July 2014 Blog with Durk and Sandy

July 30, 2014

July 2014 Blog with Durk and Sandy

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

 




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