September 2011 Blog with Durk and Sandy

Facts are the air of scientists. Without them you can never fly. 

Satisfaction of one’s curiosity is one of the greatest sources of happiness in life.— Linus PaulingThere are two possible outcomes: if the result confirms the hypothesis, then you’ve made a measurement. If the result is contrary to the hypothesis, then you’ve made a discovery.— Enrico Fermi

The 2nd law of thermodynamics has the same degree of truth as the statement that if you throw a tumblerful of water into the sea, you cannot get the same tumblerful of water out again.— James Clerk Maxwell

In God we trust; all others must bring data. 

If you can’t describe what you are doing as a process, you don’t know what you are doing. 

Learning is not compulsory ... neither is survival.— W. Edwards Deming (Deming (1900–1993) was a statistician who pioneered the application of statistical techniques to the solving of manufacturing and industrial problems, especially in the area of quality control. It was largely through his influence that post-war Japanese manufactured goods went from being considered “junk” to being state of the art high quality.) His classic book (1950 edition) Some Theory of Sampling is available from Dover Publications: 

http://www.doverpublications.com 

http://www.amazon.com/ Theory-Sampling-William-Edwards-Deming/dp/048664684X/There’s talk in Hollywood about doing another “Mad Max’ movie, where gas is so expensive that people steal and kill to get it. It takes place sometime in the future — like July.— Jay LenoIntelligent design is just as bad at explaining politics and business as it is at explaining evolution.— Matt Ridley (in a book review, Nature 2 June 2011)

Central Planning As Intelligent Design 
Why Doesn’t It Work?

A remarkable book review by Matt Ridley (of Tim Harford’s “Adapt”) in the 2 June 2011 Nature describes how intelligent design is just as bad at explaining politics and business as it is at explaining evolution.

Ridley notes that “[t]he book’s message will be music to the ears of many scientists, for Harford exposes the dismal inefficiency of the preconceived, top-down grant-giving that funds much of modern academic research. He celebrates instead the power of prizes and blue-sky funding, and even molecular geneticist Mario Capecchi’s documented Nobel-prize winning decision to use grant money given for one purpose for another. Innovation and discovery come from pluralism and serendipity, not command and control.”

But, as Ridley explains,

There’s lots more wisdom in this great book review (and, it would appear, in the book “Adapt” itself): 

http://www.amazon.com/Adapt-Success-Always-Starts-Failure/dp/0374100969/

Do Products That Claim to Repair Split Ends Really Repair Split Ends?

With all the serious and even grim issues before us, who cares about split ends in their hair? Maybe some people who have split ends do! It is nice to know that there are some things that you can deal with at an individual level without any concerns about politics or voting whatsoever!

In a review¹ of a product that purports to produce “full repair” on your overworked hair, Ni’Kita Wilson, Vice President of Cosmetech Laboratories, Inc. opines:

Products claiming to repair split ends always seem to follow the same formula: a polydimethylcyclosiloxane to cut down the heaviness of the dimethicone and control the viscosity of the formulation, and a dimethicone crosspolymer to coat the hair and create a barrier around each strand. This combination holds down the cuticles, making hair appear smoother, and creates a high refractive index to impart gloss on the hair, making hair appear healthier and “repaired.”

However, that is not how our shampoo works. It really repairs split ends. There are two ingredients in our shampoo. Both are food ingredients, safe for people to eat and that you probably eat every day. One of them, isostearoyl lactylate is a dough conditioner, found in most baked goods because it affects the function and consistency of dough — the way it stretches and the way it feels when you squeeze it — and this is due to the cysteine-cysteine bonds in the dough. In the same way, isostearoyl lactylate controls cysteine-cysteine interactions in hair, which is responsible for the structure and function of your hair.

Isostearoyl lactylate repairs damaged hair, whether it has been damaged by brisk brushing and combing, ultraviolet light, age, hair dryers, or just being blown around in a heavy wind. If you look at it under a microscope, a damaged hair looks similar to an unraveled piece of rope. There’s a cuticle around the hair that holds all these strands together and, when the cuticle gets damaged, it frays and the hair strands spring loose and flop around. Isostearoyl lactylate has an incredible affinity to the cysteine in hair. It attaches to the damaged hair preferentially (it doesn’t stick to itself) and forms a molecular layer over the hair. It penetrates the hair shaft, with the other ingredient, polysorbate 80, acting as a penetration aid. Isostearoyl lactylate can fix every split end on your head in one shampoo.

Detailed information on our shampoo was originally published in an interview in Life Enhancement magazine, which also includes a before and after photomicrograph (magnified 1000 times) showing really closeup details of a split end damaged hair repaired with isostearoyl lactylate: http://www.life-enhancement.com/article template.asp?ID=258.

Reference

1. Wilson. Read the Label. Cosmetics & Toiletries.^® 126(4):244 (2011).

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

An interesting and potentially 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 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 of age-related diseases. Thus, avoiding those deficiencies in early life can have large benefits that show up in life much 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 The new paper⁴ has analyzed a huge amount of data from published studies to look at selenoproteins from the perspective of 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): 1. Essential SPs are more resistant than nonessential SPs to Se (selenium) deficiency. 2. Decreased functionality of nonessential SPs increases risk of diseases of aging. 3. 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 what 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 Gpx4 (selenium-containing glutathione peroxidase 4) was essential for embryonic development and another, mitochondrial Gpx4 (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.”

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) ...”

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 defiency 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.

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 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 103:17589-94 (2006).
2. Ames BN. Prevention of mutation, cancer, and other age-associated diseases by optimizing micronutrient intake. J Nucleic Acids 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 25:1793-1814 (2011).

Gut Microbiota (Resident Microbial Community in the GI Tract) Affect Host Use of Selenium

The gut microbiota is currently a very hot research subject because the community of gastrointestinal resident microbes is being found to have many important effects on immune activity, growth, and use of ingested nutrients, as well as metabolism of important food components such as flavonoids, inflammation, and many other aspects of health. For example, in obese mice and humans it has been found that, in comparison to their lean counterparts, obesity tended to be associated with an enhanced proportion of Firmicutes, reduced Bacterioidetes, or both.¹ In a new paper,² it is reported that dietary selenium affects the host’s production and metabolism of selenium-containing proteins by influencing the gut microbiota. The results showed that the intake of selenium by the host influenced the composition of the intestinal microflora and the microflora, which, in turn, importantly affected the host’s use of the available selenium. In this study,² 10 week-old germ-free (these animals had no gut microbiota) Swiss Webster mice were supplemented with selenium at different doses (0, 0.1, and 0.4 ppm selenium). One group was maintained germ free, while the other two groups were “conventionalized” by receiving microflora from the intestine of C57BL/6J mice.

Perhaps the most interesting finding was that selenium in the diet increased the diversity of the microbiota. The authors also found that “within the 0.1 ppm selenium groups, we observed higher Gpx1 [glutathione peroxidase 1] expression in the liver and kidney, and higher Gpx [glutathione peroxidase] in kidneys of GF [germ-free] mice, compared to CV [conventionalized] mice.” The latter finding relates to the fact that the microbes sequester some of the ingested selenium for their own use.

The authors did identify some specific changes in the makeup of the microbiota as a result of different levels of selenium supplementation, though these changes cannot be clearly interpreted in terms of an “obese vs. lean” microbiota, as not enough is known about these changes to make such correlations. By far the most significant effect on the microbiota, relative to absolute abundance in this study was the decline in Parabacteroides (a subgroup of bacteroides) in response to selenium in the diet.

Incidentally, the authors chose the 0.1 ppm selenium to mimic the human recommended dietary allowance for adults, whereas 0.4 ppm selenium may (the authors suggest) correspond to the diet supplemented with 200g selenium/day in human clinical trials involving selenium.

Consistent with the triage theory discussed above, the authors found that some selenoproteins, such as Gpx1 and MsrB1 (methionine-R-sulfoxide reductase 1) are sensitive to selenium status whereas several other selenoproteins, including TR1 (thioredoxin 1) were less susceptible to selenium changes. “Thus, mice and other mammals have a priority for Se [selenium] supply that is selenoprotein and tissue specific.”

References

1. Turnbaugh and Gordon. The core gut microbiome, energy balance and obesity. J Physiol 587:4153-8 (2009).
2. Kasaikina et al. Dietary selenium affects host selenoproteome expression by influencing the gut microbiota. FASEB J 25:2492-9 (2011).

As we have written in earlier newsletters, all HDL is not the same. While increased levels of HDL are generally protective against the risk of cardiovascular disease, under some conditions HDL loses its protective effects and actually PROMOTES cardiovascular disease. A July 2011 paper¹ explores mechanisms to explain adverse effects of HDL from patients with coronary artery disease. The results are informative but, more important, point to ways to help prevent the loss of protective effects of HDL.

The protective effects of HDL have been found to include promoting the efflux of cholesterol from macrophage foam cells in atherosclerotic plaques, to stimulate endothelial nitric oxide production (that is critical for maintaining healthy endothelial function in blood vessels), and also promotes endothelial repair mechanisms. A number of biochemical pathways have been identified by which HDL performs these protective functions. As the authors¹ note: “... endothelial dysfunction, particularly reduced endothelial NO [nitric oxide] bioavailability, is considered to play a key role in the initiation and progression of atherosclerosis and its clinical complications.”

“... the capacity of HDL to mediate cholesterol efflux [export] from lipid-laden macrophages has been observed to be impaired after substantial oxidative modification of HDL by myeloperoxidase or malondialdehyde, a lipid peroxidation product, as observed in atherosclerotic plaques. In addition, the capacity of HDL to prevent the proinflammatory effect of LDL, i.e., LDL-induced monocyte chemotactic activity, was impaired in patients with CAD [coronary artery disease].” Hence, the purpose of this study was to compare the effects of HDL from patients with stable CAD [coronary artery disease], HDL(cad), or acute coronary syndrome with those of HDL from healthy subjects, HDL(healthy), and to investigate mechanisms to explain these differences.

One of the differences, for example, was that increasing concentrations of HDL(healthy) augmented endothelial cell NO production, whereas no such effects were observed with HDL(cad). The authors explain that “[a]ctivation of eNOS in response to HDL(healthy) has been shown to be dependent on Akt-mediated eNOS Ser1177 phosphorylation, a well-known e-NOS activating pathway. We observed that HDL(healthy) but not HDL(cad) stimulated endothelial Akt phosphorylation at Ser473 and Akt-dependent phosphorylation of eNOS at Ser1177.”

The authors report that recent studies suggest that HDL from healthy subjects promotes endothelial repair. They therefore examined HDL(cad) as compared to HDL(healthy) on in vivo endothelial repair in a nude mouse model with carotid artery injury. “Administration of HDL(healthy) accelerated endothelial repair responses within 3 days after carotid injury.” However, “... treatment with HDL(cad) compared with buffer failed to significantly promote endothelial repair ...”

Some of the results indicated that increased production of MDA (malondialdehyde, a lipid peroxidation product) caused modification of HDL that could be responsible for some of the adverse effects of HDL(cad) on endothelial NO production. Notably, the authors explain, PON1, an enzyme associated with HDL, has been reported to prevent MDA formation in HDL.

PON1 activity was found to be substantially reduced in HDL(cad) as compared with HDL(healthy), even though the content of PON1 was increased in HDL(cad) as compared with HDL(healthy).This, suggest the authors, implies that the PON1 in HDL(cad) is inactivated. The authors here note (no reference given) that a human study of extended-release niacin therapy was associated with significantly increased HDL PON1 activity. This is good news, but keep in mind that the potential for liver toxicity is increased in some people by extended-release niacin as compared to ordinary niacin. Hence, if you want to take extended-release niacin or ordinary niacin at doses of 800 mg per day or more, it is essential that you have your doctor order liver tests to detect any potential liver toxicity. In another study, supplementation of HDL from patients with CAD with purified PON1 partially improved the capacity of HDL to stimulate endothelial NO production under physiological conditions.

“... in experimental studies PON1 has been observed to prevent atherosclerotic lesion development and in recent clinical studies reduced serum activity of paraoxonase [PON] was associated with increased cardiovascular risk.” The authors conclude that “[t]he present study for the first time to our knowledge provides evidence that HDL-associated PON1 activity plays a role in maintaining the endothelial-atheroprotective effects of HDL ...”

Natural Products That Have Been Reported To Increase PON1 Activity

The good news is that there have been reports of increased PON1 activity by various natural products in peer-reviewed published scientific papers. For example, one study²reported that POMEGRANATE JUICE polyphenols increased recombinant paraoxonase-1 (PON1) binding to HDL in plasma collected from six male patients with type 2 diabetes mellitus after they drank 50 mL of concentrated pomegranate juice daily for a period of 4 weeks. The results indicated that PJ increased the capacity of HDL to bind rePON1 (recombinant PON1) not only in vitro, but in vivo. As the authors² noted, PON1 activity has been shown to be reduced in patients with type 2 diabetes and, in these patients, a more severe coronary artery disease was observed by coronary angiography.

Another paper³ reports that the paraoxonase- (PON1) gene expression was induced (>2 fold increase in PON-1 mRNA levels) by RESVERATROL in a study of cell cultures. These authors note that “[b]oth WINE consumption and the isolated flavonoids QUERCETIN and CATECHIN increase serum PON1 activity in human and mice. We recently reported that quercetin, a partial agonist of the aryl hydrocarbon receptor ... induce the PON-1 gene expression.” Quercetin is naturally enriched in onions. Both our high-potency muti-vitamin/mineral/antioxidant formulations contain quercetin, and catechin is found in tea, especially white and green tea, and is also included in our special teas and EGCG booster formulation.

Another natural product reported to protect PON-1 from free radical inactivation is extract of Ilex paraguariensis (YERBA MATE).⁴ In this study, healthy volunteers drank either 0.5 L of IP (yerba mate) extract, 0.5 L of coffee and milk or nothing. PON-1 activity was reported to increase an average of 10% with yerba mate extract ingestion above the changes seen when the intake was coffee and milk (p <0.05). As the authors note, “[t]he magnitude of the effect [increased activity of PON-1], although modest, is similar to that found for statins or other polyphenol-containing beverages.” Moreover, the authors explain, “[s]everal communications from our laboratory and from other authors show that Ilex paraguariensis extracts are potent inhibitors of LDL oxidative modifications, cell oxidative stress and atherogenesis in a rabbit model.” “Chlorogenic acid and its isomers constitute the major polyphenolic fraction of mate tea.”

BUT DON’T EAT THIS ... Meanwhile, serum paraoxonase activity was reported in another paper⁵ to be decreased in 12 healthy men (22–63 years of age) after a meal rich in used cooking fat from deep fat frying. If you eat french fries or fried foods at fast food restaurants, you will be getting a lot of it in your food, as the cooking oils are re-used. They found that peroxide content of LDL tended to increase after the used fat meal and tended to decrease after the meal rich in unused fat. These changes were significantly different.

References

1. Besler et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest 121(7):2693-2708 (2011).
2. Fuhrman et al. Pomegranate juice polyphenols increase recombinant paraoxonase-1 binding to high-density lipoprotein: studies in vitro and in diabetic patients. Nutrition 26:359-66 (2010).
3. Gouedard et al. Induction of the paraoxonase-1 gene expression by resveratrol. Arterioscler Thromb Vasc Biol 24:2378-2383 (2004).
4. Menini. Protective action of Ilex paraguariensis extract against free radical inactivation of paraoxonase-1 in high- density lipoprotein. Planta Med 73:1141-7 (2007).
5. Sutherland et al. Reduced postprandial serum paraoxonase activity after a meal rich in used cooking fat. Arterioscler Thromb Vasc Biol 19:1340-7 (1999).

(1) Can Congress Force You to Buy Broccoli? 
(2) Is That a Hard Question?

The immense quantity of and the pathetic quality of commentary devoted to politics in certain professional scientific and medical journals can really degrade the value of subscribing to them. Publications emerging from organized medicine and big science are almost entirely run by left-wing zealots whose solution to every societal problem is more government spending and more government rules and regulations. A good example is the commentary published in the Jan. 20, 2011 New England Journal of Medicine on the purported difficulty of deciding whether the federal government has the constitutional authority to force you to buy broccoli: (“Can Congress Make You Buy Broccoli? And Why That’s a Hard Question.”)

It might be a “hard” question to the authors (all JD’s, incidentally), but it is only “hard” to them because they are desperately struggling to find some Constitutional justification for forcing Americans to buy Obamacare. The difficulty for them is that there is no authorization in the Constitution for the feds to require Americans to buy broccoli or anything else, including purported government health plans. But at least these authors are honest liberals who realize that if the government can force you to buy into a health plan, then they can also force you to buy broccoli and feel they must justify the latter (at least to themselves) if they can.