

Reference

1. Ekuni et al. Hydrogen-rich water prevents lipid deposition in the descending aorta in a rat periodontitis model. Arch Oral Biol. 57:1615-22 (2012).

HYDROGEN MAKES “THE BIG TIME”!
JOURNAL OF THE AMERICAN HEART ASSOCIATION
PUBLISHES NEW HYDROGEN THERAPY PAPER

Hydrogen Gas Improves Functional Outcome Following Cardiac Arrest to an Extent Comparable to That of Therapeutic Hypothermia in Rats

The potential benefits of hydrogen therapy are beginning to appear in major journals. A 2012 paper¹ reports that hydrogen gas treatment (via inhalation) was as effective as therapeutic cooling (hypothermia) in mitigating mortality and functional outcome following cardiac arrest in a rat model. The paper starts by introducing hypothermia for cardiac arrest as being “widely accepted as the gold standard method to improve survival and limit neurological outcomes in patients who achieve return of spontaneous circulation (ROSC) after CA [cardiac arrest]. Despite that, it is still underutilized.” The authors suggest that the treatment of cardiac arrest is an unmet medical need. They hypothesized that hydrogen gas inhalation, having been shown to be effective in ameliorating the damage caused by ischemia/reperfusion in heart and brain of different animal models, might be an effective therapy for CA. They also cite some papers providing preliminary human clinical data on hydrogen in various medical conditions.

In this study, rats were subject to cardiac arrest and treated with isotonic saline, hydrogen gas, therapeutic hypothermia, or hydrogen gas + therapeutic hypothermia. The researchers found the survival rate after ROSC was 43% (6/13) in the control group, 92% (12/13) in the hydrogen group, 77% (10/13) in the TH (therapeutic hypothermia) group and 100% (13/13) in the hydrogen + TH group, whereas 72 hour survival rates were 31% (4/13), 69% (9/13), 69% (9/13), and 77% (10/13) respectively.

The oxygen tanks carried in ambulances already contain a small amount of carbon dioxide to help stimulate respiration. It would be simple and inexpensive to include 1% hydrogen (which is below the minimum flammability threshold) in the oxygen; this might save a lot of lives and prevent much disability. Simple and inexpensive? Oh, sorry, we forgot about FDA regulations on medical oxygen … Unfortunately for heart attack victims, the FDA has declared that the oxygen they receive is a drug, which means that addition of 1% hydrogen would make it an unapproved new drug. Since this addition is unpatentable, no one is going to spend a billion dollars or more to obtain FDA approval. The Federal Death Agency strikes again!

Reference

1. Hayashida et al. H2 gas improves functional outcome after cardiac arrest to an extent comparable to therapeutic hypothermia in a rat model. J Am Heart Assoc.1:e003459 (2012) doi: 10.1161/JAHA.112.003459.

 

INCREASING CGMP PROMOTES THE EXPANSION AND
BROWNING OF WHITE ADIPOSE TISSUE

A BRITE FUTURE FOR THE TREATMENT OF OBESITY

A remarkable new discovery¹ published this year reports that increasing cyclic GMP (cGMP) signaling can cause white adipose tissue to develop the properties of “brown-like” or “brite” (also sometimes called beige) fat tissue that, like brown adipose tissue (BAT), uncouple mitochondrial metabolism from ATP synthesis to the generation of heat (thermogenesis) via UCP-1 (uncoupling protein 1). Also, like brown adipose tissue, the browned white adipose tissue have larger numbers of mitochondria than white adipose tissue and also increased insulin sensitivity. The authors¹ suggest (and we agree) that browning white adipose tissue is a potential treatment for obesity.

One way to increase cGMP is with phosphodiesterase 5 inhibitors (which inhibit the degradation of cGMP) such as those used in the treatment of erectile dysfunction. Some of the experiments in this paper¹ tested the effects of sildenafil (Viagra^®) as a browning agent. (Note: Cialis^® is another phosphodiesterase 5 inhibitor, which however has a far longer half-life than sildenafil; we expect that it would have similar effects on browning white adipose tissue though the effect of the longer half-life is unclear but might be expected to be advantageous. Further testing will provide answers.)

The researchers studied the effect of cGMP signaling, focusing on cGMP-dependent protein kinase I (PKGI), which is expressed in white adipose tissue. By inducing overexpression of PKGI, there was a 4.3 fold increase in the abundance of UCP-1, uncoupling protein 1, the uncoupling protein found in brown adipose tissue (BAT) that is part of BAT’s thermogenic program. Importantly, “treatment of DC57BL/6 mice with phosphodiesterase inhibitor sildenafil (12 mg/kg/d) for 7 days caused 4.6 fold increase in uncoupling protein-1 expression and promoted establishment of a brown fat cell-like phenotype (“browning”) of WAT in vivo.”¹ The basal expression of PKGI in white adipose tissue is negligible.¹ “Our study clearly shows that activation of PKGI in adipocytes increases adiponectin expression and, in parallel, decreases gene expression of proinflammatory cytokines (MCP1, CCL3, CCL7, IL6, and TNFA).”¹

The researchers also investigated the effects of a demethylating agent, 5-aza-deoxycytidine, on the UCP-1 gene promoter. They found that the treatment of 3T3-LI adipocytes with this drug increased basal levels of UCP-1 mRNA levels, which (they also report) were even further increased in cells expressing high levels of PKGI treated with cGMP. Moreover, the expression of adiponectin by the 3T3-LI adipocytes treated with cGMP was increased and this effect was also further increased in cells overexpressing PKGI. The expression of PGC-1alpha, a “master” regulator of mitochondrial biosynthesis, was also increased in the white adipose tissue of mice treated with sildenafil.

Possible Enhanced Expression of UCP1 With Curcumin or EGCG

In a separate paper,³ the UCP1 gene was demethylated by 5-aza-deoxycytidine that increased the expression of the gene. The natural substances curcumin⁴ and EGCG⁵have been found to be demethylating agents and might, therefore, have similar effects to that of 5-Aza-deoxycytidine by increasing basal levels of UCP-1 mRNA. If so, these substances may also act as “browning” agents. We expect to see papers published on these effects, should they be revealed in new experiments, following hot on the heels of these new findings on UCP1 demethylation.

The bottom line is that both cGMP and sildenafil promote browning of white adipose tissue. The effect, the authors say, can be induced by phosphodiesterase 5 or phosphodiesterase 3B inhibitors, via increase in cGMP or cAMP (cyclic AMP). The researchers cite a study in which 12 weeks of sildenafil (Viagra) treatment of normal mice fed a high fat diet reduced body weight and improved energy balance.²

In their “Discussion” section in the paper,¹ the authors note that cGMP has been shown to regulate glucagon secretion (and, thus, gluconeogenesis by the liver), mitochondrial biogenesis, and the development of “classical” BAT (brown adipose tissue). Out-of-control gluconeogenesis, that is, excessive release of glucose by the liver (which is supposed to be suppressed by insulin following a meal), is a major cause of the hyperglycemia of diabetes.

We look forward to a “brite” future that may result from the treatment of obesity with compounds that increase cGMP.

References

1. Mitschke et al. Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J. 27:1621-30 (2013).
2. Ayala et al. Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice. Diabetes. 56:1025-33 (2007).
3. Shore et al. Role of Ucp1 enhancer methylation and chromatin remodelling in the control of Ucp1 expression in murine adipose tissue. Diabetologia. 53:1164-73 (2010).
4. Liu et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett. 19:706-9 (2009).
5. Fang et al. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 63:7563-7570 (2003).

PROTECTION AGAINST RECURRENT
STROKES WITH RESVERATROL

Having suffered a transient ischemic attack (a TIA, or partial stroke) or a minor stroke greatly increases one’s risk of having a more serious recurrent stroke. One paper¹reports that 6–15% of these people suffer stroke recurrence within 90 days and in up to 21% of patients by one year after the initial insult. The researchers¹ had found that an MCAO (middle carotid artery occlusion), a very common rodent model of a stroke, can after a short period result in scattered brain cell death (necrosis) and that a moderate stroke following this event had exacerbated damage. They note that damage from a TIA or minor stroke is not always detectable with standard diagnostic imaging techniques.

The researchers studied 42 rats that were subject to MCAO, which resulted in their suffering a greater than 90% reduction in cortical perfusion in the core region. They modeled a recurrent stroke by subjecting the rats to a mild ischemic stroke followed by another mild stroke, which resulted in a higher damage score than what occurred from just the initial stroke with more dead tissue. Treating the animals with oral resveratrol for three days (25 mg/kg/day) prior to a single mild stroke reduced the amount of damage detected as compared with animals that received vehicle (same as that carrying the resveratrol). Interestingly, resveratrol did not improve cerebral blood flow in the affected areas, but did improve blood-brain-barrier function, thereby reducing leakage and edema. “Rather unexpected was our finding that resveratrol-treated rats subjected to recurrent stroke had less ischemic injury than untreated rats with a single mild ischemic stroke.”¹

The scientists also studied the protective effects of resveratrol in vitro in endothelial cells. “… we found that pre-treatment of brain endothelial cells in culture with low doses of resveratrol improved their viability following oxygen glucose deprivation which could also explain improved BBB [blood-brain-barrier] following cerebral ischemia. The improved viability observed in their study was, the authors point out, consistent with the resveratrol-mediated protection of cerebral endothelial cells against apoptosis induced by oxidized low-density lipoproteins, as well as protection against high-glucose induced damage or death from oxidative stress as reported in other studies.

These results suggest a possible means of reducing the damage of a recurrent stroke in those who may have already had a minor stroke. As the authors sum it up: “Collectively, the results support that oral resveratrol treatment provides a low risk strategy to protect the brain from enhanced damage produced by recurrent stroke which is mediated in part by a protective effect of resveratrol on the endothelium of the cerebrovasculature.”

Reference

1. Clark et al. Protection against recurrent stroke with resveratrol: endothelial protection. PLoS One. 7(10):e47792 (Oct. 2012).

BEWARE OF FALLING DINOSAURS:
A CONTINUING SAGA OF CORRUPTION AND REVOLUTION

The article “FDA’s Changing Culture: What Every Food Company Needs to Know” in the April/May 2013 Food Safety Magazine, came as quite a surprise. Trade publications, as a rule, defer to regulatory agencies. A food industry publication would never call the FDA personnel that inspect food plants “thugs” for example. This deference may be coming to an end as we approach levels of FDA (and other regulatory agency) corruption that makes such attempts at industry politeness as you are hit over the head by agency gangsters simply futile. The new article is a warning to the food industry by a food industry trade publication of what to expect from FDA operating under the new Food Safety Modernization Act (FSMA).This article is a continuation of the talk we gave at Life Enhancement Products’ symposium in Las Vegas on preparing for an oncoming economic collapse which, among other things, will require planning ahead for your medical needs. Here we explore how food prices will slowly increase, then soar, as a result of taxes and regulations, including new FDA authority over the food industry. Stockpiling food may also be an important part of planning ahead to avoid falling dinosaurs.

The article explains that “the agency [FDA] is quietly becoming much more inspection-oriented and enforcement-minded, even before FSMA is fully implemented.” The article notes that “[t]he demeanor of FDA personnel during inspections has changed as well. Inspectors (or ‘investigators’ as FDA refers to them) are much more assertive, often insisting on access to records before the new legal authority becomes effective and asserting their ‘right’ to take photographs even without express legal authority.” “Moreover, instead of simply collecting product samples for laboratory testing of finished product, inspectors are increasingly conducting extensive environmental testing throughout facilities. Environmental testing is more likely to detect a problem than finished product testing, making it an important tool for the agency during inspections. Such testing can be so extensive that some have dubbed this practice a ‘swab-a-thon.’” For an agency seeking to increase its power, a testing regime that is able to magnify the appearance of danger is simply made to order.

What the article is saying here, in plain English, is that FDA inspectors are often thugs who make demands for which they have no legal authority. The inspection of every detail of a food plant is not the most cost-effective way to establish safety. Most economists agree that the inspection of final products, which are after all the source of any potential health and safety risks to the public, is far more cost-effective than examining everything in a manufacturing facility. It is, however, much easier for the FDA to identify supposed safety problems when every feature of a food plant is examined rather than just the finished products, giving the FDA the opportunity to milk companies by assessing large fines. And unsurprisingly, bullies are the type of people who fit in well with an agency culture of enforcement.

The cost of protecting a food plant from such intensive searches (all without a search warrant), requiring extensive lawyer assistance, plus the costs of the fines that the FDA can demand for the slightest deviation from the myriad and often vague rules and regulations will increase the price of food. Moreover, the practice of defensive food production, just as in the case of doctors practicing defensive medicine,* piles on costs to production that eventually are passed on to consumers. When you see food prices go up, you might give a thought to how much of that the FDA is responsible for. The failure of the TSA to improve airline safety despite their “inspections” (tests have found it easy to sneak prohibited items, even guns, past these inspections^†) suggests that the FDA’s intensive food plant inspections are performed at a heavy cost. The TSA, in fact, frequently violates the First Amendment free speech rights of “inspected” passengers by arresting those that complain of mistreatment. Would it come as a surprise if we see the same from these more aggressive FDA inspectors?^‡

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* Defensive product production involving testing excessively in order to catch even unlikely sources of FDA inspectors’ attention, simply adds costs to production without benefit to customers but of course customers will have to pay the extra costs. In addition, whereas those doing a good job of producing food products for the public should feel a sense of achievement as benefactors of the general public, the threat of FDA demands and punishment hanging over your head and determining much of what you have to do in your daily work will rapidly change that to a culture of defensiveness and hostility.

† This reminds us of the time that Sandy sat down in a commercial airliner to find that the very intoxicated and scruffy looking guy next to her had taken out a very large (9“ long) switchblade knife from his carryon and was attempting to impress her with it. She was impressed all right and, claiming she needed to use the toilet, had warned the plane personnel just before takeoff in time for airport security to come in and remove the guy from the plane. Every passenger on this plane as well as the crew owes Sandy a thanks for performing the real security check on this flight. Oh, and how did the knife get by airport security? Easy. The knife was made of titanium.

‡ We heartily recommend Emord & Associates as a source of legal advice on FDA inspections. (202-466-6937) (This is an entirely unsolicited endorsement for which we receive no payment of any kind. We have used the legal services of Jonathan W. Emord in our FDA lawsuits and other legal representation for over 20 years and recommend him and his firm without hesitation. The firm offers classes for how to deal with FDA inspections.)

The article goes on to explain how the FDA plans to expand implementation of the Park doctrine, where company executives can be held responsible for criminal misdemeanors for which they had no responsibility or knowledge, with personal fines of up to $100,000 if no deaths are involved, $250,000 if a death occurs, and up to 1 year’s imprisonment. The Park doctrine is considered a type of strict liability, where you don’t have to have had anything to do with the criminal act to be held responsible, hence, fined or imprisoned. And interestingly, if you are charged with one of these criminal misdemeanors, you are allowed no right to a jury trial! Whatever happened to the Sixth Amendment, which says, “In all criminal prosecutions, the accused shall enjoy the right to a speedy and public trial, by an impartial jury of the State and district wherein the crime shall have been committed …” The Sixth Amendment, like much else of the Constitution, has been made a nullity by power-lusting politicians and bureaucrats and by Courts unwilling or unable to defend the Constitution.

CORRUPTION AND THE CAUSE OF REVOLUTIONS

We highly recommend Alexis de Tocqueville’s The Old Regime and the French Revolution (Anchor Books, 1955^§) for understanding how corruption in governments is a major forerunner of revolution. It starts with the loss of legitimacy fostered by corruption. Remarkably, the Chinese communist party, concerned about rapidly spreading government corruption in China and the possibility of a revolution as a result of it, is now recommending this Tocqueville book and even giving out copies to major party officials to attempt to warn of the consequences of increasing government corruption.

FREE SPEECH UPDATE

U.S. DEPT. OF JUSTICE AND DEPT. OF EDUCATION MANDATE UNCONSTITUTIONAL SPEECH CODES AT VIRTUALLY ALL COLLEGES AND UNIVERSITIES

The Foundation for Individual Rights in Education (FIRE) (www.thefire.org) has sent out a press release warning that on May 10, 2013, the U.S. Dept. of Education joined by the U.S. Dept. of Justice have mandated a speech code concerning “sexual harassment” that is so broad in its scope that virtually every student would be in violation of its provisions. The mandate will apply to any college or university that receives federal funding or where even one student receives a federal scholarship or loan, thereby including nearly all such institutions.

Continuing on a trend of ignoring Constitutional prohibitions on government actions, the new speech codes will now mandate punishment for such student actions as (these are just examples):

1. Any expression related to sexual topics that offends any person.
2. Any sexually themed joke overheard by any person who finds that joke offensive for any reason.
3. Any request for dates or any flirtation that is not welcomed by the recipient of such a request or flirtation.

Lest anyone misunderstand, the Executive Branch of the federal government is running totally amuck by making laws on what you can say (in violation of Article I Section 1 which grants all lawmaking powers to Congress) as well as ignoring the First Amendment’s prohibition (“Congress shall make no law … abridging the freedom of speech …”) denying the federal government’s legislative body the authority to limit free speech.

We can hardly wait for the backlash to come, both from the Courts and from the general public. The media, in the meantime, may find themselves stuck in the trap of their own political correctness. Attempting to extricate themselves from the authoritarians at the Obama White House should make for an amusing spectacle.

For more on the incredible details, see FIRE and The Volokh Conspiracy (posted 13 May 2013):

http://thefire.org/case/925

http://thefire.org/article/15767.html

http://thefire.org/article/15835.html

http://thefire.org/article/16050.html

We donate to FIRE and encourage you to do so, too.

https://secure.commonground.convio.com/FIRE/generaldonationform/

The Administration Says Universities Must Implement Broad Speech Codes

See also:

http://www.openmarket.org/2013/05/10/federal-title-ix-enforcers-effectively-define-dating-and-sex-education-as-sexual-harassment/

And finally for something beautiful that touched our hearts:

“Space Oddity”

 

PROGRESS SLOW IN DEVELOPING AN OVERALL
MODEL OF THE AGING PROCESS

A recent paper¹ proposes some reasons why progress has been slow in closing in on a comprehensive explanation of aging. As the authors note, “over 300 mechanisms have been proposed in the literature to explain the underlying molecular and physiological processes of the aging process.”

They suggest two particular problems in pulling all this diverse data together:

1. “Limiting an open communication between different investigators and diverse disciplines. Investigators involved in the exploration of one single pathway might be unable to adequately appreciate advancements in other aspects of the very same phenomenon under study. Also, some fields of research are extremely far from each other (for what concerns backgrounds, methodologies, and measurements) to easily develop effective and successful collaborations.”

2. “Driving the development of interventions too narrowly focused. In other words, experts of one specific mechanism of aging are more likely to exclusively explore preventive/therapeutical protocols for that selected target.”

These problems were the reasons why we wrote our book Life Extension, a Practical Scientific Approach (Warner Books, 1982) that became a #1 bestseller, selling over 1,000,000 copies. We realized that there were many diverse areas of science (for example, food science, petroleum science, animal husbandry, toxicology, etc.) that were developing work that was very relevant to the study of aging and, yet, workers in one of these scientific fields could be entirely unaware of what researchers in another area were doing. We felt that it was extremely important to help bring out the relatedness of much of this important work in order to speed up the development of aging research and, according to feedback we got from many other scientists, we succeeded in doing so. That’s why Life Extension, a Practical Scientific Approach became a classic. It wasn’t because we were doing all this work. It was because a lot of people were doing work that added up to considerably more knowledge of the aging process than the scientific community (and, indeed, the public at large) realized we had. In the process, of course, it became clear that there was an awful lot more left to be learned (still is) which pointed in a number of directions that hadn’t received much attention before.

Reference

1. Cesari et al. The stress of aging. Exp Gerontol. 48:451-6 (2013).

HOW YOU, TOO, MAY BENEFIT FROM THE
NEW RESEARCH ON DNA METHYLATION AND
“BROWNING” OF WHITE ADIPOSE TISSUE

As we have been writing in recent newsletters, DNA methylation is a widely investigated way that gene transcription (expression or non-expression) is regulated. DNA hypermethylation seems to generally (but not always) suppress gene expression, whereas DNA hypomethylation generally (but not always) increases gene expression. Both EGCG and curcumin have been discovered to act as hypomethylation agents, that is, to decrease DNA methylation and to possibly increase gene expression. (See, for example, references 4 and 5 in the article above.)

A recent paper¹ reports the good news that methylation of the UCP1 enhancer is responsible in mice adipose tissue for the regulation of UCP1 gene expression. This could be important because UCP1 (uncoupling protein 1) is a major genetic factor that is responsible for regulating thermogenesis (energy expenditure) in brown adipose tissue (brown fat). The fact that methylation controls the expression of UCP1 suggests that the use of demethylating agents such as EGCG or curcumin might increase its expression, at least in brown fat or “browned” white fat. The researchers¹ found, in fact, that demethylation of the UCP1 promoter by the demethylating agent 5-aza-deoxycytidine increased UCP1 expression while methylation of UCP1 promoter-reporter constructs decreased expression.

It has been discovered that it is possible to cause white adipose tissue to become “browned,” (as discussed in the article above) that is to change its properties to more closely resemble brown adipose tissue. One of the most important of those changes is for adipocytes to become able to express Ucp1 and to engage in thermogenesis. We anticipate additional publications on the use of demethylating agents for the browning of white fat.

Reference

1. Shore et al. Role of Ucp1 enhancer methylation and chromatin remodelling in the control of Ucp1 expression in murine adipose tissue. Diabetologia. 53:1164-73 (2010).

CLOSING IN ON EXERCISE IN A PILL? MAYBE.
DECREASED METHYLATION IN MUSCLE GENOME
TURNS ON EXERCISE-INDUCED GENE EXPRESSION

Researchers have identified many of the skeletal muscle genes that are triggered by exercise and contribute importantly to the benefits of exercise. A new paper¹ now identifies an important role played by DNA methylation in exercise-induced gene expression. DNA methylation is an important process for determining when genes are expressed (turned on) or silenced (turned off) and much has been learned about natural products that are able to trigger increased DNA methylation (which generally decreases gene expression) or decreased DNA methylation (which generally increases gene expression). With these discoveries, we are moving ever closer to pharmacological control of enhancing genetic expression that would otherwise require exercise as a trigger. Here’s the latest story:

A recent paper¹ found that DNA methylation was decreased in skeletal muscle biopsies obtained from healthy sedentary men and women after they performed acute exercise. “Exercise induced a dose-dependent expression of PGC-1alpha [an important regulator of mitochondrial biogenesis], PDK4, and PPAR-delta, together with a marked hypomethylation on each respective promoter. Similarly promoter methylation of PGC-1alpha, PDK4, and PPAR-delta was markedly decreased in mouse soleus muscles 45 minutes after ex vivo contraction.” “Promoter methylation of PGC-1alpha, Tfam, Mef2a, and Cs, but not PDK4, decreased prior to gene expression changes.”¹ “Conversely, reactive oxygen species (ROS) production (induced by H2O2 [hydrogen peroxide]) elicitated hypermethylation.” The authors suggest, therefore that “DNA hypomethylation is an early event in [muscle] contraction-induced gene expression.”

In other recent work, EGCG^1A and curcumin^1B have been identified as natural substances that act as hypomethylating agents, e.g., they decrease DNA methylation. In light of the above study,¹ this suggests (we speculate) that taking proper doses of EGCG and/or curcumin shortly before exercise might enhance the hypomethylation induced by muscle contraction, increasing the beneficial effects of exercise. Mild exercise might be able to provide the benefits that would otherwise require more energetic exercise. (The latter has not been demonstrated but we hope to see studies published in the near future testing this hypothesis.)

The authors¹ suggest, however, that DNA methylation does not exclusively control exercise-induced gene expression as they have found that ionomycin, AICAR, or ROS production increased mRNA expression without altering promoter methylation. Thus, they propose that DNA methylation “may serve as a selective mechanism to orchestrate the activation of a subset of genes but, clearly, other mechanisms, such as transcription factor activation and recruitment to the chromatin, are likely to be involved.”

Exercise Alters Epigenetic Parameters in Rat Hippocampus

In a second paper on exercise and DNA methylation (an epigenetic process),²researchers found that exercise can alter DNA methylation in the hippocampus of 3 month and 20 month old Wistar rats. As it is known that exercise can improve cognitive processes, DNA methylation is an interesting link that suggests a possible mechanism for the effect of exercise on cognition.

The authors first point out that epigenetic mechanisms have been shown to affect cognition in earlier studies where histone deacetylase (HDAC) inhibitors improved memory in aged rodents.² Moreover, exercise has also been shown to ameliorate age-related cognitive decline in rodents. Other studies have reported that exercise modulation of histone deacetylase status in the brain enhanced transcription of genes in the brain related to cognitive function.

The researchers therefore studied the effects of exercise on epigenetic changes as a consequence of aging. They followed the effects of two exercise regimens, a single session of treadmill exercise or chronic treadmill exercise, on changes in DNA methylation in the hippocampus.

The findings included that methylation changes as a result of exercise differed in 3 month old (young) and 20 month-old (aged) male Wistar rat hippocampi. They report decreased DNMT1 (DNA methyltransferase 1) activity in senescent human fibroblasts and suggest that this is correlated with a genome-wide tendency to DNA hypomethylation in multiple vertebrate organs during the aging process.² Aged hippocampi were found to have lower levels of H3-K9 methylation levels. As the researchers explain, histone methylation can cause either gene activation or gene repression.

The single exercise experiment in young adult rats resulted in significant decrease in both DNMT1 and DNMT3b, two methyltransferases, which could reduce DNA methylation and, consequently, affect gene expression. In contrast, the single exercise test did not have an effect on DNMT1 or DNMT3b levels in the hippocampi of the 20 month-old (aged) rats. Other details reveal considerable complexity to the pattern of epigenetic changes in the hippocampus in conjunction with exercise in young and old rats. It is interesting to note that EGCG inhibits methyltransferases.

It appears quite plausible (but not proven) that DNA methylation changes in the hippocampus as a consequence of exercise may play a role in the improved cognition resulting from exercise but that these effects are different in young vs. old rats. Exercise in a pill? We aren’t there yet, but come back in five years or so.

References

1. Barres et al. Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab. 15:405-11 (2012).
1A. Yang et al. Reversal of hypermethylation and reactivation of genes by dietary polyphenolic compounds. Nutr Rev. 66 (Suppl 1):S18-S20 (2008).
1B. Liu et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett. 19:706-9 (2009).
2. Elsner et al, Exercise induces age-dependent changes on epigenetic parameters in rat hippocampus: a preliminary study. Exp Gerontol. 48:136-9 (2013).

REDUCING THE RISK TO MALE HUMANS OF
MAKING EXCESSIVELY GENEROUS ECONOMIC OFFERS TO
PHYSICALLY ATTRACTIVE FEMALES

Continuing our reports on new findings in the biology of economic behavior, we offer the following humdinger. A new paper¹ reports that minocycline, an antibiotic in the tetracycline family, reduces the risk to men of making excessively generous offers in economic exchanges with very attractive females, what is called a “honey trap.”

Recognizing that this sort of behavior can be a risky, costly form of bias in economic exchanges, this information may be quite beneficial to those inclined to the “honey trap.” The description of a number of past studies showed that in economic exchanges, minocycline pretreatment resulted in less of a “high” feeling in economic transactions with very attractive women and induced more sober decision-making. In the experiments reported in the new study,¹ 98 healthy men played a trust game with 8 photographed young females after four days of treatment with either 200 mg/day of minocycline (usually used as an antibiotic at this dose) or placebo. The photos of the women’s faces formed the basis for a decision on the part of each male participant of how much out of 1300 yen (about $13 at that time) they would give a woman.

As the authors explain, “[r]ecent studies with human subjects show that minocycline, a commonly used tetracycline antibiotic, may facilitate focus on appropriate environmental cues for social decision-making, possibly by reducing noise and other factors (e.g., personality and arousal) that can obstruct decisions.”¹

It is not clear how the females “betrayed” their benefactors or expressed untrustworthiness, but the results clearly showed that men in the placebo group offered more money to the females that were more attractive, while the men in the minocycline group did not. For the most attractive women, the difference between the amounts of money offered by the men in the placebo group was statistically significantly greater than that offered by the men in the minocycline group, but the difference was not significant for the less attractive women.

There was some discussion of possible neurological mechanisms to explain these effects. In rodent models, minocycline is reported to reduce microglial activation (inflammation*) in certain areas of the brain, including the putamen, thalamus, and frontal cortex. The researchers also report that, in some studies, minocycline may link microglia with glutamate and dopamine interaction. It appears that the effect on “honey trap” behavior is, at present, though, poorly understood.

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* The phrase “inflamed by lust” may be literally true! We hope that this experiment will be repeated with gay men viewing photos of other guys. Although we expect a similar result, you can never tell …

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Reference

1. Watabe et al. Minocycline, a microglial inhibitor, reduces “honey trap” risk in human economic exchanges. Sci Rep. 3:1685 DOI: 10.1038/srep01685.

IT’S A NAD+, NAD+, NAD+, NAD+ WORLD

[CAUTION: This article is unusually complex. Life can be like that.]

There is growing interest in the nucleotide NAD+ (nicotinamide adenine dinucleotide) because of recent research revealing it’s regulation of diverse pathways controlling lifespan.¹ A paper by Belensky et al² in the same issue of Cell as a commentary on it¹found that a precursor of NAD+ (nicotinamide riboside) extended yeast life span via activation of pathways that respond to increased NAD+, such as those that depend upon the SIR2 gene. Moreover, the beneficial effects of caloric restriction appear to be NAD+ dependent, as well as mediated by the NAD+-dependent SIRT1/Sir2 activity.^3,4

The ratio of NAD+/NADH regulate many aspects of metabolism, including DNA repair, stress resistance, and cell death.⁴

“Changes in NAD+ metabolism have been associated with several pathologies, including neurodegenerative diseases, cancer, cardiovascular disease, and normal ageing.”⁴ In fact, the authors of paper #4 suggest that, “NAD+ synthesis through the kynurenine pathway [de novo synthesis of NAD+ from tryptophan] and/or salvage pathway [from nicotinamide] is an attractive target for therapeutic intervention in age-associated degenerative disorders.”

NAD+ is also reported to play a critical role as part of cellular respiration during the process of oxidative phosphorylation and ATP production.⁴ “Therefore, ATP synthesis and redox potential is directly proportional to intracellular NAD+ concentration.”⁴ The NAD+/NADH ratio is a measure of the metabolic state because of its importance in regulating intracellular redox state.⁴

Sirtuins are deacetylases that regulate large numbers of genes by removing acetyl groups from DNA. The function of the longevity gene SIRT1 has been shown to depend on the availability of NAD+. “Not surprisingly, the life-enhancing properties of sirtuins go hand in hand with those of NAD+ metabolism, suggesting a causal relationship where SIRT1 translates alterations of NAD+ levels into transcriptional events.”⁴ Interestingly, the DNA repair enzyme PARP (poly(ADP-ribose) polymerase) uses large amounts of intracellular NAD+ and is thereby in competition with sirtuins for the limited supply of NAD+. Under conditions of excessive expression of PARP, cellular NAD+ can be depleted, killing the cell. “Hyperactivation of PARP1 following DNA strand breaks can rapidly consume intracellular NAD+ pools, resulting in a loss of ability to synthesize ATP, and the cessation of all energy-dependent functions and consequent cell death.”⁴

The authors of paper #4 note that over-activation of PARP1 has been reported in the brains of Alzheimer’s disease patients, as well as in those with diabetes, MTPT-caused Parkinson’s disease, shock, and other conditions. It has been suggested that PARPs may play a role in aging by promoting NAD+ depletion. One study⁵ reported that PARP-1 activity in mononuclear blood cells increases with aging in at least thirteen mammalian species. In another study,^5A researchers reported that “[o]ur results suggest that oxidative stress induced NAD+ depletion could play a significant role in the aging process, by compromising energy production, DNA repair and genomic surveillance.” The latter study^5A examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female Wistar rats, reporting that “[o]ur results are the first to show a significant decline in intracellular NAD+ levels and NAD/NADH ratio in all organs by middle age (i.e., 12 months) compared to young (i.e., 3 month old) rats … The strong positive correlation observed between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor.”

The authors of one paper^5B write that “… when cells are subjected to oxidative stress by exposure to H2O2 [hydrogen peroxide], PARP-1 is activated and SIRT1 activity is robustly reduced, as PARP-1 activation limits NAD+ bioavailability. Treatment with PARP inhibitors in these circumstances allows the cell to maintain NAD+ levels and SIRT1 activity. … these observations indication that PARP-1 is a gatekeeper for SIRT1 activity by limiting NAD+ availability.”

The authors of paper #4 report that “[p]revious work from our group has shown for the first time that resveratrol induces a dose-dependent increase in activity of the NAD+ synthetic enzyme nicotinamide mononucleotide adenyl transferase (NMNAT1)” but that this is unpublished data.

Interestingly, a very recent paper found that “enhancement of the NAD+/NADH balance through treatment with NAD+ precursors inhibited metastasis in xenograft models [of breast cancer], increased animal survival, and strongly interfered with oncogene-driven breast cancer progression in the MMTV-PyMT mouse model.”⁶

Mitochondrial Biogenesis Induced by SirT1 Depends on Availability of NAD+

A very recent paper,^6A in explaining how exercise or SirT1 activates PGC-1alpha, a master regulator of mitochondrial biogenesis, points out that the activity of SirT1 relies on NAD+ as a necessary coenzyme. The paper^6A goes on to describe how, in its study of exercise in mice, chronic contractile activity (exercise) has a robust effect on mitochondrial biogenesis and that resveratrol acted synergistically with exercise to increase mitochondrial content when SirT1 was activated. “[T]he maximal effect of RSV [resveratrol] requires both SirT1 and a condition of energy demand in muscle that would be high in NAD+ and AMP, cofactors which activate SirT1 and AMPK, respectively.” ^6A

Precursors That Can Be Taken As Supplements to Increase NAD+

There is (so far) remarkably little information on ways to increase NAD+ with natural products that are commercially available. There are three main physiological precursors: tryptophan, niacin, and niacinamide. It is reported that, “the administration of radiolabeled nicotinamide and nicotinic acid [niacin] has clearly shown that nicotinamide is a better precursor of NAD+ and that nicotinic acid is rapidly cleared by being converted to nicotinamide and excreted as nicotinuric acid.”^6B Resveratrol was reported in paper #4 (but only as unpublished data) to dose-dependently increase the activity of the NAD+ synthetic enzyme nicotinamide mononucleotide adenyl transferase. In another paper,⁷ quercetin was reported to oxidize NADH to NAD+ in rat liver, thus increasing the availability of NAD+. However, as the researchers also explain, “direct measurements of NADH/NAD+ are very difficult to perform.”⁷ This was as of the paper’s publication in 2005. The researchers inferred the NADH/NAD+ ratio from the ratio of beta-hydroxybutyrate to acetoacetate. Quercetin has also been reported to be a PARP-1 inhibitor.^7B Niacinamide is known to be an inhibitor of PARP, thus may prevent the decrease in NAD+ that results from PARP activity. There is a salvage pathway of specific enzymes that converts niacinamide to NAD+.

Niacinamide (NAM) As a PARP Inhibitor May Explain NAM’s Antiviral Effects

Interestingly, PARP is reported to be critical for the integration of foreign DNA, as absence of the PARP enzyme interrupts the HIV life cycle.^7C An early study published in 1996 on the effects of niacin reported that a daily niacin (combining niacin and niacinamide) intake in AIDS patients that equaled only 3–4 times the U.S. recommended daily allowance (at that time) of 20 mg/day experienced slower progression and improved survival.^7D That was, of course, well before the current multidrug cocktails were developed that enable HIV infected individuals to survive 20 years or more, but still demonstrates the anti-viral effects of the vitamin.

Other natural PARP inhibitors include the flavonoids fisetin and tricetin⁸ and flavone.⁹

More About PARP Inhibitors

Keep in mind that PARP is an important enzyme for DNA repair and transcription. Hence, PARP inhibition has to be limited so as to avoid excessive impairment of DNA repair. “Impaired SIRT1 activity due to PARP mediated NAD+ depletion allows increased activity of several apoptotic effectors such as p53, therefore sensitizing cells to apoptosis. Adequate NAD+ levels are therefore critical to maintaining Sirt1 activity which can delay apoptosis and provide vulnerable cells with additional time to repair even after repeated exposure to oxidative stress.”^5A

PARP inhibitors are now being incorporated into therapy for diseases such as cancer and diabetes.^10–12 This cripples the DNA repair ability of cancer cells, which generally have deficient DNA repair to start with, further limiting their ability to repair DNA and making the cancer cells more vulnerable to apoptosis. In diabetes, moderate PARP inhibition can help maintain cellular NAD+ availability for ATP synthesis. In fact, as mentioned above, overactivation of PARP1 has been reported in diabetes, Alzheimer’s disease, traumatic brain injury, shock, and other conditions.⁴ A recent paper^5C reported that PARP is hyperactivated by oxidative stress induced by beta amyloid; this PARP overactivation (and depletion of NAD+) could be an important source of cell death in Alzheimer’s disease.

Another recent paper “provided quantitative evidence in support of the hypothesis that hyperactivation of PARP due to an accumulation of oxidative damage to DNA during aging may be responsible for increased NAD+ catabolism in human tissue. The resulting NAD+ depletion may play a major role in the aging process by limiting energy production, DNA repair and genomic signaling.”¹³ In this paper, the authors note that other investigators have linked PARP1 hyperactivity to diseases such as diabetes, MPTP-induced Parkinson’s disease and injury induced brain disorders. They further reported for the first time, in this study,¹³ that PARP activity increases with age in human skin, correlating with both age and NAD+ depletion (in males, but not in females). Consistent with the regulation of SIRT1 activity by NAD+ availability, they found a significant decline in SIRT1 activity with age in post-pubescent males but, again, not in females. The authors suggest that one possibility is that females have a greater capacity to recycle NAD+ from the PARP metabolite nicotinamide; however this remains to be determined.

References

1. Denu. Vitamins and aging: pathways to NAD+ synthesis. Cell. 1293):453-4 (May 4, 2007).
2. Belenky et al. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell. 129:473-84 (2007).
3. Wolf. Calorie restriction increases life span: a molecular mechanism. Nutr Rev. 64(2):89-92 (2006).
4. Massudi et al. NAD+ metabolism and oxidative stress: the golden nucleotide on a crown of thorns. Redox Rep. 17(1):28-47 (2012).
5. Grube and Burkle. Poly(ADP-ribose) polynerase activity in mononuclear cell lines of 13 mammalian species correlates with species specific lifespan. Proc Natl Acad Sci USA. 89:11759-63 (1992).
5A. Braidy et al. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in Wistar rats. PLoS One. 6(4):e19194 (Apr. 2011).
5B. Canto and Auwerx. Interference between PARPs and SIRT1: a novel approach to healthy ageing? Aging. 3(5):543-7 (2011).
5C. Abeti and Duchen. Activation of PARP by oxidative stress induced by beta amyloid: implications for Alzheimer’s disease. Neurochem Res. 37:2589-96 (2012).
6. Santidrian et al. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest. 123(3):1068-81 (2013).
6A. Menzies et al. Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis. J Biol Chem. 288(10):6968-79 (2013).
6B. Imai. The NAD world: a new systemic regulatory network for metabolism and aging — Sirt1, systemic NAD biosynthesis, and their importance. Cell Biochem Biophys. 53:65-74 (2009).
7. Buss et al. The action of quercetin on the mitochondrial NADH to NAD+ ratio in the isolated perfused rat liver. Planta Med. 71:1118-22 (2005).
7B. Milo et al. Inhibition of carcinogen-induced cellular transformation of human fibroblasts by drugs that interact with the poly(ADP-ribose) polymerase system. FEBS J. 179(2):332-6 (1985).
7C. Murray. Nicotinamide: an oral antimicrobial agent with activity against both Mycobacterium tuberculosis and human immunodeficiency virus. Clin Infect Dis. 36:453-60 (2003)
7D. Tang et al. Effects of micronutrient intake on survival in human immunodeficiency virus type 1 infection. [a study of the Multicenter AIDS Cohort Study] Am J Epidemiol.143:1244-56 (1996)
8. Weseler et al. Poly (ADP-ribose) polymerase-1-inhibiting flavonoids attenuate cytokine release in blood from male patients with chronic obstructive disease or type 2 diabetes. J Nutr. 139:952-7 (2009).
9. Geraets et al. Flavone as PARP-1 inhibitor: its effect on lipopolysaccharide induced gene-expression. Eur J Pharmacol. 573:241-8 (2007).
10. Peralta-Leal et al. PARP inhibitors: new partners in the therapy of cancer and inflammatory diseases. Free Radic Biol Med. 47:13-26 (2009).
11. Soriano et al. Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase. Circ Res. 89:684-91 (2001).
12. Du et al. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 112(7):1049-57 (2003).
13. Massudi et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One. 7(7):e42357 (July 2012).

CLIMATE MODELS DEAL POORLY WITH CLOUDS AND VEGETATION

STATE OF THE ART MODEL COULDN’T SIMULATE KNOWN DROUGHTS

The latest report in the 18 April 2013 Nature on climate models indicates continuing difficulties in dealing with environmental factors affecting the climatic influence of water (as in clouds, vegetation, precipitation, and droughts). Indeed, the test discussed in the Nature news article¹ showed that the model couldn’t figure out what had actually taken place using data on large droughts (those lasting several decades each), which is far easier to do than to start from now and project into the future to predict the occurrence of droughts where you don’t have any data on when and where such large drought events may take place. And when you add to that the fact that water vapor is a vastly more important greenhouse gas than carbon dioxide, it would appear that current, even state-of-the-art models are unlikely to provide usable projections on what future climate will be doing.

The article was based on work done by Sloan Coats of Columbia University’s Lamont-Doherty Earth Observatory in Palisades, New York and his colleagues. Although the simulations did “find” a number of droughts lasting several decades each, these droughts didn’t happen when the real mega-droughts happened. In fact, the article said, “drought occurrences were no more in agreement when the model was fed realistic values for variables that influence rainfall than when it ran control simulations in which the values were unrealistically held constant.”¹ One of the study participants, Jason Smerdon, was quoted as saying “The model seems to miss some of the dynamics that drive large droughts.” The group also tested other models, which did no better, even failing to reproduce a series of multi-decadal droughts that occurred in the southwest U.S. during the Medieval Climate Anomaly (until recently known as the Medieval Warming).

Finally, the article reported that a projection prepared for the Colorado Water Conservation Board revealed that models even disagreed on the direction of regional changes, with disagreements on whether mean precipitation in Colorado will increase or decrease.

After telling us this, the last paragraph assures us that these failures “don’t change the larger picture.” We should feel pretty confident, “scientists” say, that the southwest will warm and that water will become scarcer. Yes indeed. We would have to be downright mean and nasty skeptics (or, gasp, “deniers”) to doubt the “big picture” (of human-caused warming disaster presumably) when the models deal poorly with the dynamics of water, which in a climate model (for planet Earth, in any event) is surely the biggest factor affecting the overall picture.

Reference

1. Schiermeier. Climate models fail to “predict” US droughts. Nature. 496:284 (2013).

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It is in the nature of a hypothesis, when once a man has conceived it, that it assimilates everything to itself, as proper nourishment; and, from the first moment of your begetting it, it generally grows stronger by everything you see, hear, or understand.
— Laurence Sterne

APPETIZERS

Theory guides; experiment decides.
— motto of analytical chemist Izaak Maurits Kolthoff

Theory is a good thing, but a good experiment is forever.
— Peter Leonidovich Kapitza, Soviet physicist

The future is already here—It’s just not very evenly distributed.
— William Gibson, science fiction author

 

IFOIA, NEW RESOURCE FROM THE REPORTERS COMMITTEE FOR FREEDOM OF THE PRESS ONLINE TOOL TO CREATE, SEND, AND TRACK FEDERAL AND STATE FREEDOM OF INFORMATION REQUESTS

For those wanting to get information via the FOIA or Privacy Act, this is a website set up especially to help you do that. You can even deliver your FOIA request to the relevant agency with the help of iFOIA. iFOIA can be found at www.ifoia.org. At www.rcfp.org, you can also get help from their Federal FOIA Appeals Guide.

Uncovering and bringing to public attention the illegal goings on at Federal agencies is one of the best ways to help fight back.

APPETIZERS

But ambitious encroachments of the federal government, on the authority of the State governments, would not excite the opposition of a single State, or of a few States only. They would be signals of general alarm … But what degree of madness could ever drive the federal government to such an extremity.
— James Madison, Federalist No. 46, 1788
(Unfortunately, the anti-federalists
were correct in almost every respect.)

Well, fancy giving money to the Government! Might as well have put it down the drain. Fancy giving money to the Government! Nobody will see the stuff again. Well, they’ve no idea what money’s for—Ten to one they’ll start another war. 
— A. P. Herbert (1890–1971, English
novelist, playwright, and humorist

Money will buy you a pretty good dog, but it won’t buy the wag of his tail. 
— Henry Wheeler Shaw (1815–1885
American writer-humorist

The most improper job of any man, even saints … is bossing around other men. Not one in a million is fit for it, and least of all those who seek the opportunity. 
— J. R. R. Tolkien (in a personal letter)

The avoidance of taxes is the only intellectual pursuit that carries any reward. 
— John Maynard Keynes, a very rich man

GARY BECKER, RIP:

When I think of my children and grand-children,” he says, “yes, they’ll have to fight. Liberty can’t be had on the cheap. But it’s not a hopeless fight. It’s not a hopeless fight by any means. I remain basically an optimist.” 
— Gary Becker, Nobel Prize winning economist,
Mar. 27, 2010 interview in the Wall Street Journal (1957)

The Tax Foundation reports:

… the nation’s Tax Freedom Day will come on April 1st this year [2014], which is three days later than last year. In total, Americans will pay more in taxes in 2014 than on food, clothing, and shelter combined. They note that this includes $3 trillion in federal taxes and $1.5 trillion in states taxes, amounting to 30.2 percent of income.
(D&S Comment: This does not include the costs of regulation. Every bottle of a dietary supplement includes the cost of several hundred pages of regulations.)

An old Soviet joke goes like this:

A guy in a Gulag asks another guy:

How long are you in for?

Twenty years.

What did you do?

Nothing.

Nonsense. The sentence for nothing is only ten years.

War is when your government tells you who the enemy is. Revolution is when you figure it out for yourself. 
— from a poster circulating by email

ONE REQUIREMENT FOR THE NOBEL PRIZE:
YOU HAVE TO LIVE LONG ENOUGH TO RECEIVE IT

A letter to Nature from a Finnish scientist warns that the time from a researcher’s discovery to when he or she receives the Nobel Prize is growing longer. In the letter, Dr. Santo Fortunato said, “Before 1940, Nobels were awarded more than 20 years after the original discovery for only about 11% of physics, 15% of chemistry and 24% of physiology or medicine prizes, respectively. Since 1985, however, such lengthy delays have featured in 60%, 52%, and 45% of these awards, respectively.”

In support of this, the author provided a plot of “years since discovery” versus “year of Nobel prizes” showing an upward sloping curve. Dr. Fortunato deplores the fact that by the end of this century, the predicted average age of prizewinners is likely to exceed his or her projected life expectancy and, since the Nobels are not awarded posthumously, many who deserved the award will not be able to receive it. The longer it takes, the more numerous the scientists involved in developing a hypothesis and this is also a difficulty as no more than 3 scientists can share a prize.

One potential Nobel prize winner who immediately comes to our minds is Dr. Denham Harman, particularly for his free radical theory of aging (1956) extended to the mitochondrial theory of aging (1972).¹ As Dr. Harman is now in his 90s, he may very well be one of those who will miss out on a Nobel Prize simply because his work involves a very complex subject; it has now been over 40 years since his pathbreaking hypothesis of mitochondria as a key element in the aging process, requiring the development of free radical chemistry, hormesis, the human genome, and more in order to reach the substantial support required for the Nobel.

Reference

1. Harman Denham. The biologic clock: the mitochondria? J Am Geriatr Soc.20:145-7 (1972).

 

THE NOSE KNOWS …
HUMAN SENSE OF SMELL SURPRISES RESEARCHERS:
WE CAN DETECT LEVELS OF FAT IN MILK BY SMELL

A new study¹ reports that humans can actually smell the difference between milk containing fat at levels of 0.125%, 1.4%, or 2.7%. The subjects were blindfolded and presented with three vials of milk. Two of them contained milk with the same amount of fat, while the other contained milk with a different amount of fat. The subjects were asked to identify which vial was different from the other two. One of the groups tested consisted of healthy normal weight individuals, the second was conducted in a different cultural milieu, the Wageningen area of the Netherlands, and the third included both normal weight and overweight people. “In all three experiments, participants were able to discriminate between different levels of fat in the milk.”¹

The researchers are now hoping to discover the actual molecule(s) that enabled the subjects’ noses to sense the amount of fat.

Reference

1. PLoS ONE (http://dx.plos.org/10.1371/journal.pone.0085977, 2014)

THE AFFORDABLE CARE ACT AS TRANSLATIONAL RESEARCH

An op-ed published in the 27 Nov. 2013 issue of Science Translational Medicine shows how far the supporters of government controlled “health care” are willing to go. The three authors included William H. Frist, MD, former U.S. Senate Majority Leader, Harry P. Selker, Professor of Medicine, Tufts University, and Stuart H. Altman, Professor of National Health Policy, Brandeis University. These three men praised the Affordable Care Act as a wonderful example of translational research, which should provide huge amounts of data to “advance health care and health in the nation.”

Oddly, the authors ignore entirely the fact that the “research subjects” in this translational research are largely unwilling participants, as they are forced at the point of the government’s IRS guns to either participate in the Affordable Care Act or to pay a tax. Haven’t these three authoritarians masquerading as humanitarians ever heard of the Tuskegee experiments, which involved unwilling research subjects, universally considered a crime against humanity? Have they never heard of experiments done by doctors in Nazi Germany using unwilling research subjects that are also viewed as crimes against humanity? Don’t they know that the NIH has current requirements for the protection of research subjects which include informed CONSENT? Where is the consent when research subjects either participate in the “research” or get hit up with a substantial tax?

Do these guys actually believe they are the good guys? They are, in our view, dangerous and despicable and the fact that the editors of Science Translational Medicine published their op-ed without comment is another scary example of government “science” gone bad. Several geneticists were murdered in the Soviet Union because they disagreed with Lysenko’s genetic theories. Now “our” leaders force millions of people to participate in a government health care system that delivers poor quality medical services, and some cheer it on, calling it translational research. How many of these conscripted guinea pigs will die prematurely as a result of their serving as unwilling research subjects in this lousy system, the pawns of scientists gleefully looking forward to lots of medical data thanks to the “Affordable” Care Act?

Oops. Bad news: The Bureau of the Census has changed the health questions they ask; as a result, it will not be possible to directly compare health data derived from their survey questions collected from just before the initiation of the Affordable Care Act to after its emplacement. The wonderful trove of medical data envisioned by the three men mentioned above will be impossible to find, thanks to the federals. This couldn’t have been done deliberately, could it? Nah.

OVERRUN BY ANTS?
HERE’S A REMEDY THAT WE RECOMMEND

We had a terrible ant problem here in our home in Central Nevada. The ants were not only all over the kitchen, but also biting us as we tried to sleep or to read in our beds. Life threatening? No, but quite an annoyance. How dare these little buggers invade our peaceful home!

Enter Terro™ Liquid Ant Baits, and exit the ants! We got these as a result of a friend’s recommendation. The product is a plastic container that holds an ant-attractive solution of borax that poses no significant risk to mammals, though the product label is covered with warnings not to use the product in areas where food is prepared and to keep away from children and pets. We assume these warnings are to protect themselves from liability suits, where you can be sued even if your product had nothing to do with whatever took place that somebody thought they could or should blame on your product.

But what about the ants? The ants love the stuff and rush into the traps to ingest it, not appearing to pay any attention to the many dead ants in the immediate vicinity. We found that it took a few days but the population of foraging ants in our house was reduced by about 95% and we were no longer being bitten (by ants) while minding our own business in our beds.

Now if only there were such a simple final solution to the government thug problem. …

 

HOW DRY I AM …

AGED MICE AND HUMANS DO NOT FEEL AS THIRSTY IN A DEHYDRATED CONDITION AS YOUNG ONES DO

Thirst Deficits Reversed by Omega-3 Fatty Acids in Aged Rats

A recent paper¹ reported that one reason elderly humans die in disproportionally large numbers during heat waves is dehydration, where they do not seem to feel thirst to the same extent as young people, resulting in the aged drinking too little water to rehydrate. The paper mentions a heat wave in Europe in 2003, when some 30,000 extra deaths occurred, and that in Paris, 82% of those excess deaths were people older than 75 years. This thirst deficit in the elderly has been verified. In studies where subjects were challenged with stimuli that would normally induce thirst, such as dehydration; elderly individuals showed a reduced drive to consume fluids.

The researchers note that the deficit in drinking fluids is not generally seen at basal levels, but emerges under conditions when body water is depleted, such as in response to osmotic stimuli, fluid deprivation, and thermal dehydration. They describe mechanisms that might account for this reduced sensitivity to thirst in the aged that included higher levels of atrial natriuretic peptide, a hormone that inhibits thirst.

Interestingly, the authors cite incidents where heat waves taking place in areas where people eat a lot of fish resulted in fewer deaths, and the deaths were less likely to be concentrated among the elderly.¹ The researchers examined the effect of dietary omega-3 fatty acids on thirst in aged male Brown Norway rats.

The rats (elderly were 22–23 months old; young were 2 months old) received one of two synthetic diets. The diets were identical except for the sources of fat for four months. The omega-3 deficient diet (DEF) contained 7% safflower oil, whereas the omega-3 fatty acid supplemented (SUP) diet contained 5.5% safflower oil, 1% flaxseed oil, and 0.5% fish oil. The animals on the SUP diet ate about 85 mg of fish oil per day containing 15.3 mg. EPA (eicosapentaenoic acid) and 10.2 mg. DHA (docosahexaenoic acid. “In a 70 kg. human this would equate to 4 gm per day of concentrated fish oil …”¹

Tested at 22 months of age, the old rats were verified to have a thirst deficit compared to the young rats.

“After 3 months on the experimental diets, the thirst response following 24 hour fluid deprivation was again examined. It was found that omega-3 fatty acid supplemented aged animals had a complete restoration of the thirst response when compared with aged animals on the omega-3 fatty acid deficient diet. [Emphasis added]”

Some evidence emerged that suggested that elevated PGE2 levels in the hypothalamus of aged rats might be involved in the thirst deficit. The researchers mentioned that the administration of bacterial endotoxin to experimental animals causes a reduction of thirst in conjunction with an increase in the E series prostaglandins (to which PGE2 belongs). In aging, an increase in midbrain PGE2 concentration has been reported.¹Hypothalamic PGE2 was elevated only in the aged rats that were fed the omega-3 deficient diet. The authors point out that though the data were consistent with the possible mechanism the association observed between PGE2 and fluid intake is correlational, and causation has not been demonstrated.¹

The results of this study suggest that it may be lifesaving for elderly individuals to take omega-3 fatty acids during heat waves to support the drinking of enough water. More research will be required to identify the mechanism responsible for the effect. We are both 70 years old and are each taking over 4 grams of omega-3 fatty acids (as a marine lipid concentrate) per day. It gets really hot and dry during summers in Central Nevada, especially at over 1 mile in altitude.

Reference

1. Begg et al. Thirst deficits in aged rats are reversed by dietary omega-3 fatty acid supplementation. Neurobiol Aging.2422-30 (2012).

 

SELENIUM PROTECTS AGAINST CALCIFICATION IN BLOOD VESSELS
BY PREVENTING VASCULAR SMOOTH MUSCLE CELLS FROM ACTING LIKE BONE

A recent study¹ of rat vascular smooth muscle cells (VSMCs) in culture reports strong protective effects by selenium (in the form of sodium selenite) against calcification, frequently associated with atherosclerosis. Vascular calcification has been associated with oxidative stress, such as that of hydrogen peroxide, minimally modified oxidized LDL and different lipid peroxidation products.

Vascular calcification is an amazing (though damaging) process. VSMCs actually become induced (by oxidative stress, for example) to undergo differentiation to function like osteoblasts (bone-making cells). This osteoblastic differentiation is characterized by the expression of multiple bone-related molecules including ALP, Col I, and OC [osteocalcin] and upregulation of Runx2, a key transcription factor during osteoblastic differentiation of VSMCs.¹ The researchers explained that a growing body of evidence pointed to the importance of the activation of the ERK (extracellular signal-regulated kinase) pathway in the osteoblastic differentiation of VSMCs. They found that “sodium selenite alone at 0.1 μM did not affect the level of ERK phosphorylation [activation](data not shown), but markedly inhibited H2O2 [hydrogen peroxide]-induced ERK activation [in the VSMCs].”

Moreover, the researchers showed that the intracellular ROS (reactive oxygen species) generation and MDA (malondialdehyde, a major lipid peroxidation product) content were significantly increased in the hydrogen peroxide treated VSMCs, while the content of protein thiols (that include molecules such as glutathione) and glutathione peroxidase activity were significantly decreased (indicating oxidative stress) after hydrogen peroxide treatment. Pretreatment with 0.1 μM sodium selenite for 24 hours significantly reversed the effects of hydrogen peroxide on intracellular ROS generation and the cellular contents of MDA and protein thiols.

The authors conclude: “These results indicate a potential preventive role for Se in vascular calcification, suggesting that vascular calcification may be another target of Se action in anti-atherosclerosis. However, our conclusion is just drawn from an in vitro experiment. Due to the potential side effects of Se, the safety using Se as preventive drug for vascular calcification needs to be further addressed in animal experiments, especially in human experiments.”

We both take 400 μg of selenium per day in the form of sodium selenite. This is the upper limit of selenium doses considered safe by the Institute of Medicine of the National Academy of Sciences. We have been taking this for about 40 of our 70 years. We have some of our major arteries checked (via ultrasound) for plaque and calcification annually and the testing technicians are always amazed at the results and spend extra time looking around thinking that there must be something there that they somehow missed. We welcome the extra checking and also the fact that they have never found a significant problem. We recommend 200 μg of selenium per day of sodium selenite for adults, as a moderate dose, cheap and safe at that dose.

Reference

1. Liu et al. Selenium suppressed hydrogen peroxide-induced vascular smooth muscle cells calcification through inhibiting oxidative stress and ERK activation. J Cell Biochem.111:1556-64 (2010).

DIETARY FIBER ➞ SHORT CHAIN FATTY ACIDS ➞ BUTYRATE ➞ CANCER PREVENTION

How Dietary Fiber Helps Prevent Colorectal Cancer
The Butyrate Connection

A new paper¹ identifies colorectal cancer as the third most diagnosed cancer in both men and women in the U.S. and also as the third most deadly cancer. In an analysis of potential mechanisms to explain the protective effects of dietary fiber against colorectal cancer, the author discusses the effects of short chain fatty acids,^A especially butyrate, produced via fermentation of dietary fiber by gut bacteria.

In the gastrointestinal tract, low to moderate concentrations of butyrate released by gut microbes in the metabolism of dietary fiber acts as the preferred food source for normal colonocytes (colon cells), where it is metabolized (like other fatty acids) by beta oxidation in mitochondria. The author says that butyrate is selectively taken up by colonocytes and provides approximately 70% of their energy. Glucose is the preferred food for cancerous colon cells, however, as a result of their obtaining their energy via glycolysis (the Warburg Effect) while decreasing oxidative metabolism in mitochondria. At the high concentrations of butyrate found in the lower digestive tract, when there is too much butyrate for the colonocytes to metabolize, butyrate enters the cell nucleus where it acts as a histone deacetylase inhibitor, which inhibits cell division. For this reason, butyrate is often considered a candidate “tumor suppressor metabolite.”¹Because butyrate metabolism is decreased in colorectal cancer cells, it accumulates in the nucleus, and acts there as a histone deacetylase inhibitor, decreasing cell division.

Interestingly, the author notes that butyrate enemas “strongly ameliorate colonic inflammation associated with [ ] inflammatory bowel diseases (IBD) in both rodent models and human patients.”¹ Now, there is an interesting suggestion—butyrate enemas! You can get a similar effect, however, by increasing your intake of fermentable dietary fibers such as the long chain inulin oligofructose (as is found in our hydrogen-producing formulation). Not quite as sexy as an enema, but a heck of a lot less messy. One of the major dietary changes in the human diet has been a reduction in the intake of fermentable fiber and the change in the gut microbiota that results from that. Your health has a lot to do with the proper feeding of the gut microbes that ferment dietary fiber, so don’t forget you aren’t eating for just one but for literally trillions!

Not discussed in this paper is the possibility that hydrogen produced in the gut by bacterial fermentation of certain types of dietary fiber could also be protecting against the development of colorectal cancer.³

Butyrate Binds to the Niacin Receptor

The paper mentions that butyrate binds to a receptor that niacin is known to bind to, GPR109A, a G protein coupled receptor that is highly expressed on the apical membrane of colonic epithelial cells.¹ GPR109A is said to be silenced in human colorectal cancers, a mouse model of colorectal cancer, and colorectal cancer cell lines.¹ It is also interesting to note, though not mentioned in the paper, that GPR109A is “the” niacin receptor.²

References

1. Tarini and Wolever. The fermentable fibre inulin increases postprandial serum short-chain fatty acids and reduces free fatty acids and ghrelin in healthy subjects. Appl Physiol Nutr Metab.35:9-16 (2010).
   1. Bultman. Molecular pathways: gene-environment interactions regulating dietary fiber induction of proliferation and apoptosis via butyrate for cancer prevention. Clin Cancer Res.20(4):799-803 (2013).
   2. Thangaraju et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 69(7):2826-32 (2009).
   3. Ohsawa et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 13(6):688-94 (2007).

THE SHORT CHAIN FATTY ACID BUTYRATE ACTIVATES THE NIACIN RECEPTOR GPR109A

The Anti-Atherosclerotic Plot Thickens: Niacin and Dietary Fiber for “Clean” Arteries

The short chain fatty acid butyrate (produced by certain microbes in the lower digestive tract from indigestible fermentable fiber that reaches the colon) and the vitamin niacin (nicotinic acid, vitamin B3) both act as ligands for (activating) the GPR109A receptor.^1,2This surprising link has resulted in both additional understanding of how niacin works and what butyrate does, but also introduces additional questions concerning how this all adds up, as not that much is known about GPR109A or how niacin works.

Niacin was proposed to reduce the progression of atherosclerosis independently of its lipid-modifying effects through GPR109A mediated antiinflammatory effects in immune cells.¹ In one paper,⁴ human monocytes were pretreated with niacin and then activated by the addition of the Toll-like receptor 4 immune stimulant bacterial lipopolysaccharide. Determination of the resulting secretion of proinflammatory mediators revealed that niacin reduced the secretion of TNF-alpha by 49.2 ± 4.5%, reduced IL-6 by 56.2 ± 2.8%, and reduced monocyte chemoattractant protein 1 by 59.3 ± 5.3% (p<0.01, n=7). Interestingly, inhibition of prostaglandin D2 receptor (activation of which causes niacin flushing), did not alter the antiinflammatory effects of niacin described here. This may mean that preventing niacin flushing won’t interfere with niacin’s antiinflammatory effects, but doesn’t tell us whether preventing niacin flushing would interfere with niacin’s effects on HDL and LDL. “The jury is still out” on whether it is a good idea to interfere with niacin flushing. See the June 2009 issue of this newsletter for a speculative article we wrote on the niacin flush.A recent paper³ explains that in a mouse model lacking the GPR109A receptor, the antilipolytic effect of niacin (inhibition of enzymatic release of free fatty acids) is blocked, but this didn’t have an effect on the usual beneficial changes in plasma LDL and HDL levels produced by high-dose niacin. Thus, niacin’s effects on LDL and HDL are not linked to GPR109A, but its antilipolytic effect is. Meanwhile, the tumor-suppressive effects of butyrate in the colon were found to be mediated by butyrate acting as a ligand at the GPR109A receptor.² As the authors explain, the circulating level of butyrate (about 5 mmol/L) is not high enough to activate the GPR109A receptor, but in the colon, butyrate levels are much higher (about 20 mmol/L) and, at that concentration, able to activate the receptor. Thus, the researchers conclude that, “GPR109A mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in colon.”

Colon cancer is reported to be able to silence GPR109A by increasing DNA methylation at that receptor, but the expression of GPR109A can be restored in the presence of butyrate and niacin.²

We wonder about the possibility of an additive anti­lipolytic effect of butyrate and niacin in the general circulation. Although the concentration of butyrate is much too low (about 4000 times too low in the general circulation) to activate GPR109A by itself, it would be interesting to determine whether it might add anything to the antilipolytic effect of niacin. As powerful anti-inflammatory effects of niacin in monocytes have been identified recently as mediated by GR109A, and as butyrate is a ligand of GPR109A (at least at its concentration in the colon), the combination could be very potent in reducing the risk of colon cancer and inflammatory conditions in the lower digestive tract.4

Conspicuously absent from these data and from the analysis of anti-atherosclerotic mechanisms resulting from fermentation of indigestible fiber reaching the lower digestive tract is the large amounts of hydrogen that can be produced by gut microbes in residence there. Whether the presence of all that hydrogen (which avidly scavenges hydroxyl radicals and the powerful oxidant peroxynitrite⁵) is additive with or synergistic with the anti-atherosclerotic properties of the short chain fatty acids, if it is, remains to be determined.

References

1. Lukasova et al. Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells.J Clin Invest. 121(3):1163-73 (2011).
2. Thangaraju et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 69(7):2826-32 Apr. 1, 2009.
3. Lauring et al. Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression. Sci Transl Med. 4:148ra115 (2012).
4. Digby et al. Anti-inflammatory effects of nicotinic acid in human monocytes are mediated by GPR109A dependent mechanisms. Arterioscler Thromb Vasc Biol. 32:669-76 (2012).
5. Ohsawa et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med.13(6):688-94 (2007).

BUTYRATE PROTECTS AGAINST ATHEROSCLEROSIS

Butyrate Inhibition of Vascular Smooth Muscle
Proliferation, a Major Mechanism in Atherosclerosis,
May Be the Result of Increased Glutathione

Finally, we report a somewhat earlier (2007) paper on butyrate that found that the treatment of rat vascular smooth muscle cells (VSMC) with butyrate potently inhibited VSMC proliferation, which is important in the development of atherosclerosis.¹ In the atherosclerotic process, VSMC proliferation is followed by cellular migration, where cells can migrate from the arterial media to the intima, where they continue to proliferate and, switching to an inflammatory phenotype, accumulate excessive amounts of extracellular matrix proteins and attract cholesterol laden macrophages into a developing atherosclerotic plaque.¹

Earlier studies by the paper’s authors had shown that butyrate acts as an anti-proliferative agent on VSMCs. In this study,¹ the researchers decided to examine further butyrate’s effects on the glutathione S-transferase (GST) family that has been reported to be upregulated in conjunction with the induction of cellular glutathione by butyrate in normal and transformed colorectal cells. The researchers had observed these changes to be induced by butyrate in VSMCs. The study¹ reports that “butyrate upregulates GSTs and appropriately modulates cellular GSH [glutathione] and reactive oxygen species (ROS) levels to influence VSMC proliferation, a critical element in the pathogenesis of AT [atherosclerosis].”

The authors measured the concentration-dependent induction of GST-P1 (a member of the GST family) by butyrate. Though the VSMCs had very little expression of GST-P1under basal conditions, 1 μM butyrate stimulated an approximately threefold increase in its expression within 48 hours. The increase continued almost linearly up to 5 μM of butyrate, but discontinued increasing after that. They found that proliferation was completely inhibited at a concentration between 5 μM and 8 μM, but observed no toxic effects at those concentrations.

We have been studying the processes by which vascular smooth muscle cells enter the pathways that lead to atherosclerosis and to later complications (such as arterial restenosis, pulmonary hypertension, and heart failure) for many years, looking for safe, effective, and inexpensive ways to intervene. We believe butyrate is an excellent candidate for prevention and possibly treatment by intervening in some of these pathways. All we need to do is consume a healthy quantity of indigestible fermentable dietary fiber, such as the long chain inulin oligofructose that we take as a supplement, and let our gut microbiota take care of the rest! They not only make short chain fatty acids, including butyrate, from this type of fiber, but some gut microbes process the fiber, creating and releasing hydrogen. Hydrogen is another atheroprotective substance, being a selective anti­oxidant that scavenges the potent oxidant peroxynitrite and hydroxyl radicals (perhaps the most damaging type of radical).²

Finally, note that glutathione peroxidase is a selenium-dependent antioxidant enzyme.

References

1. Ranganna, Mathew, Yatsu, et al. Involvement of glutathione/glutathione S-transferase antioxidant system in butyrate-inhibited vascular smooth muscle cell proliferation. FEBS J. 274:5962-78 (2007).
2. Ohsawa et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med.13(6):688-94 (2007).

 

BUTYRATE PROTECTS AGAINST ATHEROSCLEROSIS

Butyrate Inhibition of Vascular Smooth Muscle
Proliferation, a Major Mechanism in Atherosclerosis,
May Be the Result of Increased Glutathione

Finally, we report a somewhat earlier (2007) paper on butyrate that found that the treatment of rat vascular smooth muscle cells (VSMC) with butyrate potently inhibited VSMC proliferation, which is important in the development of atherosclerosis.¹ In the atherosclerotic process, VSMC proliferation is followed by cellular migration, where cells can migrate from the arterial media to the intima, where they continue to proliferate and, switching to an inflammatory phenotype, accumulate excessive amounts of extracellular matrix proteins and attract cholesterol laden macrophages into a developing atherosclerotic plaque.¹

Earlier studies by the paper’s authors had shown that butyrate acts as an anti-proliferative agent on VSMCs. In this study,¹ the researchers decided to examine further butyrate’s effects on the glutathione S-transferase (GST) family that has been reported to be upregulated in conjunction with the induction of cellular glutathione by butyrate in normal and transformed colorectal cells. The researchers had observed these changes to be induced by butyrate in VSMCs. The study¹ reports that “butyrate upregulates GSTs and appropriately modulates cellular GSH [glutathione] and reactive oxygen species (ROS) levels to influence VSMC proliferation, a critical element in the pathogenesis of AT [atherosclerosis].”

The authors measured the concentration-dependent induction of GST-P1 (a member of the GST family) by butyrate. Though the VSMCs had very little expression of GST-P1under basal conditions, 1 μM butyrate stimulated an approximately threefold increase in its expression within 48 hours. The increase continued almost linearly up to 5 μM of butyrate, but discontinued increasing after that. They found that proliferation was completely inhibited at a concentration between 5 μM and 8 μM, but observed no toxic effects at those concentrations.

We have been studying the processes by which vascular smooth muscle cells enter the pathways that lead to atherosclerosis and to later complications (such as arterial restenosis, pulmonary hypertension, and heart failure) for many years, looking for safe, effective, and inexpensive ways to intervene. We believe butyrate is an excellent candidate for prevention and possibly treatment by intervening in some of these pathways. All we need to do is consume a healthy quantity of indigestible fermentable dietary fiber, such as the long chain inulin oligofructose that we take as a supplement, and let our gut microbiota take care of the rest! They not only make short chain fatty acids, including butyrate, from this type of fiber, but some gut microbes process the fiber, creating and releasing hydrogen. Hydrogen is another atheroprotective substance, being a selective anti­oxidant that scavenges the potent oxidant peroxynitrite and hydroxyl radicals (perhaps the most damaging type of radical).²

Finally, note that glutathione peroxidase is a selenium-dependent antioxidant enzyme.

References

1. Ranganna, Mathew, Yatsu, et al. Involvement of glutathione/glutathione S-transferase antioxidant system in butyrate-inhibited vascular smooth muscle cell proliferation. FEBS J. 274:5962-78 (2007).
2. Ohsawa et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med.13(6):688-94 (2007).

FLASH! MITOCHONDRIAL THEORY OF AGING SUPPORTED IN NEW STUDY

Production of Superoxide Bursts by Mitochondria Can Be Detected as Flashes

Rate of Flashes in Early Adulthood Predicts Lifespan in C. elegans

In 2008, researchers published a paper demonstrating that “mitochondria in mammalian cells undergo quantal, stochastic bursts of superoxide production, which can be visualized as ‘mitochondrial flashes’ (mitoflashes) by the sensor protein circularly permuted yellow fluorescent protein (cpYFP) in the mitochondrial matrix.”¹

As the researchers explain in their introduction to their 2014 paper on mitoflashes, Dr. Denham Harman conceptualized the mitochondrial theory of aging (MTA) in 1972.²They go on to say: “The mitoflash frequency is highly sensitive to oxidative stress and metabolic changes; it can therefore be exploited as a readout of energy metabolism and free radical production for testing MTA.”³

Using this ingenious method, the researchers now report that there was a highly significant “negative correlation between the day 3 mitoflash frequency and lifespan” that held true for strains of C. elegans with a normal, faster, or slower aging rate. “… worms with low mitoflash activity as a group lived significantly longer than those with medium or high mitoflash activity.”³

Furthermore, the researchers explain, “In long-lived daf-2 animals [C. elegans with a mutated daf-2 gene], decreased mitochondrial production of superoxide through a shift in metabolic flux from Complex I to Complex II contributes to a slowing of organismal aging.” “These data strongly support a coupling between the mitochondrial function and the process of ageing … .” Indeed, the researchers report in this study that the variation of day 3 mitoflash frequency alone explained 59% of the variation in lifespan using a nonlinear cubic spline regression model or 50% using a simple linear regression model. The scientists even tested their model in C. elegans exposed to 26 conditions that have been found experimentally to alter lifespan, finding that the strong negative correlation between day 3 mitoflash frequency and lifespan held, with the 3 day mitoflash frequency alone explaining 52% of the lifespan variation with the linear regression model or 70% using the cubic spline regression model.

The researchers conclude: “This finding provides the most direct evidence for a central role of mitochondria in lifespan regulation.”

Our thanks to Dr. Denham Harman for his early recognition of the importance of mitochondria in aging. We thank the researchers who did this mitoflash study for citing Dr. Harman’s 1972 publication on the subject;¹ being ahead of your time can often mean, in science, that your early work isn’t always cited and later elaborations on the subject by others often get the recognition.

References

1. Wang et al. Superoxide flashes in single mitochondria. 134:279-90 (2008).
2. The biologic clock: the mitochondria? J Am Geriatr Soc.20:145-147 (1972).
3. Shen, Song, Lin, et al. Mitoflash frequency in early adulthood predicts lifespan in Caenorhabditis elegans. Nature.508:128-32 (2014).

ON INCOME INEQUALITY, AND WHY THE MIDDLE CLASS IS VANISHING

The Gini coefficient that measures income inequality does NOT take into consideration either reduction of that income by progressive income taxes nor increases of that income via receipt of transfer payment benefits either in cash (such as the refundable Earned Income Tax Credit) or in kind (such as food stamps, Medicaid, SCHIP, LIHEAP, Section 8, etc.).

This results in a grossly misleading measure of income inequality. How gross? Take a look at the table below. Note that it is for Mississippi, one of the lowest welfare payment states. Note, too, that this chart is pre-Obamacare, which is hugely redistributive. As you can see, after considering taxes and redistribution, someone earning $60,000 per year has about $3,400 less effective income than someone earning $14,500 per year. The trend toward part time jobs started before Obamacare, though that made the incentives for part time work even stronger than shown in the chart.

The big drop in the percentages of people participating in the work force is not due to aging Baby Boom demographics. The percentage of the 55 and older cohort that is employed has actually increased since 2009. The prime working age participation of the 18–44 and 45–54 year olds has dropped dramatically.

Between $3,625 income and $14,500 income, your effective marginal tax rate on your additional income, including means tested benefit phaseouts = 43.5%Look at the chart.

Between $14,500 income and $30,000 income, your effective marginal tax rate on your additional income, including means tested benefit phaseouts = 167%. In this income range, every additional $1.00 that you earn makes you lose $1.67, making you worse off!

Between $30,000 income and $60,000 income, your effective marginal tax rate on your additional income, including means tested benefit phaseouts = 76.7%. In this income range, for every additional $1.00 that you earn, you get to keep only $0.23! If you have a $30 per hour job, you get to keep only $6.90 of it. Why study? Why work? You racked up a fortune in college debt for $6.90 per hour net income?

Between $14,500 income and $60,000 income, your effective marginal tax rate on your additional income, including means tested benefit phaseouts = 107.5%. In this income range, every additional $1.00 that you earn makes you lose $1.07, making you worse off!

Can you see why there is so much more part time work than full time work, even before Obamacare?

When one’s income becomes sufficiently large, the means tested benefits phaseouts become relatively smaller in their effects, though ones not shown here (such as some personal deductions) continue to phase out at over $100,000 per year income.

Can you see why there is a divergence between upper class and lower class with the middle class disappearing? People respond to incentives. The phaseouts of means tested transfer payment benefits, both in cash and in kind, are making a middle class income less beneficial than a low class income, hence the middle class is vanishing!

The greatest force for the disappearance of the middle class is Demopublican/Republicrat means tested safety nets, yet only “heartless” Tea Party and libertarian “extremists” would repeal them …

This is not going to end well. The taxes to pay for this wealth redistribution come mainly from the shrinking upper middle class; there simply isn’t enough 1 percenters to pay the bill, and their incomes vary far more with economic conditions, going down when the demand for transfer payments is going up. Those who are in the upper middle class and above are working to an older age, but they will eventually be forced to retire by declining health, vigor, and deaths. Then where will the money to redistribute come from?

The income dependent phase-outs of these means tested redistribution programs place a prohibitively high effective marginal tax rate on anyone trying to move from lower class or lower middle class to upper middle class. This move upwards takes decades of full time work. Who would be willing to work for decades with effective marginal tax rates of 167% between $14,500 and $30,000 and 77% between $30,000 and $60,000? (Now even worse due to ObamaCare.)

Getting a college education is a rational attempt (if courses are wisely chosen with the job market in mind) to vault over this high effective marginal tax rate chasm. But this strategy often creates a morass of student debt that takes a decade or more to repay. Moreover, only those a standard deviation or more out on the right hand tail of the IQ bell curve have what takes to profit from even a wisely chosen college education investment.

People of average IQ can make a good living if they learn the right skilled trade, such as welding—if they have the self restraint needed to pass a drug test. Skilled trades aren’t what they used to be, though; many now require an expensive license that takes years to obtain—if your established competitors allow you to ever get it.

Even IQ 85 (one standard deviation below average) people eventually figure out that being on vacation 6–8 months per year beats full time year round work. Note that the table below does not include income from unemployment compensation. In many States, three months of work—even part time—qualify one for months of unemployment compensation. Lots of people have figured out how to work the system.

PREDICTING BIODIVERSITY AND SPECIES EXTINCTION USING FAILED MODEL

The Model Used in Predicting Biodiversity and Species Extinction for Government Policies Fails When Applied to Forest Fragments in Human-Dominated Ecosystems

We report very briefly here a VERY IMPORTANT paper from the 8 May 2014 Nature¹ showing that the island biogeographic model that has been used for more than 30 years in estimating extinction rates (“a pillar of conservation science”¹) does not provide the expected results for forest fragments in an agricultural or countryside human-dominated ecosystem. As the authors say, “Despite its known shortcomings, this theory [the island biogeographic model] persists as the basis for estimating extinction rates and making policy recommendations.”¹

The authors analyze neotropical bat biodiversity, that the authors identify as a group acutely sensitive to tropical deforestation, in a true island habitat and in forest fragments embedded in human-created habitat (farmland). The two ecosystems were chosen for their similar ages, close geographic locations, and their evolutionarily homologous bat diversity.

The authors found that, in comparison with true islands, the forest fragments/farmland habitat supported more species with lower rates of local extinction. The authors said, “… we found that declines in bat species richness expected from island biogeography were almost never realized in countryside forest fragments.”

The authors conclude that their evidence supports the view that a “countryside biogeographic framework that is inclusive of human-made habitats and the opportunities it can afford to many species—given appropriate management of those habitats*—better represents how, at least, bat diversity is responding in the Anthropocene.”¹

* The authors refer to problems in agricultural lands that included the use of “chemical inputs and practices that sterilize, structurally level, and standardize plots — homogenizing and decimating biodiversity.” We note that much of the homogenization of farmlands is the result of government subsidies to promote the production of certain crops, such as corn for ethanol, and especially the mandate to use that subsidized ethanol as an automobile fuel. Indeed, 40% of corn is now grown for that purpose. All that extra cropland devoted to corn is part of the increased uniformity of the crops grown in areas by agribusiness (crony capitalism) wanting to receive subsidies.

A Reality Check on the Endangered Species Act

One wonders how many of the “endangered” species listed by the EPA that forces private landowners to abide by innumerable costly rules and regulations are truly endangered or, if their estimated rate of extinction was derived from the island model as described in the paper. This information (how the agency determined whether a species should be listed) should be available by FOIA.

Reference

1. Mendenhall, Karp, Meyer, et al. Predicting biodiversity change and averting collapse in agriculture landscapes. 509:213-7 (2014).

A TRUE STORY — DURK’S PARTICIPATION IN THE NEGOTIATIONS WITH THE BUREAU OF LAND MANAGEMENT AND TWO RANCHER FRIENDS FOR GRAZING RIGHTS

PLUS:

Why the BLM Wouldn’t Let Cliven Bundy Pay His Grazing Fee

The Ugly Truth About the Grazing Rights Contract Required By the Bureau of Land Management

This is a true story. The names of the two ranchers discussed in the first part that follows, personal friends of ours (one is, however, deceased), are not given here.

As is typically the case in the West, the two ranchers had been grazing cattle on federal lands as successors to prior owners of grazing rights and water since long before there was a Bureau of Land Management (BLM). The grazing permits that became a requirement for ranchers to continue grazing lands that had been privately grazed for long before the existence of federal land management agencies started out simple. Those who had been grazing the lands previously, who held stockwater rights under state law had priority in terms of being able to continue using the lands. It was a prior right recognized in the Taylor Grazing Act of 1934.

Over the years, the BLM unilaterally changed the conditions that ranchers had to meet in order to have grazing rights in lands claimed by the federal government (“federal lands”).

Durk’s two rancher friends had seen additions to the grazing rights contracts that the BLM asked them to sign, and didn’t understand what this new stuff meant. They, therefore, asked Durk to accompany them to meetings with BLM representatives to advise them during their contract negotiations.

Durk had expected that the disagreements would be over the number of cattle that the ranchers would be allowed to run. That was NOT the case.

One of the new provisions required that the rancher “maintain satisfactory conditions of riparian areas.” Yet, the contract had no definition of “satisfactory” or of “riparian.” Durk told his two rancher friends that they had to get the BLM to put definitions of these terms into the contract or at least put in a reference to where these terms are defined in BLM regulations. Otherwise, they (the ranchers) could be found to be in violation of the contract at any time. A key feature of a contract is that, as a meeting of minds, each party to a contract has to understand what is being said in the same way. There can be no valid contract where terms are left undefined and, hence, the party expected to comply with a provision with undefined terms doesn’t know what is expected of him and is at the mercy of the party controlling the interpretation of key terms.

When the two ranchers requested that definitions for these terms be put into the grazing rights contract, the BLM refused. Durk was there and personally heard the BLM negotiator say (this is a paraphrase): “No. We like to keep things flexible.”

One of the ranchers suggested that he could run a fence around the green areas (the water sources), with a pipe delivering the water to an outside water tank. In this way, the cattle couldn’t even approach the water source and, hence, there could be no question of the riparian areas being maintained in a satisfactory condition. The BLM guy responded that they could do that but they would have to get a permit from the BLM to do that and, to get the permit from the BLM, they would have to deed 1/2 of their water rights to the BLM. “That’s our policy,” the BLM guy said (and this is a quote, not a paraphrase). And even if the ranchers actually put in the fence to “maintain a satisfactory condition” to the riparian area around the water source, there would still be no definitions in the contract for what was meant by “satisfactory condition” or “riparian.” Durk told the two ranchers that if they signed the contract the BLM could find them in violation at any time.

Soon Afterward …

One of the ranchers received a notice from the BLM that they intended to seize all his cattle that were grazing on the “federal lands.” He went out of business. The other rancher (who is still alive) had his cattle stolen by the BLM, which simply removed them and sold them to a crony for far less than market value without having a court order for their removal and sale. Simple cattle rustling, folks, a hangable offense in the old West. Yes, the rancher did try to sue the agency for commpensation, but he lost in the courts. Unfortunately, the courts generally ASSUME that a regulatory agency is in the right—keep in mind that the BLM controls the administrative record—and the magistrate Judges (BLM employees) know very little if anything about the legal issues involved, once again assuming that the BLM doesn’t claim authority it doesn’t have.

The State of Nevada Was Not Amused

As a result of these and similar BLM actions, the Nevada legislature passed a law, which the governor signed, that required that the state branding inspector could not approve transfer of cattle to the BLM except under a court order.

The State of Nevada legislature also passed legislation, signed by the governor, which prohibited the transfer of water rights to the BLM. This action by the State is legal under the federal law called the McCarran Amendment (43 U.S.C. 666 (1952)), under which non-interstate water in the West is regulated by the States, with the federal government having waived its sovereign immunity and supremacy and having waived any claim that State water law doesn’t apply to the federal government.

Cliven Bundy Has a Problem With His Grazing Permit Contract with the BLM

Not so surprisingly, then, rancher Cliven Bundy stopped paying his grazing fees to the BLM (though he offered to pay them to Clark County, Nevada) because of BLM-added changes in his grazing contract, like what happened to the two ranchers described above. The claim that Bundy owes the BLM over $1,000,000 for unpaid grazing fees makes it sound as though Bundy is in the wrong—but doesn’t tell you that the “contract” the BLM expected him to sign was no contract at all because, as explained above, you could never know what you were expected to do. Bundy wouldn’t sign it. Note that the BLM will NOT cash your check—e.g., you cannot pay your grazing fees—unless you have signed this so-called “contract.”

A Personal Friend Was At the Bundy Ranch During the Federal Invasion

A very close friend of ours (another rancher) was at the Bundy Ranch during the entire recent incident. He was shocked at the extent of the armaments the federal agents had at their disposal, which included machine guns. (YOU NEED TO KNOW that, a few years ago, the BLM requested law enforcement authority from the State of Nevada, permission they had to have in order to be able to enforce laws in the State of Nevada—but the State refused to give it to them. This is a fact. The law enforcement officer impersonation by BLM agents and their pointing guns at people at the Bundy Ranch was entirely unlawful. We hope to see this become the basis for a lawsuit against the BLM.)

Our friend witnessed the damage done by a large backhoe brought in by the feds to destroy Bundy’s “unpermitted” water tanks and water pipelines. The court order the feds had authorized them to seize “trespass cattle”—but gave them NO authority to damage water tanks and pipelines. So much for the rule of law.

Bundy Did Not Make Racist Statements

While we are giving you the perspective of witnesses to some of the issues involved in the clashes between ranchers and the BLM, we might as well straighten out any idea you may have that Cliven Bundy made racist remarks.

The ongoing claims in the media that Cliven Bundy is a racist because of allegedly racist statements he made is based entirely upon a campaign by the The New York Times to misrepresent what Bundy actually said. The Times took actual statements of Bundy’s (we have seen the taped interview with Bundy) and edited them to make it appear that Bundy had made racist remarks. Despite the fact that these allegations were the result of shamelessly selective editing by The New York Times, and that corrective information has now become available, media (even including The Wall Street Journal, to their shame) with lazy reporters who do not bother to check the accuracy of material when they quote from supposedly authoritative media such as The New York Times, continue to claim that Bundy is a racist. We are here to tell you that Mr. Bundy is NOT a racist and that if you rely on The New York Times (and even The Wall Street Journal), you had better not assume that they (a) don’t disseminate false and misleading information and/or (b) check the accuracy of their sources.

Why Have We Reported This in Our “Life Extension Newsletter”?

First, as regular readers are aware, this isn’t a newsletter JUST about life extension. Second, we have firsthand information to offer in an issue of considerable public confusion and of some importance. We hope to help keep the discussion focused on the facts, not somebody’s contrived version of events.

The federal government is a major threat to our life expectancies and its usurpations go far beyond the U.S. Food and Drug Administration.

Sincerely,

Durk Pearson & Sandy Shaw

APPETIZERS

The accumulation of all powers, legislative, executive, and judiciary, in the same hands, whether of one, a few, or many, and whether hereditary, self-appointed, or elective, may justly be pronounced the very definition of tyranny.
— James Madison, Federalist No. 48

In 2012, sales of adult diapers [in Japan] surpassed sales of baby diapers for the first time.
— from Code Red (Wiley, 2014)
by John Mauldin and Jonathan Tepper

It is hard to imagine a more stupid or dangerous way of making decisions than by putting those decisions in the hands of people who pay no price for being wrong.
— Thomas Sowell, economist, historian, philosopher

The Second Amendment is a doomsday provision, one designed for those exceptionally rare circumstances where all other rights have failed—where the government refuses to stand for reelection and silences those who protest; where courts have lost the courage to oppose, or can find no one to enforce their decrees. However improbable these contingencies may seem today, facing them unprepared is a mistake a free people get to make only once.
— Judge Alex Kozinski, Chief Judge,
U.S. Court of Appeals, 9th Circuit

INDEPENDENCEI would never invade the United States. There would be a gun behind every blade of grass. 
— Isoroku Yamamoto, commander
of Japanese naval military forces in WWII

When you see that trading is done, not by consent but by compulsion, When you see that in order to produce, you need to obtain permission from men who produce nothing, When you see that money is flowing to those who deal, not in goods, but in favors, When you see that men get richer by graft and by pull than by work, and your laws don’t protect you against them, but protect them against you, When you see corruption being rewarded and honesty becoming a self-sacrifice—you may know that your society is doomed.
— Ayn Rand, Atlas Shrugged (1957)

Everything that is right or reasonable pleads for separation. The blood of the slain, the weeping voice of nature cries, ’tis time to part.
— Thomas Paine, Common Sense (Jan. 9, 1776)

Quantity produces quality. If you only write a few things, you’re doomed.
— Ray Bradbury

IMAGINE THERE’S NO FDA

Imagine there’s no FDA
It’s easy if you try
No more illegal rules and regulations
No more they decide if you live or die
Imagine there’s no one there
Let the whole world declare
It’s up to you
To decide what you do
They’ve gone away
Imagine being free today.

A CASE OF SEVERE IRON DEPLETION RAPIDLY CORRECTED BY A SUPPLEMENT

THE IRON LADY: SANDY’S CLOSE CALL

As you may have read in earlier newsletters, Sandy had to undergo three operations for a life-threatening bowel obstruction about two years ago and lost about 2/3rd of her colon and 5 feet of her small intestine. Since the lower intestinal tract is importantly involved in absorbing water and minerals, among other things, a problem for people with “short bowel syndrome” is getting adequate quantities of certain nutrients that would normally be absorbed in the lower tract. (If too little water is reabsorbed from the intestinal fluids, for example, then you can have chronic diarrhea, which also causes losses of electrolytes. Indeed, Sandy’s sodium levels were low so she is now taking sodium chloride tablets to normalize that.)

So it was that we recently found out from routine lab tests that Sandy was remarkably deficient in iron (with reduced levels of red blood cells and hemoglobin, as well as a shockingly low transferrin saturation level of 4%). Transferrin is a protein that transports and stores iron and is supposed to be saturated in the range of 15 to 50%. Sandy’s local physician (head of our regional hospital) said that he didn’t know anybody could be walking around with such a low level of available iron! Sandy’s main problem that could definitely be attributed to low iron was a dramatic worsening of her restless legs syndrome symptoms.¹ This disorder is known to be associated with inadequate iron supplies and it is hypothesized that deficiency of iron in dopamine-containing neurons in the brain may be a cause.²

Iron supplementation to the rescue! We have described an iron formulation we put together for our own personal use that has the tremendous advantage over other forms of iron in that it is very unlikely to cause stomach upset. She started with two capsules a day of the iron supplement (one capsule contains the RDA of iron) on Jan. 31, 2014. At that time, she had a measured iron level of 20 mcg/dL, whereas the normal range is 40–160 mcg/dL. As mentioned above, her transferrin saturation was 4%, only about 25% of the value at the low end of the normal range.

Today, March 28, 2014, her latest iron and transferrin measurements have come back, the blood having been drawn on March 14th. We (Durk and me as well as our doctor) were all amazed at the new numbers: her iron had increased to 229 and was now HIGH, so she has reduced her supplement to a single RDA level capsule of iron a day. Her transferrin saturation level had increased to 54%, which is slightly higher than the 50% upper end of the normal range. She will return for further testing in a few weeks. Her hemoglobin, which was 10.9 g/dL (with the normal range being 12.2–16.2 g/dL) as of Jan. 31st, had also increased to 12.5 and is now in the normal range.

Moreover, the improvement in her restless legs syndrome symptoms has been dramatic, with her need for dopaminergic agonist medications to control it reduced by about 80%.

References

1. Restless legs syndrome is now being called Willis-Ekbom Disease by a foundation devoted to its treatment and cure. Apparently, the fear was that “restless legs” sounded too trivial and because the disease can have a highly negative effect on the quality of life, depending upon its severity, the disease was renamed apparently to convey a more serious image. The Willis-Ekbom Disease Foundation, formerly the Restless Legs Syndrome Foundation, has a variety of literature available, including “Nightwalkers” (a newsletter for sufferers — the nightwalking refers to the difficulty sleeping that is often a problem with the disease), plus surveys of available treatments for clinicians. If you have this condition and are not able to find satisfactory treatment, it would likely be worth your while to contact them. They can be reached at 1530 Greenview Dr. SW, Suite 210, Rochester, MN 55902 (www.willis-ekbom.org ; PH 507–287–6465).
2. Allen and Earley. The role of iron in restless legs syndrome. Mov Disord.22(Suppl 18):S440-8 (2007).

RAPID NEW ADVANCES IN THE UNDERSTANDING OF SENESCENCE LEADING TO PRACTICAL METHODS OF DETERRING AGING SUCH AS DECREASING LOSS OF MUSCLE

EXTENDING THE REPLICATIVE LIFESPAN OF WI-38 HUMAN FIBROBLASTS WITH SELENIUM

SELENIUM INCREASES POPULATION DOUBLINGS, REDUCES RATE OF TELOMERE SHORTENING, AND DECREASES RATE OF AGE-ASSOCIATED SENESCENCE IN HUMAN WI-38 CELLS

The WI-38 human fibroblast is the cell line that Leonard Hayflick used in the discovery of the famous Hayflick limit, where he demonstrated that cells would replicate only a limited number of times before becoming terminally senescent.^AA Senescent cells don’t immediately die but they no longer replicate and they undergo many changes that distinguish them from non-senescent cells. It has been learned, for example, that senescent cells are not generally beneficial to have around, other than the fact that their exit from the cell cycle acts as a protective mechanism against those cells becoming cancerous. A growing population of senescent cells with age has been found to have a deleterious effect on the functioning of non-senescent cells in their neighborhood by, for example, sustaining chronic inflammation and extracellular matrix remodeling.^A The Hayflick limit was one of the earliest studies in which the processes that impair the function of aging cells started to be discovered.

Today, we report the publication of a new study (published today, Feb. 28, 2014 in the Journal of Biological Chemistry.¹) describing how selenium depletion (Dpl) impairs the proliferative capacity of WI-38 cells and accelerates their conversion to senescence and how the cells could undergo additional doublings by being supplemented with selenium (Sup) beyond the amount of selenium considered adequate (Ctrl). The form of selenium used was sodium selenite, the form we recommend and take ourselves. [See “If You Take Selenium To Help Reduce Your Risk of Cancer …” in the October 2010 issue of Life Enhancement.]

The researchers first note that selenium levels decline with age and describe two independent studies that suggest a link between lifespan and selenium, finding that selenium levels in the blood of elderly people was a predictor of longevity^2,3 The results of their new work¹ showed that “the change in selenium concentrations in young cells triggers rapid changes in replicative senescence-associated markers and signaling pathways and regulates the entry into replicative senescence.”¹

Consistent with prior studies, the researchers found that their cells grown in Ctrl (Control) conditions maintained their proliferative capacity until the level of population doubling #51 (CPD 51). At that time they showed signs of early senescence (presenescence) and they became senescent at CPD 57. The researchers separated cells that had reached CPD 36 (late middle aged) and were still actively dividing and exposed them to the different concentrations of selenium, finding that in two passages (two divisions) the effect of different concentrations of selenium was already apparent. Hence, these changes can take place fast at a late stage of replicative lifespan under the influence of either deficient selenium or selenium supplementation. In all cases, they reported, “selenium supplementation led to an extended replicative lifetime.”

The scientists examined changes in markers of senescence in young proliferating WI-38 fibroblasts in Dpl, Ctrl, and Sup media for two passages and found a nearly threefold increase in one such marker, SAHF, between the cells grown under Dpl conditions as compared to those grown in the Ctrl condition. Again, these changes were in response to different media selenium concentrations. The researchers propose that, “the entry into replicative senescence of cultured human diploid fibroblasts is due to an irreversible cell cycle arrest mainly controlled by the p53-p21 and p-16-pRb signaling pathways.”¹Selenium supplementation was found to significantly reduce (by more than 3 times) the expression levels of p16, p21, p53, and pRb as compared with cells grown under Ctrl conditions.

Young WI-38 Cells Grown Under Conditions of Selenium Deficiency (Dpl) Look Like Senescent Cells

Very interestingly, the researchers found that the young WI-38 cells, after growing in Dpl media for two passages “present several characteristics very similar to those of senescent cells, which include morphological changes, increased number of positive cells for SAHF and SABG [biomarkers of senescence], and telomere length shortening.”¹

Similarities in Senescent Cells and Cells Exposed to Chronically Elevated Levels of Oxygen

Another paper^1B reports finding similar gene expression in senescent and chronic mild hyperoxic cells (cells exposed to higher than normal oxygen), suggesting that hyperoxia could be considered a model of accelerated senescence and, therefore, another good reason to avoid chronic oxidative stress as much as possible.

PREVENTING MUSCLE LOSS WITH AGING

Can Selenium Supplementation Prevent Age-Associated Sarcopenia?

A very recent paper⁴ reported that p16INK4a, a p16 tumor suppressor protein (part of the p16 signaling pathway), was responsible for inducing senescence in the regenerative capacity of muscle stem cells. These researchers found that p16INK4a, thought to be a master regulator of cellular senescence, is (as part of the p16INK4a/Rb/E2F-signaling axis) responsible for a senescent-like state that may be a key part of the process of sarcopenia, the age-associated loss of muscle. In the new study,⁴ the scientists found that genetically silencing p16INK4a expression restored self-renewal and proliferation in aged skeletal muscle satellite cells.

We wonder: Would selenium supplementation tend to reduce the expression of p16INK4a as it did the expression of p16 in the WI-38 fibroblast study discussed above? If so, selenium supplementation could be a practical means of protecting against sarcopenia.

Magnesium Deficiency Accelerates Cellular Senescence in Cultured Human Fibroblasts

According to this 2008 paper,^4B more than half the population of the U.S. ingests an inadequate amount of dietary magnesium. The researchers cultured human diploid lung fibroblasts (IMR-90) in media containing various amounts of magnesium. Cells cultured in media with 50% of the magnesium contained in standard media were shown, in four independent lifespan studies, to lose 2.5 population doublings as compared with cells grown in media with the full amount of magnesium. Cells cultured in 13% of normal magnesium concentration lost 4.5 population doublings. [See “Durk Pearson & Sandy Shaw Ring the Bell for … Magnesium Aspartate” in the August 1998 issue of Life Enhancement.]

Is It Beneficial To Remove Senescent Cells?

Removing p16INK4a-positive senescent cells from experimental animals (mice) has already been done in order to see whether that might be beneficial (or not).⁶ In that study, mice with a progeroid genetic background were treated with an experimental drug to eliminate p16INK4a-positive senescent cells. The researchers reported that, “In tissues—such as adipose tissue, skeletal muscle, and eye—in which p16INK4a contributes to the acquisition of age-related pathologies, lifelong removal of p16INK4a-expressing cells delayed onset of these phenotypes. Furthermore, late life clearance attenuated progression of already established age-related disorders.” Hence, at least in this model, it would appear that senescent cells can be removed with beneficial effects.

p16INK4a Positive Cells in Human Skin Found to Reflect Biological Age

A powerful link between the p16INK4a senescence marker and biological age was reported in another new paper,⁷ when researchers found that a younger biological age associates with lower levels of p16INK4a positive cells in human skin. (The researchers were referring to chronological age as biological age, presumably due to the lack of a standardized way of distinguishing between them.) They observed that increased numbers of senescent cells were associated with age-related pathologies such as atherosclerosis, diabetes, and kidney disease. This makes it possible for a test to be developed in which one could find out how well he or she is doing in terms of aging through the detection of this senescence marker in their skin cells. (NOTE: The FDA is likely to try to block this information from being made available directly to the public. However, under the First Amendment, they do not have the authority to do so.)

Osteoarthritis Characterized by Accumulation of Senescent p16INK4a Positive Cells

A very common age-associated disease that has been linked to cellular senescence is osteoarthritis, which can be a source of considerable pain and disability. In a 2014 paper,^A researchers reported that “[o]steoarthritis (OA) is characterized by the accumulation of chondrocytes expressing p16INK4a and markers of the senescence-associated secretory phenotype (SASP) including the matrix remodelling metallo-proteases MMP1/MMP13 and pro-inflammatory cytokines IL-8, and IL-6.” The researchers found that p16INK4a is induced by treatment with the pro-inflammatory cytokine IL-1beta and also during in vitro chondrogenesis.

Senescence Can Be Transmitted to Non-Senescent Neighboring Cells

It is interesting to note that recent studies cited in another paper⁹ have shown that “some SASP factors, including IL-1beta, can induce senescence in normal cells. Thus, senescence can be transmitted to untransformed neighboring cells through the paracrine activity of the SASP.”⁹ There goes the neighborhood! (Seriously, this is another reason to try to prevent the buildup of senescent cells during aging.)

Metformin May Be Another Anti-Senescence Treatment

In addition to selenium, magnesium, and zinc, there is also evidence that metformin, a drug used widely in the treatment of diabetes and symptoms of metabolic syndrome, such as insulin resistance, may also protect against the premature senescence that accompanies high glucose conditions.¹⁰ In a study of kidney cells (primary rat glomerular mesangial cells) in culture, exposed to high glucose conditions, researchers found that the cells initially and transiently entered a proliferative phase, but was followed by cell cycle arrest along with changes seen in senescent cells (for example, increased expression of cyclin-dependent kinase inhibitors p21(cip1) and p27(kip1)). In addition, connexin43, a gap junction that importantly allows cells to communicate with each other, is less expressed in cells exposed to high glucose conditions and in older cells. This decreased intercellular communication is also observed in senescent cells.¹⁰

AMPK, an important regulator of energy metabolism (increased under conditions of reduced energy availability, decreased when energy supplies are plentiful) is reported to maintain the expression of connexin43 under high glucose conditions. Incubation of the rat glomerular mesangial kidney cells with metformin in this study¹⁰ significantly increased p-AMPK (phosphorylated AMPK, the active form) and up-regulated connexin43 compared to cells exposed to high glucose conditions but not treated with metformin. Metformin treatment also decreased the expression of the senescence markers p27(kip1) and p21(cip1).

Too Much Zinc May Worsen Osteoarthritis

A caution concerning zinc supplementation: A 2014 Cell paper¹¹ reported that ZIP8, a zinc transporting enzyme, is overexpressed in chondrocytes (cartilage cells) of humans with osteoarthritis. This caused increased intracellular levels of zinc and of zinc-dependent metalloprotease matrix-degrading enzymes that have been identified as causative factors in osteoarthritis. The question is: could zinc supplementation in those with osteoarthritis have an exacerbating effect on the disease? The authors¹¹ speculate that local depletion of zinc, inhibition of ZIP8 or of the metalloproteases involved in osteoarthritis might be effective therapies for osteoarthritis. Also, we note, reducing IL-1beta (which induces ZIP8) is another possible therapeutic approach. (IL-1beta is an important part of the human wound-healing response.^11A)

How old would you be if you didn’t know how old you are? 
— Leroy “Satchel” Paige

References

AA. Hayflick. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 37:614-36 (1965).
A. Philipot et al. p16INK4a and its regulator miR-24 link senescence and chrondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis. Arthritis Res Ther. 16:R58 (2014).
1. Legrain et al. Interplay between selenium levels, selenoprotein expression, and replicative senescence in WI-38 human fibroblasts. J Biol Chem. 289:6299-310 (2014).
1B. Saretzki et al. Similar gene expression pattern in senescent and hyperoxic-treated fibroblasts. J Gerontol. 53A(6):B438-42 (1998).
2. Ray et al. Low serum selenium and total carotenoids predict mortality among older women living in the community. The women’s health and aging studies. J Nutr. 136:172-6 (2006).
3. Akbaraly et al. Selenium and mortality in the elderly. Results from the EVA study. Clin Chem. 51:2117-23 (2006).
4. Sousa-Victor et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature. 506:316-21 (2014).
4B. Killilea and Ames. Magnesium deficiency accelerates cellular senescence in cultured human fibroblasts. Proc Natl Acad Sci USA. 105(15):5768-73 (2008).
5. Li and Belmonte. Genetic rejuvenation of old muscle. Nature. 506:304-5 (2014). This is the commentary on paper #2.
6. Baker et al. Clearance of p16INK4a-positive senescent cells delays ageing-associated disorders. Nature. 479:232-6 (2011).
7. Waaijer et al. The number of p16INK4a positive cells in human skin reflects biological age. Aging Cell. 114:722-5 (2012).
9. Salama et al. Cellular senescence and its effector programs. Genes Dev. 28:99-114 (2014).
10. Guo et al. AMPK-mediated downregulation of connexin43 and premature senescence of mesangial cells under high-glucose conditions. Exp Gerontol. 51:71-81 (2014).
11. Kim et al. Regulation of the catabolic cascade in osteoarthritis by the zinc-ZIP8-MTF1 axis. Cell. 156:730-43 (2014).
11A. Kraus. The zinc link. Nature. 507:441-2 (2014).

SELENIUM—WHY A MODEST
DEFICIENCY IS A HAZARD TO YOUR HEALTH

The Triage Theory of Aging: Why Modest Inadequacy of Vitamins or Minerals May Increase Diseases of Aging Later

An interesting and potentially very important new theory of aging^1–3 posits that, while modest inadequacies of vitamins or minerals may not appear to cause short-term negative effects (such as reduced survival), in the long run they may be the basis for insidious effects such as increased risk of age-related degenerative diseases. This theory may be important for explaining how the widespread modestly inadequate intake of many vitamins and minerals in the United States and other advanced industrialized countries results, in association with the increasing lifespan in those countries, with more people at risk for age-related degenerative diseases. Thus, avoiding those deficiencies in early life can have large benefits that show up in life later on.

As the latest paper on the triage theory explains,⁴ “when the dietary availability of a V/M [vitamin/mineral] is moderately inadequate, nature ensures that V/M-dependent functions that are essential from an evolutionary perspective (i.e., required for short-term survival and/or reproduction) are protected at the expense of those that are less essential (i.e., whose lack does not have acute short-term negative consequences but may have long-term insidious effects that increase risk of diseases associated with aging). The triage theory does not imply that any particular V/M deficiency is the only cause of an age-related disease but rather that it is a contributing factor along with the sum of all contributing causal factors.” The authors suggest that, if the triage theory is correct, it would have major implications for public health, since as they note (with references cited), most people are modestly deficient in one or more V/Ms and that includes not only poor countries, but wealthy countries, especially among the less wealthy, the obese and the elderly.

While this theory is very plausible, there is still a need for significant evidence in order to establish its validity. Hence, the authors have previously published a paper on Vitamin K as an example.³ Their latest paper⁴ has analyzed a huge amount of data from published studies to look at selenoproteins from the perspective of the triage theory. The paper is 21 pages long and includes 295 references.

As the authors explain in their new paper, the triage theory makes three predictions concerning selenoproteins (SPs):

• Essential SPs are more resistant than nonessential SPs to Se (selenium) deficiency.
• Decreased functionality of nonessential SPs increases risk of diseases of aging.
• There is evidence of a causal relationship between decreased functionality of nonessential SPs and increased risks of diseases of aging.

As you can well imagine, to support these hypotheses required the analysis of an immense amount of evidence. We will present a few examples of how the authors assessed the data.

First, it was necessary to determine which selenoproteins (SPs) are “essential” and which ones are “nonessential,” requiring a separate analysis. As the authors explain, they used a model for essentiality in which they looked at mouse KOs (knockouts) for various selenoproteins to determine which ones were either embryonically lethal or where offspring had severely reduced fertility. Those SPs would be “essential” from the perspective of evolution because they would have negative effects on short-term survival and/or negative effects on reproduction. Though the authors recognize that a rodent knockout model is not an ideal or perfect way to identify “essential” uses for vitamins or minerals in humans, it is a reasonable way to begin an inherently complex analysis. In this way, the authors were able to determine, for example, that cytosolic cGpx4 (selenium-containing glutathione peroxidase 4) was essential for embryonic development and another, mitochondrial mGpx4 (selenium-containing glutathione peroxidase 4) was essential for fertility. “The lethality of the cGpx4 KO is consistent with its unique function in protecting against damage from lipid peroxidation and participating in critical lipid peroxide signaling pathways. Severe infertility of mGpx4-KO offspring is also not surprising, given the fact that mGpx4 plays an essential structural role in spermatozoa.”

Distribution of Selenium When Selenium Supply Is Deficient

Prediction 1 proposed that essential SPs would be more resistant than nonessential SPs to selenium deficiency. In other words, when there is only a limited supply of selenium available, it would be expected that the essential selenoproteins would get selenium so as to be able to fulfill their more critical functions before any remaining selenium would be distributed to the nonessential selenoproteins. To determine this, in one example, the authors looked at the relative sensitivities to deficiency of Gpx4 to overall Gpx activity (primarily Gpx1) in rodent models of modest and severe selenium deficiency in liver, kidney, thyroid, muscle, heart, lung, and testis, and (as they report) the essential SP Gpx4 was more resistant to selenium deficiency (either moderate or severe) compared to overall Gpx activity (primarily Gpx1) in all rodent tissues examined. The data for these analyses were obtained from 37 research reports. “… differences between Gpx4 and overall Gpx activity are significant in almost all cases where statistical comparisons were possible (i.e., where >2 experiments were available) … .”

When Selenium Deficiency Results in Decreased Function of Selenoproteins That Protect Against Diseases of Aging

Going on to Predictions 2 and 3, the authors examined the literature to analyze whether decreased functionality of nonessential SPs increase the risk of diseases of aging, and whether there is evidence of a causal relationship. As the authors note, “[i]t is extremely difficult, if not impossible, to test this prediction directly in long-term randomized controlled trials, as we have discussed.” Hence, this analysis used epidemiological studies and other genetic and mechanistic evidence, “to ask whether the same diseases or conditions of aging that are prospectively associated with modest Se [selenium] deficiency are also linked to phenotypes of nonessential SP mouse KOs or human mutants, and whether plausible mechanisms suggest a causal connection between these same SPs and diseases.” The authors point out that there is a large body of evidence that links genetic loss of nonessential SP activities to phenotypes similar to those of diseases or conditions of aging associated with modest Se deficiency, suggesting that causal linkages between dysfunction of nonessential SPs and diseases of aging is possible. As they explain, the intent of these data “is not to imply that relationships are necessarily fully established or that causal linkages have been clearly demonstrated” but to establish that enough evidence exists to provide plausibility to the causal relationship.

The authors also note that mutated versions (SNPs, single nucleotide polymorphisms, of the selenoprotein gene) of essential SPs are also linked to age-related diseases and point out this is not inconsistent with the triage theory, which “predicts only that modest Se deficiency is more likely to impair nonessential SPs than essential SPs.” Moreover, as they also point out, there are many causal factors other than genetic and nutritional ones that may impact the likelihood of disease.

Modest Selenium Deficiency Linked to Increased Risks of Cancer, Cardiovascular Disease, and Infection

The authors conclude that predictions 1, 2, and 3 were largely borne out by the data. They note, for example, that numerous epidemiological studies “suggest that Se deficiency is prospectively linked to increased cancer risk, and various [selenoprotein] mutants in mice and humans, are also linked to increases in cancer risk. Other diseases or conditions prospectively associated with modest Se deficiency that are similar to nonessential SP mutant phenotypes … include increased DNA damage, increased cardiovascular disease and related conditions, reduced resistance to infection (primarily viral), and poor cognitive function.” The authors then go on to analyze a variety of mechanisms that might be involved in the increased risk of these diseases.

In summing up, the authors explain that, “The most obvious value of the theory is that it provides a rationale for why a particular class of V/M [vitamin-mineral]-dependent proteins (i.e., those that are nonessential) may not be fully functional even at modest levels of V/M [vitamin-mineral] deficiency not accompanied by any obvious clinical signs. The value of this insight is that it suggests a strategy for identifying sensitive biomarkers of V/M [vitamin-mineral] deficiency and candidate proteins mechanistically linked to disease. An important limitation of broadly applying the approach followed here is that mouse KOs are not necessarily reliable predictors of essentiality in humans … because of many species differences, some known and some as yet unknown.”

We thank the authors both for creating the triage theory^1,2 and for the incredible amount of work done in the examination of the evidentiary basis for the triage theory.^3,4 The result is truly a valuable contribution to public health. We hope it gets the attention it deserves.

References

1. Ames BN. Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage. Proc Natl Acad Sci USA. 2103:17589-94 (2006). THIS PAPER CAN BE DOWNLOADED FREE AT:www.PNAS.org/content /103/47/17589.long www.PNAS.org/content /103/47/17589.long.
2. Ames BN. Prevention of mutation, cancer, and other age-associated diseases by optimizing micronutrient intake. J Nucleic Acids. pii: 725071. doi: 10.4061/2010/725071 (2010).
3. McCann and Ames. Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? Am J Clin Nutr. 90:889-907 (2009).
4. McCann and Ames. Adaptive dysfunction of selenoproteins from the perspective of the triage theory: why modest selenium deficiency may increase risk of diseases of aging. FASEB J. 25:1793-814 (2011).

INCREASING THERMOGENESIS OF
BROWN FAT WITH A SUPPLEMENT

Uncoupling Protein 1 (Ucp1) Increases Energy Expenditure in Brown Adipose Tissue

Possible Induction of Expression of Ucp1 With EGCG or Curcumin

A recent paper¹ reports increased expression of the thermogenesis gene Ucp1 (uncoupling protein 1) that increases energy expenditure in brown fat with a demethylating drug, 5-aza-deoxycytidine. This proof of principle paper suggests that other demethylating agents, such as EGCG (the major green tea catechin) and curcumin (found in turmeric root) may also have this effect. If so, it provides evidence of a potential mechanism to support the use of EGCG and curcumin in weight control regimens.

One of the distinguishing features of brown fat as compared to white fat is that brown fat, but not white fat, contains Ucp1 and when activated (by adrenergic stimulation^1B or exposure to cold) burns off fat to generate heat, a process called thermogenesis. The Ucp1 is called an uncoupling protein because the way it works is by disengaging the oxidative phosphorylation that would otherwise take place in mitochondria to produce ATP to the use of that fuel to create heat.¹

The authors¹ report data in this study that shows that demethylation of the Ucp1 promoter by the drug 5-aza-deoxycytidine results in increased expression of Ucp1. They also report that there is a silencing modification on the Ucp1 enhancer in white fat, while a marker indicating activation appears on the Ucp1 promoter in brown fat in response to a cold environment. The control of whether a gene is turned on or off by methylation in genes or histones is called epigenetics. The silencing feature in the Ucp1 gene in white fat is essential to white fat acting as a “thrifty” store of fuel for when food is scarce.

This discovery is very important because for a long time scientists have been studying how to cause white fat to undergo “browning,” natural processes that stimulate white fat to express some of the properties of brown fat, especially the all-important energy expenditure that helps eliminate excess storage of white fat and its associated negative effects on health. In fact, it has been found possible to produce “browning” of white fat to become more like brown fat.^1C,1D But increasing the expression of Ucp1 to increase energy expenditure in brown fat via an epigenetic mechanism is a different way of increasing energy expenditure to help prevent obesity and its associated disorders (e.g., type 2 diabetes). Importantly, this method may be easier at present with the availability of safe-to-use natural products that have been shown to act as demethylating agents.^1F,1G

References

1. Shore et al. Role of Ucp1 enhancer methylation and chromatin remodelling in the control of Ucp1 expression in murine adipose tissue. Diabetologia. 53:1164-73 (2010).
1B. Inokuma et al. Indispensable role of mitochondrial UCP1 for antiobesity effect of beta3-adrenergic stimulation. Am J Physiol Endocrinol Metab. 290:E1014-21 (2006).
1C. Fisher et al. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 26:271-81 (2012).
1D. Mitschke et al. Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J. 27:1621-30 (2013).
1E. Liu et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett.19:706-9 (2009).
1F. Fang 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).

THE SHORT CHAIN FATTY ACID BUTYRATE ACTIVATES THE NIACIN RECEPTOR GPR109A

THE ANTI-ATHEROSCLEROTIC PLOT THICKENS: NIACIN AND DIETARY FIBER FOR “CLEAN” ARTERIES

The short chain fatty acid butyrate (produced by certain microbes in the lower digestive tract from indigestible fermentable fiber that reaches the colon) and the vitamin niacin (nicotinic acid, vitamin B3) both act as ligands for (activating) the GPR109A receptor.^1,2This surprising link has resulted in both additional understanding of how niacin works and what butyrate does, but also introduces additional questions concerning how this all adds up, as not that much is known about GPR109A or how niacin works.

A recent paper³ explains that in a mouse model lacking the GPR109A receptor, the anti-lipolytic effect of niacin (inhibition of enzymatic release of free fatty acids) is blocked—but this didn’t have an effect on the usual beneficial changes in plasma LDL and HDL levels produced by high-dose niacin. Thus, niacin’s effects on LDL and HDL are not linked to GPR109A, but its antilipolytic effect is. Meanwhile, the tumor-suppressive effects of butyrate in the colon were found to be mediated by butyrate acting as a ligand at the GPR109A receptor.² As the authors² explain, the circulating level of butyrate (about 5 μmol/L) is not high enough to activate the GPR109A receptor, but in the colon, butyrate levels are much higher (about 20 mmol/L) and, at that concentration, able to activate the receptor. Thus, the researchers conclude that, “GPR109A mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in colon.”

Niacin was proposed to reduce the progression of atherosclerosis independently of its lipid-modifying effects through GPR109A mediated antiinflammatory effects in immune cells.¹ In one paper,⁴ human monocytes were pretreated with niacin and then activated by the addition of the Toll-like receptor 4 immune stimulant bacterial lipopolysaccharide. Determination of the resulting secretion of proinflammatory mediators revealed that niacin reduced the secretion of TNF-alpha by 49.2 ± 4.5%, reduced IL-6 by 56.2 ± 2.8%, and reduced monocyte chemoattractant protein 1 by 59.3 ± 5.3%. Interestingly, inhibition of prostaglandin D2 receptor (activation of which causes niacin flushing) did not alter the antiinflammatory effects of niacin described here. This may mean that preventing niacin flushing won’t interfere with niacin’s antiinflammatory effects, but doesn’t tell us whether preventing niacin flushing would interfere with niacin’s effects on HDL and LDL. “The jury is still out” on whether it is a good idea to interfere with niacin flushing. See the June 2009 issue of this newsletter for a speculative article we wrote on the niacin flush.

Colon cancer is reported to be able to silence GPR109A by increasing DNA methylation at that receptor, but the expression of GPR109A can be restored in the presence of butyrate and niacin.²

We wonder about the possibility of an additive antilipolytic effect of butyrate and niacin in the general circulation. Although the concentration of butyrate is much too low (about 4000 times too low in the general circulation) to activate GPR109A by itself, it would be interesting to determine whether it might add anything to the antilipolytic effect of niacin. As powerful anti-inflammatory effects of niacin in monocytes have been identified recently as mediated by GR109A, and as butyrate is a ligand of GPR109A (at least at its concentration in the colon), the combination could be very potent in reducing the risk of colon cancer and inflammatory conditions in the lower digestive tract.⁴

Conspicuously absent from these data and from the analysis of anti-atherosclerotic mechanisms resulting from fermentation of indigestible fiber reaching the lower digestive tract is the large amounts of hydrogen that can be produced by gut microbes in residence there. Whether the presence of all that hydrogen is additive with or synergistic with the anti-atherosclerotic properties of the short chain fatty acids, if it is, remains to be explained.

References

1. Lukasova et al. Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. J Clin Invest.1213:1163-73 (2011).
2. Thangaraju et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 69(7):2826-32 (Apr. 1, 2009).
3. Lauring et al. Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression. Sci Transl Med. 4(148):148ra115 (2012).
4. Digby et al. Anti-inflammatory effects of nicotinic acid in human monocytes are mediated by GPR109A dependent mechanisms. Arterioscler Thromb Vasc Biol.32(3):669-76 (2012).

APPETIZERS

I am an advocate of paper money, but that paper money must represent what it professes on its face. I do not wish to hold in my hands the printed lies of government. He who controls the money supply of a nation controls the nation. 
— James A. Garfield, twentieth U. S. President

If I owe you a pound, I have a problem; but if I owe you a million, the problem is yours. 
— John Maynard Keynes

The only time to eat diet food is while you’re waiting for the steak to cook. 
— Julia Child

Just taught my kids about taxes by eating 38% of their ice cream. 
— Conan O’Brien

Treason doth never prosper, what’s the reason? For if it prosper, none dare call it Treason. 
— Sir John Harington, Epigrams (1603)
(with thanks to Eugene Kontorovich,
posted 15 Dec. 2013 in The Volokh Conspiracy)

A human being should be able to change a diaper, plan an invasion, butcher a hog, conn a ship, design a building, write a sonnet, balance accounts, build a wall, set a bone, comfort the dying, take orders, give orders, cooperate, act alone, solve equations, analyze a new problem, pitch manure, program a computer, cook a tasty meal, fight efficiently, die gallantly. Specialization is for insects. 
— Robert Heinlein

AND THIS VITALLY IMPORTANT NEWS ITEM
REPORTED IN THE YAHOO NEWS (12/15/13)

We have now learned why certain evil characters (such as Gollum, Smaug, and an orc) in J.R.R. Tolkien’s The Hobbit were all losers in their battles with humans, elves, and dwarves: they had a severe vitamin deficiency! Yes, they were felled as a result of a vitamin D deficiency, thus answering a longstanding question concerning how such powerful evil characters could have been such overwhelming losers.

As reported in the Christmas edition of the Medical Journal Of Australia, Nicholas Hopkinson, a doctor at Imperial College London and his son Joseph studied the diet, living conditions, and habitat of the characters in The Hobbit and made the Earth-shaking discovery that the evil characters were all living in the dark, with poor diets and hence were deficient in vitamin D. Meanwhile, the hobbit diet was varied, with plenty of vitamin D, and although Bilbo lived in a hole, he liked sitting in a sunny window as well as gardening, getting plenty of exposure to the sun.

The lesson to be derived from this story, according to the doctor and his son, was that the triumph of good over evil could be explained to some extent by the evil characters’ poor diet and lack of exposure to sunlight. Ah, so now we know!!

 

NEW RECORD OF –135.8 DEGREES F SET
FOR COLDEST TEMPERATURE ON EARTH

This news of lowest temperature recorded was measured by satellite in Antarctica and reported by the Associated Press on Dec. 9, 2013. The AP news report explains that this temperature will not appear in the Guinness Book of World Recordsbecause it wasn’t measured by a thermometer at ground level. The AP reporter noted correctly that the occurrence of a single temperature wouldn’t be enough to either support or disprove global warming. However, it’s been cold for a while in Antarctica. According to the AP report, the old cold record was –128.6 set at Russia’s Vostok Station in Antarctica in 1983. Then a new record was set in August 2010 when it reached –135.8 at a new location. In July 31, 2013, the temperature was recorded as –135.3 at another location fairly close to the location of the temperature recorded in August 2010. And now we have another record, –135.8. See the map of Antarctica with the locations of the record cold temperatures at www.nbcnews.com/science/now-thats-c-c-c-cold-antarctica …

REWARDS TRIGGER BIGGER LEARNING RESPONSE WITH GREEN TEA

MONETARY INCENTIVE-INDUCED REWARD LEARNING ENHANCED, DEPRESSIVE SYMPTOMS DECREASED IN HUMAN PILOT STUDY

The results of a recent randomized, double-blind, placebo-controlled study involving 74 human subjects suggest that it might be a good idea to offer your employees (if you have them) free green tea to enhance their response to incentives such as raises or bonuses. The study¹ found that participants receiving green tea for 5 weeks had improved reward learning (decreasing the reaction time in a monetary incentive delay task) compared to those receiving a placebo. Plus, the subjects showed improved mood scores on a measure of depressive symptoms.

Impairment of reward learning is associated with depression. Receiving a raise or bonus or similar incentive is not going to provide a rewarding boost to mood when depression has reduced your ability to respond to rewards (a state called anhedonia). Thus, the results of this study might be of particular interest to entrepreneurs trying to find ways to increase the rewarding effect of monetary incentives. The incentive trials allowed participants to earn money or to avoid losing money by pressing a button during the presentation of a cue (shown for a period of 4.5 to 9.5 seconds). The reaction time (time to push the button following the presentation of the cue) was taken as a measure of depression when response time was retarded.

The results showed significantly enhanced reward learning (faster response to the cue indicating an available reward) in those receiving the green tea. The tea was administered as 400 mg of green tea powder dissolved in hot water three times a day (one serving 30 minutes after each of three meals) and contained 45.6% of polyphenols as EGCG.

In discussing the mechanisms that might be responsible for the improvement in reward learning, the authors note that dopamine deficiency has been proposed as an important cause of anhedonia, an individual’s loss of response to rewarding stimuli in depression. “The mesolimbic and nigrostriatal DA [dopamine] system appears to be related primarily to reward system function and responsiveness to the environment.”¹ “It has been reported that the active component of green tea, EGCG, inhibited psychostimulants-induced hyperactivity in part by modulating dopaminergic transmission.”¹ “A recent study showed that green tea extract treatment can reduce hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in response to stress in mice.”¹ (See “Would You Like To Enjoy Life More?” in the March 2014 issue of Life Enhancement.)

Effects of EGCG on Brain Activity and Mood

Another recent paper² reports on potential benefits of the green tea polyphenol EGCG on brain activity and mood. They refer to an earlier study showing a modest but significant association between green tea consumption and lower psychological distress. Green tea, of course, contains considerable amounts of EGCG but also other components that could have effects on psychological distress, such as theanine and caffeine.

In this human study, there were 31 volunteers (mean age 27.74 years, SD (standard deviation) 9.28, with 12 males and 19 females). This was, therefore, a small study but the researchers measured a number of interesting parameters that are not generally included in studies of mood, specifically EEG data that included theta, alpha, and beta activity. The treatment (with placebo controls) consisted of 300 mg of Teavigo,^® a caffeine-free purified and refined extract of Camelia sinensis (tea) that consisted of approximately 94% EGCG and 6% vitamin C (in the form of ascorbyl palmitate). The researchers note that the results of testing for cognitive and cardiovascular functioning was to be published elsewhere, while this paper reports on mood and resting state EEG.

The EGCG treatment was reported to significantly increase calmness and reduce stress as assessed by the Bond-Lader mood scale. More interestingly, compared with placebo, “EGCG administration was associated with a significant overall increase in alpha, beta, and theta activity (data not shown) more dominant in midline frontal and central regions.”² The data were summarized in Figure 1b of the paper.

The researchers state that: “Previously an increase in both alpha and theta activity has been observed during non-directed meditation …” and they speculate that, “the changes in these same waveforms in the EGCG condition may reflect a relaxed yet attentive state due to the intervention.” (Keep in mind that this is speculative. Moreover, the EGCG was combined with ascorbyl palmitate and it has been reported that vitamin C increases the bioavailability of EGCG.³)

EGCG INHIBITS AMYLOID BETA-INDUCED COGNITIVE DYSFUNCTION

Mechanisms Identified for Protective Effect of EGCG Against Cognitive Dysfunction Resulting from Amyloid Beta Buildup As Occurs in Alzheimer’s

A recent study of a mouse model of Alzheimer’s disease⁴ reports that mice pretreated with EGCG for three weeks before receiving intracerebroventricular administration of amyloid beta had reduced toxic effects as compared to animals receiving the amyloid beta but not being pretreated with EGCG. The authors suggest, on the basis of their data, that, “EGCG may be a beneficial agent in the prevention of development or progression of AD [Alzheimer’s disease].”⁴

The mice receiving EGCG were given doses of 1.5 or 3 mg/kg body weight in their drinking water.

One of the measures of cognition used by the authors was the Morris water maze test, where treatment with amyloid beta resulted in significantly slower arrival times at the platform location (where the mice escaped the need to continually tread water), whereas pretreatment with EGCG (either dose) significantly inhibited the effects of amyloid beta on escape latencies.

The apoptotic death of neurons induced by amyloid beta was reported to be prevented by pretreatment with EGCG. The researchers explain that activation of MAP kinase and NFkappaB as well as the activation of alpha, beta, and gamma-secretase are implicated as causes of amyloid beta-induced neuronal cell apoptosis and that pretreatment with EGCG significantly inhibited the expression of these molecules. Other mechanisms were discussed in the paper.

EGCG Suppresses Gluconeogenesis in Liver Cells, Protecting Against Major Pathway Leading to Excess Blood Sugar in Type 2 Diabetes

Failure of feedback mechanisms to inhibit gluconeogenesis in the liver (eating is supposed to shut down gluconeogenesis, as glucose derived from food acts as a negative feedback signal) is a major reason for excess blood sugar in type 2 diabetics. The release of GLP-1 (glucagon like peptide 1) is a molecule involved in the feedback inhibition of eating to tell liver cells to stop gluconeogenesis. In a fairly recent paper,⁵researchers were able to show in mouse liver cells that EGCG suppressed gluconeogenesis by activating 5’-AMP-activated protein kinase (AMPK), an important regulator of energy metabolism that responds to eating by (for one thing) suppressing gluconeogenesis. (The authors point out that the activation of AMPK is associated with EGCG-induced apoptosis in cancer cells, but that is another story.)

The results of this study suggest that EGCG could, as the authors note in their summary (last paragraph in the paper), point to a new therapeutic approach for the management of diabetes.⁵

References

1. Zhang et al. Effect of green tea on reward learning in healthy individuals: a randomized, double-blind, placebo-controlled pilot study. Nutr J. 12:84 (2013).
2. Scholey et al. Acute neurocognitive effects of epigallocatechin gallate (EGCG). Appetite. 58:767-70 (2012).
3. Green et al. Common tea formulations modulate in vitro digestive recovery of green tea catechins. Mol Nutr Food Res. 51:1152-62 (2007).
4. Lee et al. Green tea (-)-Epigallocatechin-3-gallate inhibits beta-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NFkappaB pathways in mice. J Nutr. 139:1987-93 (2009).
5. Collins et al. Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, suppresses hepatic gluconeogenesis through 5’-AMP-activated protein kinase. J Biol Chem. 282(41):30143-9 (2007).

HYDROGEN POWER UPDATE:
HYDROGEN DOSE-RESPONSE RELATIONSHIP

Aspirin-induced Gastric Damage Inhibited by Hydrogen Administered in Drinking Water to RatsGastric mucosal damage induced by aspirin or other NSAIDS (non-steroidal antiinflammatory drugs such as ibuprofen) is a frequent side effect of these pain killers. Using the aspirin gastric mucosal injury as a model in rats of these effects in humans to study how hydrogen is able to provide protection was reported in a new study.¹ At the same time, the researchers investigated whether there is a dose-response relationship for hydrogen in its protective effects against gastric mucosal injury and why a dose-response relationship has not been observed in other studies of hydrogen’s protective effects, as seen in cerebral infarction (stroke), ischemia/reperfusion, metabolic syndrome, Parkinson’s disease, and other human diseases and disease models.¹

With respect to the dose-response relationship, the scientists observed such a relationship in the stomach, but not in the serum which suggests, they believe, that “a dose response effect exists when hydrogen interacts directly with the tissue, but a high dose of hydrogen may not increase the beneficial effects in target organs via blood transportation.” Apparently, the hydrogen reaches the stomach at a certain concentration but that after leaving the stomach, it is diffused through the body’s tissues and also excreted rapidly, thus the concentration available to other tissues is much lower than in the stomach. The amount of hydrogen was adequate, however, to alkalize the water which inhibited increased urinary excretion of minerals such as calcium and magnesium.

The scientists observed that hydrogen protected against aspirin-induced gastric mucosal injury in a dose-dependent manner.

Reference

1. Xue et al. Dose-dependent inhibition of gastric injury by hydrogen in alkaline electrolyzed drinking water. BMC Complement Altern Med. 14:81 (2014).

DO BIRDS LOOK AT THE FUTURE WITH ROSE-COLORED GLASSES?
A RECENT STUDY CLEVERLY SHOWS HOW EXCESSIVE OPTIMISM BIAS WORKS IN BIRDS

The recognition that people are prone to an optimism bias, expecting more positive outcomes than what objective data would suggest, resulted in a fascinating study of certain birds that was described in The Optimism Bias: A Tour of the Irrationally Positive Brain by Tali Sharot (a scientist who has done considerable original research in this field), Pantheon Books, 2011.

In this experiment,¹ the researchers wanted to see whether birds would have an optimism bias like people often do. Naturally it required a cleverly designed experiment since they couldn’t just ASK the birds. They got the information by this ingenious approach: They trained birds to press a blue lever whenever they heard a short tone (2 seconds) and the birds would receive an immediate food reward after pressing the blue lever. They also trained the birds to press a red lever when they heard a long tone (10 seconds), which would result in a food reward following a delay. The birds were not happy waiting for the food during the delay and associated the long tone with a negative outcome.

The birds had to get their response right. If they pressed the wrong lever, they didn’t get any food. The big question was how the birds would respond to a tone that was neither short nor long but ambiguously somewhere in the middle. The researchers wondered whether they would be “optimistic” by pressing the blue lever or “pessimistic” by pressing the red lever. In fact, the ambiguous tone tended to result in the birds pressing the blue lever, in the absence of anything that would tell them what the outcome would be. And, the real eye opener was that only birds living in the larger, cleaner cages with toys and continuous reliable access to food, water, and baths were “optimistic.” Birds living in smaller, less clean cages with unreliable access to these comforts tended to be more “realistic” and to have more accurate expectations. The researchers interpreted this as a “depressive realism” derived from living in more difficult conditions

The experiment very skillfully permitted the researchers to perceive the birds’ future expectations and how remarkably similar to the human optimism bias it was. We can extrapolate from that to the unrealistically optimistic view of government programs that we so frequently see inexplicably (it would seem) from those with higher incomes and educational attainment. The larger houses with the enriched environments that such people live in appears to have a similar effect (excessively optimistic bias) to that of the birds living in the larger, more enriched cages.

Reference

1. pp. 37 & 38, book cited above. Original study: Matheson, Asher, and Bateson. Larger, enriched cages are associated with ‘optimistic’ response biases in captive European starlings (Sturnus vulgaris). Appl Anim Behav Sci. 109:374-83 (2008).

LATEST TASTY/EASY TO MAKE
NUTRITIOUS MEAL FROM SANDY’S KITCHEN.
TUNA AND CHERRY TOMATO FRITTATA

This is a really tasty, REALLY easy/fast to make meal, great for lunch or dinner. Add mushrooms, cheese, or pine nuts (for example) for fun variations.

You’ll need

• A largish skillet
• 5 eggs
• 1½ tbsp. mustard, your choice of styles
• 2 tbsp cream
• A little salt to taste
• 1 tbsp butter/olive oil combination for cooking
• 2 cans of 5 oz. tuna each (dark tuna has higher content of healthful omega-3 fatty acids), drained
• About ½ pound of cherry tomatoes, cut into halves
• 6 tbsp sliced or chopped green olives
• 5 scallions, cut into rings
• 2 tbsp. capers

Beat eggs, mustard, and cream together; add a little salt.

Melt the butter/olive oil combo in your skillet and set the heat level on low. Pour in the egg mixture and cover with the sliced cherry tomatoes. Cook uncovered on low for about 25 minutes until the top has set.

About 12 minutes from the end of the cooking period, spread the tuna over the top, along with the olives, scallion rings, capers, and any other toppings.

Cover the skillet and cook over low for the remaining 12 minutes. Remove and eat at once! CAUTION: You may find that you have made too little! This makes a great party food.)

This recipe is based on one Sandy found in My Favourite Ingredient: TUNA by Thea Spierings, Miller Books, 2008. Sadly, she didn’t find any others that sounded nearly as good or as easy to make but it was worth getting the cookbook for that one recipe alone as we will be having it frequently.

REMOTE ISCHEMIC CONDITIONING COULD IT BE AN EXERCISE MIMIC?REDUCING DAMAGE DONE BY EVOLVING HEART ATTACK
WITH SIMPLE INEXPENSIVE METHOD

A safe, simple, and effective way to reduce the damage resulting from an ongoing heart attack called remote ischemic preconditioning has been described in the Feb. 27, 2010 Lancet.¹ A variation of this method, called Enhanced External Counterpulsation (EECP), is used at the Whitaker Wellness Center* in their program of treating patients with cardiovascular disease. A similar device is used at some hospitals to decrease the risk of blood clots in patients bedridden following major surgery.^†

*Whitaker Wellness Center (www.whitakerwellness.com), 1-800-488-1500; reported by Julian Whitaker, M.D., Director of the Whitaker Wellness Center, to stimulate the formation of collateral circulation (new blood vessels) around clogged arteries. (Improved collateral circulation is also an effect induced by exercise.)

†Sandy was hooked up to such a device at the Mayo Clinic following her surgery for bowel obstruction about two years ago. Her legs were cyclically pulsed to compress and then the pressure released for decompression to take place. This was a very pleasant, enjoyable form of massage to help prevent blood clots in a patient stuck in bed. For use as a device to reduce the risk of blood clots, this would be considered a medical device and regulated by the FDA. It would cost a lot less as a device for massaging the legs that could do the same thing mechanistically but not be regulated as a medical device. Such devices are available via Amazon.com.

The Lancet Study Reported Significantly Less Heart Damage in Heart Attack Patients

The study¹ followed 126 patients being taken to the hospital by ambulance. During the trip (following oral administration of aspirin or i.v. clopidogrel along with heparin, acting as anticlotting agents), these individuals were administered remote ischemic conditioning followed (at the hospital) by percutaneous angioplasty or percutaneous angioplasty without remote ischemic conditioning.

The remote ischemic conditioning procedure was very simple and could even be done by laypersons: a blood pressure cuff was attached to the upper arm and then subjected to four cycles of 5 minutes inflation followed by 5 minutes deflation. You pump up the cuff until circulation to the arm is cut off for 5 minutes (cuff pressure above systolic peak) then deflate it for 5 minutes. Repeat three more times. Very simple, safe, and easy.

The primary endpoint was myocardial salvage index at 30 days after percutaneous angioplasty, estimated by gated single photon emission CT. Salvage (heart cells protected against dying) as a percentage of the left ventricle was significantly higher in the intervention group (16%, 8–24, n=82) than in the control group (11%, 3–22, n=83; p=0.0391).

Heart Damage Reduced by Remote Ischemic Conditioning in Patients Undergoing Coronary Artery Bypass Graft Surgery

Another paper^1B reported on a similar experimental protocol in patients undergoing coronary artery bypass graft surgery just after the induction of anesthesia. They were administered remote ischemia conditioning similar to that received by the patients described above.¹ These patients^1B received three cycles of right upper limb ischemia by a cuff-inflator; 5 min. inflation to 200 mm Hg was followed by 5 min. of reperfusion (the cuff was deflated). In these patients, the levels of serum troponin T were measured to detect heart injury before surgery and at 6, 12, 24, 48, and 72 hours after surgery. (Increased troponin T is typically detected in those suffering heart attacks; it is a protein released from dead muscle cells.) Remote ischemic preconditioning significantly reduced overall serum troponin T release at 6, 12, 24, and 48 hours after surgery. “The total area under the curve was reduced by 43% from 36.12 μg/L (SD 26.08) in the control group to 20.58 μg/L (9.58) in the remote ischemic preconditioning group …” The mean difference was 15.55 (SD 5.32; 95% CI 4.88 – 26.21, p=0.005). Thus, this very simple, safe technique significantly reduced heart damage that occurs in the hearts of patients undergoing coronary artery bypass graft surgery that has been a matter of considerable concern since these patients already have damaged hearts.

Mechanisms That May Be Responsible for the Protective Effect of Remote Ischemic Conditioning

A number of mechanisms for the effects of remote ischemic conditioning have been proposed: upregulation of IL-6,² activation of the potassium ATP channel which then induces the generation of reactive oxygen species and nitric oxide, both of which are required for preconditioning protection,³ and mediation by opioid receptors has also been suggested.4

Could Remote Ischemic Conditioning Mimic Exercise?

It is interesting to note that the mechanisms proposed as being responsible for remote ischemic conditioning are all mechanisms that may be (at least in part) responsible for the beneficial effects of exercise.^2B Therefore, we are wondering whether this simple technique of cyclically inflating and then deflating a blood pressure cuff could act as an exercise mimic, allowing even the most sedentary of us to “exercise” daily virtually without effort. One could simply read, watch TV, or just relax during the procedure to get a daily “dose” of simulated exercise.

In support of the hypothesis that remote ischemic conditioning may improve nitric oxide availability are data from a study of the variability in uptake efficiency for pulsed versus constant concentration delivery of inhaled nitric oxide.⁵ This study showed that pulsed nitric oxide delivery via inhalation of nitric oxide improved uptake efficiency compared with constant concentration delivery. Although the study involved inhalation of nitric oxide gas rather than induced release of nitric oxide by remote ischemic conditioning (as described above), the improved efficiency of pulsed nitric oxide release as compared to constant release may be similar. Additionally, the nitric oxide release by remote ischemic conditioning has been found to be a safe technique for increasing nitric oxide, whereas the paper on nitric oxide inhalation indicated the need for careful control of the amount and timing of the nitric oxide to achieve optimal delivery of nitric oxide. This shouldn’t be a concern with remote ischemic conditioning, where natural regulatory processes control the release of nitric oxide.

Another paper⁶ from 2000 suggested in its “speculative review” that vascular pulsations in mild exercise that stimulate nitric oxide release may be a source of some of the beneficial effects in exercise. The authors surmised that eNOS activation by acute changes in pulsatile pressure (or shear stress) is the cause of the pulsatile release of nitric oxide. “In doing this, the restoration of NO balance may serve to decrease the presence of free radicals, allowing the vascular endothelium to return to a state of inhibition while simultaneously protecting sympathetic nerve endings.” We found this paper surprisingly ahead of its time and think their suggested mechanism for beneficial effects of mild exercise via pulsatile nitric oxide release is a plausible one. If so, the use of a system to produce pulsatile compression and decompression of skeletal muscle via inflation/deflation of a blood pressure cuff with release of pulses of nitric oxide is, we think, likely to act as an exercise mimic.

References

1. Botker et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial.Lancet.375:727-34 (2010).
   1B. Hausenloy et al. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet. 370:575-9 (2007)
   2. Tacchini et al. Up regulation of IL- 6 by ischemic preconditioning in normal and fatty rat livers: association with reduction of oxidative stress. Free Radic Res. 40(11):1206-17 (2006).
   2B. Keller et al. Interleukin-6 receptor expression in contracting human skeletal muscle: regulating role of IL-6. FASEB J. 19:1181-3 (2005).
   3. Lebuffe et al. ROS and NO trigger early preconditioning: relationship to mitochondrial KATP channel. Am J Physiol Heart Circ Physiol. 284:H299-H308 (2003).
   4. Weber. Receptor cross-talk in remote conditioning. Nat Med. 16(7):760-2 (2010).
   5. Martin et al. Variability in uptake efficiency for pulsed versus constant concentration delivery of inhaled nitric oxide. Med Gas Res. (open access) 4:1 (2014) doi:10.1186/2045-9912-4-1.

SIMPLE TEST FOR HEART FUNCTION IS
POWERFUL PREDICTOR OF MORTALITY

A 1999 paper¹ reports that “a delayed decrease in the heart rate during the first minute after graded exercise, which may be a reflection of decreased vagal activity, is a powerful predictor of overall mortality, independent of workload, the presence or absence of myocardial perfusion defects, and changes in heart rate during exercise.” A similar result was reported by a different group in a 2006 paper,² which found that the deceleration capacity of heart rate is “a powerful predictor of mortality after myocardial infarction” and is more accurate than conventional measures of heart-rate variability.

References

1. Cole et al. Heart rate recovery immediately after exercise as a predictor of mortality. N Engl J Med. 341:1351-7 (1999).
2. Bauer et al. Deceleration capacity of heart rate as a predictor of mortality after myocardial infarction: cohort study. Lancet. 367:1674-81 (2006).

BLOOD TEST PROVIDES HIGHLY PREDICTIVE DATA ON
10 YEAR ALL-CAUSE MORTALITY IN OLDER ADULTS

In a February 2014 paper,¹ scientists report a new inflammatory index comprised of just two proinflammatory cytokines that can be measured from blood samples and provide a highly predictive correlation with 10 year all-cause mortality in older adults. “Although all five inflammatory markers significantly predicted mortality, log IL-6 and log soluble tumor necrosis factor-alpha receptor 1 (sTNFR1) were the most predictive among the five.”¹

Reference

1. Varadhan et al. Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults. J Gerontol A Biol Sci Med Sci. 69(2):165-73 (2014).

DEPRESSED? HAVING PAIN?TURMERIC ROOT TO THE RESCUE!MECHANISMS FOR ANTIDEPRESSANT PROPERTY OF CURCUMIN

COMPLETE RELIEF OF PAIN FROM BURSITIS OF THE HIP PROVIDED BY TURMERIC ROOT

We received correspondence from a fan of our turmeric root powder in capsules telling us that she and her sister have bursitis of the hip and have experienced complete relief of all pain with turmeric root powder in caps. Our thanks to this fan for the tip. Not all pain responds the same to pain relievers, but in this case, bursitis was responsive to turmeric root powder.

Meanwhile, a recent paper provides new details on the antidepressant properties of curcumin (a major component of turmeric root powder).¹ The authors explore several mechanisms that may account for these effects.

Surprisingly, the researchers¹ note, in some earlier studies on curcumin’s effects on pain in rodent models of depression, curcumin had similar antidepressant efficacy to fluoxetine (Prozac^®) in the forced swimming test and the tail suspension test. The sorts of behavior that are considered signs of depression in these animals include decreased interest in drinking a sucrose solution and immobility when subjected to stressful conditions.

Depression Associated with Higher Levels of Pro-inflammatory Cytokines

Importantly, the researchers explain, “[t]hree recent meta-analyses have all confirmed that depression is associated with elevated levels of pro-inflammatory cytokines and other inflammatory mediators.”¹ Pro-inflammatory cytokines that have been reported at higher levels during depression-like episodes in animals include C-reactive protein, interleukin-1, interleukin-6, and tumor necrosis factor-alpha. (We suggest that you try to include measurements of blood IL-6 and TNF-alpha when you have lab blood tests. Although C-reactive protein is becoming a fairly common lab test, it will still require a request to get the other pro-inflammatory cytokines measured as well. Most doctors will not have heard of IL-6 and TNF-alpha. But—see left—a 2014 paper has reported that an inflammatory index looking at the levels of serum IL-6 and sTNFR1 provides an accurate prediction of 10 year all-cause mortality.²)

Not all depressed individuals have increased inflammation, but it is an important feature of at least a sizeable subset of depressed persons. (One problem with these cytokine tests is that they are currently not standardized and the measurements determined by different tests cannot generally be directly compared with one another.) Hopefully, as interest in the clinical implications of inflammatory cytokines increases, we will see the development of standardized tests that will make it much easier to compare and interpret them. In the meantime, you can check to see where your TNF-alpha level falls in the normal range provided by the laboratory that measured the TNF-alpha (a lab using a different test may report a different normal range). If it is at the high end, you may want to consider supplementation to reduce inflammation, whereas if it is at the low end of the normal range, this is probably a good indication for your level of inflammation.)

Human studies that have reported antiinflammatory activity of curcumin were cited and described in paper #1, including a study of osteoarthritis patients, a study of patients with diabetic nephropathy (reduced TGF-beta and IL-8 with curcumin), and in type 2 diabetics, curcumin lowered TNF-alpha and IL-6.¹

Increased Serotonin Induced by Curcumin

Another mechanism for curcumin’s antidepressant properties¹ was its dose-dependent increase of serotonin in rats. One way it does this is to reduce the activity of the enzyme indoleamine dioxygenase (IDO), which breaks down tryptophan. As part of the body’s immune response to bacteria (lipopolysaccharide), IDO is increased which decreases the availability of tryptophan to invading bacteria.

Decreased Gut Hyperpermeability with Curcumin

Lipopolysaccharide, an inflammation-causing compound produced by many harmful bacteria, is known to increase gut permeability, which permits some of the trillions of bacteria in the gut to reach other areas of the body. (The importance of maintaining the gut barrier has been known since Elie Metchnikoff’s time, when he predicted that eating yogurt would be a way to protect the gut barrier and perhaps extend lifespan. See Metchnikoff, The Prolongation of Life, G. P. Putnam’s Sons (1908). Depression increases gut permeability and this effect can be ameliorated by curcumin.¹

References

1. Lopresti et al. Multiple antidepressant potential modes of action of curcumin: a review of its anti-inflammatory, monoaminergic, antioxidant, immune-modulating, and neuroprotective effects. J Psychopharmacol. 26:1512-24 (2012).
2. Varadhan et al. Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults. J Gerontol A Biol Sci Med Sci. 69(2):165-73 (2014).