October 2012 Blog with Durk and Sandy

APPETIZERS

We are especially moved by events that did not have to be, but that occurred for identifiable reasons subject to endless mulling and stewing …When we realize that the actual outcome did not have to be, that any alteration in any step along the way would have unleashed a cascade down a different channel, we grasp the causal power of individual events. We can argue, lament, or exult over each detail because each holds the power of transformation. Contingency is the affirmation of control by immediate events over destiny, the kingdom lost for want of a horseshoe nail. 

— Stephen Jay Gould

Instead of union, let us have disunion now. Instead of fusing the small, let us dismember the big. Instead of creating fewer and larger states, let us create more and smaller ones.

— Leopold Kohr, The Breakdown of Nations (1957)

Don’t you see that the whole aim of Newspeak is to narrow the range of thought? In the end we shall make thoughtcrime literally impossible, because there will be no words in which to express it. 

— George Orwell, Nineteen Eighty-Four (1949)

Things are always going to be falling apart on Earth, you might as well get used to it. 

— Kim Stanley Robinson, Red Mars (1992)

Of all checks on democracy, federalism has been the most efficacious and the most congenial … The federal system limits and restrains the sovereign power by dividing it and by assigning to Government only certain defined rights. It is the only method of curbing not only the majority but the power of the whole people. 

— Lord Acton [as quoted in F. A. Hayek’s The Road to Serfdom. This quote uses the word “federalism” as was used in the original quote by Lord Acton rather than the word “federation” which was substituted for “federalism” by Hayek—the correction was noted by Bruce Caldwell, who edited the 2007 “Definitive Edition” of Hayek’s The Road to Serfdom.]

(D&S comments on federalism: The rise of the administrative state (e.g., lawmaking by regulatory agencies) has resulted in the bypass of most Constitutional protections (for example, there is no right to trial by jury in the administrative law courts nor is there any Fourth Amendment requirement of a court ordered warrant to access an individual’s property or papers under administrative law). This has done immense harm to the protection of liberty rights built into the federalist design of the U.S. government. We favor getting rid of the administrative agencies altogether and abiding by the Constitutional specification of Congress as the sole author of laws. “All legislative Powers herein granted shall be vested in a Congress of the United States …”, Article I Section I of the U.S. Constitution)

Gillian Taylor: Don’t tell me — you’re from outer space! Kirk: No, I’m from Iowa. I only work in outer space. . 

— Meerson, Krikes, Bennett, and Meyer, Star Trek IV: The Voyage Home (film, 1986)

The whole aim of practical politics is to keep the populace alarmed (and hence clamorous to be led to safety) by menacing it with an endless series of hobgoblins, all of them imaginary. 

— H. L. Mencken

Hydrogen Therapy Update

Human Breath Hydrogen Measurements From Hydrogen Water and From Milk

“Countless commercial hydrogen water products are marketed mostly in Japan as health-oriented water” say the authors of a new paper¹ on human breath hydrogen measurements (both from those drinking hydrogen water and from those drinking milk who have lactose intolerance). The results of their study showed that ingestion of commercial hydrogen [hydrogen water] definitely increases hydrogen concentration in the body (there were five healthy adult volunteers, two men and three women, aged 29 ±14 years). “however, the rise in breath hydrogen was transient and the hydrogen-producing capability of hydrogen water was less than that of milk in subjects with hypolactasia [deficiency of lactase resulting in lactose intolerance].” The lactose intolerant subjects couldn’t digest lactose in the milk they drank for the experiments, allowing the lactose to pass into the lower digestive tract, where certain members of the gut microbiota could ferment it, resulting in the production of hydrogen. The problem with lactose intolerance, Sandy can tell you from personal experience, is that it is all too likely to cause rapid increase in gas production that can be very uncomfortable, with bloating and pain. She drinks lactose free milk and has even found a lactose free vanilla ice cream but also takes a supplemental prebiotic (long chain fructooligosaccharides) that can be used by gut bacteria to produce hydrogen at a moderate rate and for a longer period of time than a bolus of lactose-containing milk.

pH Neutral Hydrogen Water Inhibits Cancer Cell Growth and Tumor Invasion

Another paper² reports a cell culture study of the effects of hydrogen water in the culture medium on cancer cells. Researchers observed that the colony numbers of human tongue squamous cell carcinoma-derived cell line HSC-4 (RCB1902) was decreased to 72% as compared to controls (no hydrogen in the water). The colony formation of normal human tongue epithelial-like cells was unaffected by the hydrogen water. The researchers also investigated the effects of hydrogen water on tumor invasion through the reconstituted basement membrane Matrigel in human fibrosarcoma HT-1080 cells and found “[t]he number of invasive cells was markedly lowered by incubation for 1-3 h with cell culture media containing NHE [neutral pH hydrogen water] compared with Milli-Q [purified] water.”

These are interesting results, but, as the authors note, “although NHE water is expected to become a useful tool for clinical application to anticancer therapy, further in vivo studies are necessary for clinical applications.” We agree. If an individual wanted to try hydrogen therapy in the treatment of cancer, we wouldn’t see any reason not to do so, preferably with the supervision of their physician. However, it probably would NOT be a good idea to use hydrogen at the same time as radiation therapy or free radical-dependent chemotherapy is being administered as it would very likely reduce the effectiveness of the radiation treatment or chemo in killing cancer cells.

Hydrogen Protects Mice From Cognitive Impairments and Reduced Neurogenesis Resulting from Restraint Stress

If you have felt at times like a mouse thrown into a tank of water and having to swim frantically to find a hidden platform to find some temporary safety, then you probably have an idea of what mice subject to standard stress tests feel like. (We’re just guessing, as we have never interviewed a stressed mouse; scientists judge the emotional state of animals by observing their behavior. It will probably not be long, though, before MRI scans are used while animals are experiencing emotional states, making it possible to virtually “read their minds” to see how they are feeling. In pet animals that have brains organized similarly to humans, such as dogs and cats or even rodents, areas of the brain activated during emotional states may be much like that of humans feeling similar emotions. To some extent, we really could “interview” a mouse.)

A paper³ reporting on the effects of hydrogen water (or a placebo) on mice subject to three standard stress tests finds significant protection in the mice drinking hydrogen water from the negative effects (cognitive impairments such as memory deficits, oxidative stress, and decreased proliferation of progenitor cells in neurogenesis) as compared to the placebo controls (stressed but getting degassed water).

The subject mice had to deal with the stresses of physical restraint (being placed in a 3x3x7.5 cm. stainless-steel cage for ten hours a day for 6 days each week for 8 weeks), passive avoidance learning (whether they remembered that when they entered a dark compartment (mice naturally prefer to be in the dark) of a light-dark apparatus they received a shock, object recognition task (one of the original objects in the cage was replaced by a novel object; each mouse was evaluated for how much time or how many sniffs it devoted to a new object as compared to the original one it replaced), and spatial learning (the dreaded Morris water maze where the mouse landed in a tank of water and had to swim to find a hidden platform to stay above water). The additional details of the stress tasks are reported in the paper.

Water, either with or without hydrogen, was available ad lib throughout the periods of stress.

The physical restraint test enhanced oxidative stress in the brain, as assessed by estimating the levels of 4-hydroxy-2-nonenal (HNE), an end product of lipid peroxidation, and malondialdehyde (MDA), a lipid peroxidation breakdown product. However, the hydrogen water treatment significantly decreased the levels of these markers.

In the object recognition test, hydrogen water treatment (as compared to degassed water) prevented the decline or restored function in recognition and memory. The authors note, however, that the hydrogen water did not improve the cognitive ability when there was no stress.

After a 4-week restraint stress, the animals took longer to find a hidden platform in the Morris water maze, but “continuous consumption of hydrogen water shortened the time required for mice to reach the platform compared with stressed controls [that did not receive hydrogen in their water].”³

Most interesting, to us, was the beneficial effects of hydrogen water they reported for the proliferation of progenitor cells (part of the neurogenesis process). As shown in Fig. 4 in the paper,³ the animals receiving hydrogen water had significantly increased numbers of proliferating progenitor cells from the hippocampus, as determined by counting cells that were labeled with either BrdU or Ki-67 as markers of proliferation.

References

1. Shimouchi et al. Breath hydrogen produced by ingestion of commercial hydrogen water and milk. Biomark Insights 4:27-32 (2009).
2. Saitoh et al. Neutral pH hydrogen-enriched electrolyzed water achieves tumor-preferential clonal growth inhibition over normal cells and tumor invasion inhibition concurrently with intracellular oxidant repression. Oncol Res 17:247-55 (2008).
3. Nagata et al. Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice. Neuropsychopharmacology 34:501-8 (2009).

Special Feature —The Story of Hydrogen

On the First Day, God Created Hydrogen

The first element to come out of the Big Bang, emerging within a short time out of the very hot and dense plasma, was hydrogen followed very shortly thereafter by helium (by hydrogen atoms colliding and fusing into helium) and lithium. Although the earliest events are surrounded by speculation, the current model is that “[a]pproximately 10-37 seconds into the expansion, a phase transition caused a cosmic inflation, during which the Universe grew exponentially.”¹ “A few minutes into the expansion, when the temperature was about a billion (one thousand million; 109; SI prefix giga-) kelvin and the density was about that of air, neutrons combined with protons to form the Universe’s deuterium and helium nuclei in a process called Big Bang nucleosynthesis. Most protons remained uncombined as hydrogen nuclei.”¹ “After about 379,000 years the electrons and nuclei combined into atoms (mostly hydrogen); hence, the radiation decoupled from matter and continued through space largely unimpeded. This relic radiation is known as the cosmic microwave background radiation.”¹ [references provided in the text have been deleted here]

A very long period of time passed …

The First Living Organism Arrives

According to a proposed hypothesis,² eukaryotic cells* have developed through the symbiotic association of a hydrogen-dependent archaebacterium (the host) with a eubacterium (the symbiont) that was able to respire oxygen but generated molecular hydrogen as a waste product.

 

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*Eukaryote, a cell containing a membrane-bound nucleus with chromosomes of DNA, RNA, and proteins; also containing mitochondria, and in photosynthetic species, plastids are found. The superkingdom Eukaryotae includes Protoctista, Fungi, Plantae, and Animalia. (from Stedman’s Medical Dictionary, 25th edition).

 

That hypothetical picture of the first living cells on the primitive Earth looks a lot like what is going on right now in your lower digestive tract, as the microbiota residing there include symbiotic relationships between certain bacteria that ferment indigestible (to us) carbohydrates, producing hydrogen and some other bacteria that consume hydrogen, using it as an energy source and producing methane.^2b-2c The rest of the hydrogen, and there can be quite a bit of it, circulates throughout your tissues, eventually being excreted mostly by exhalation through the lungs but also some via the flatus. (Flatus, n. —from the latin, “a blowing.”)

The authors of the hypothesis paper² ask whether associations between methanogens and hydrogen-producing organisms are observable today. They answer: “Yes, abundantly so. Anaerobic syntrophy between methanogens and hydrogen-producing organisms has been known for many years and has been studied in some detail. It is observed in marine sediments, deep in the Earth’s crust, and fascinating examples are known in which endosymbiotic methanogens cling not to free-living eubacteria, but hydrogenosomes themselves in the cytosol of amitochondriate protists.” [paper citations were deleted here] Interestingly, the researchers did not mention the association between methanogens and hydrogen-producing bacteria in the human colon. Perhaps they were not aware of it. Their hypothesis paper was published in 1998 and, although the production of hydrogen in the lower digestive tract had been known for quite some time prior to that,³ there was still little awareness of the potential health effects of endogenous hydrogen production.

They concluded their paper optimistically “Hydrogen is the key. It is the bond that forges eukaryotes out of prokaryotes.”² This might be a good time for these scientists to return to their hypothesis, looking at the colon as a site where these possibly VERY ancient interactions between the hydrogen-generating and the hydrogen-using bacteria are currently taking place practically under our noses and where they can be easily observed and experimentally manipulated. Gene microarrays could be used to investigate evolutionary pathways that have led to this symbiosis.

The Discovery of the Hydrogenosomes

The first paper on the discovery of the organelles in eukaryote cells that manufactured hydrogen was published in 1973.⁴ The discovery of hydrogenosomes was beautifully described in a 2007 book which we recently bought: William F. Martin and Miklos Muller, Editors, Origin of Mitochondria and Hydrogenosomes (Springer, 2007) “Work from many laboratories has contributed towards formulating the current hypothesis that hydrogenosomes and mitosomes, their even more reduced cousins, share common ancestry with mitochondria … Hydrogenosomes, mitosomes, and mitochondria are evolutionary homologues in the sense meant by Charles Darwin. Their shared similarities, for example their common mechanisms of protein import and their double membrane, can be explained by common ancestry, and their differences by descent with modification under contrasting lifestyles. The hypothesis that mitochondria, mitosomes and hydrogenosomes are homologous predicts that, as the organelles are studied more deeply, additional shared features will be revealed.”(quoted from the Foreword to the book)

Perhaps nobody would much care about the origin of hydrogenosomes (other than those with very high levels of curiosity) except that now that there are clearly organisms dwelling within our lower digestive tracts that make hydrogen and, hence, have hydrogenosomes, the matter of hydrogenosomes has become a matter of understanding a functional part of ourselves.

The first chapter of the book, The Road to Hydrogenosomes was written by Miklos Muller, a scientist who co-discovered hydrogenosomes. He describes the offer made to him (“the opportunity of my life”) in 1964 by Christian de Duve, who received the Nobel Prize in 1974 for the discovery of lysosomes and peroxisomes, to join his lab at the Rockefeller Institute to study these organelles. As a result of these studies and those he did elsewhere, Muller became interested in the distribution of peroxisomes, “looking for new organisms to explore. Little did I suspect that this quest would lead to a ‘novel’ organelle, the hydrogenosome.” Dr. Muller turned to the study of the cattle pathogen Tritrichomonas foetus because this organism respired by a nonmitochondrial process. Eventually, he and his colleague Lindmark published a paper⁴ in The Journal of Biological Chemistry in 1973 in which they reported that “[t]hese findings underscore the unique nature of the microbody-like particles of T. foetus. In contrast to mitochondria or peroxisomes, in which electron transfer is directed toward molecular oxygen, they utilize protons as terminal electron acceptors and thus produce molecular hydrogen. We propose the term ‘hydrogenosome’ to designate this new biochemically defined subcellular entity.” Your bowels are full of tiny single celled creatures containing these hydrogenosomes! Dr. Muller notes that the book of which his chapter is a part well presents the work that led to “a consistent picture of the until recently unsuspected diversity of mitochondria and firmly placed the trichomonad hydrogenosomes in the big family of organelles derived from the ancestral ‘protomitochondrion.’” He closes with a note of good humor, probably reflecting on a long period of disbelief by other scientists: “Finally they can be seriously considered even in polite company.”

Yes, indeed, unless you fart!

References

1. “Big Bang,” Wikipedia (http://en.wikipedia.org/wiki/Big_Bang) 
2. Martin & Muller. The hydrogen hypothesis for the first eukaryote. Nature 392:37-41 (1998).
2b,2c. Behall et al. Breath hydrogen and methane expiration in men and women after oat extract consumption,” J Nutr 128:79-84 (1998); Marthinsen and Fleming. Excretion of breath and flatus gases by humans consuming high-fiber diets. J Nutr 112:1133-43 (1982). 
3. Strocchi and Levitt. Maintaining intestinal H2 balance: credit the colonic bacteria. Gastroenterology 102(4):1424-6 (1992). 
4. Lindmark and Muller. Hydrogenosome, a cytoplasmic organelle of the anaerobic flagellate, Tritrichomonas foetus, and its role in pyruvate metabolism. J Biol Chem248:7724-8 (1973).

 

Remarkable New Finding on Weight Gain and WHEN You Eat:

Eating As Much As They Wanted But Only During the Active Part of the Day Protected Mice Against Obesity, High Insulin Levels, Fatty Liver, and Inflammation

A test of how body weight is regulated by the daily rhythms of internal clocks has been reported in a new study.¹ Mice that were allowed to eat all that they wanted of a high fat diet but only during the normally active (dark) part of the day (FT—time restricted feeding mice on a high fat diet) were protected against excess weight gain despite eating the same amount of a high fat diet (HFD) as the mice (FA) fed the same diet but that could eat anytime (day or night) and became obese. These results, which are likely to be similar in people, suggest that you might be able to eat all you want and not get fat if you do not eat after dark when circadian rhythms alter how you metabolize food.

The researchers first fed the animals a high fat diet and found that not only did they develop obesity, diabetes, and metabolic syndrome (dysfunctions associated with diabetes, such as insulin resistance), but they exhibited dampened feeding and circadian rhythms.¹ The next part of the studies involved feeding the animals the high fat diet but either restricted to the dark period of the day or not restricted. “The time-restricted high-fat-fed mice showed significantly increased thermogenesis and improved rhythms in nutrient utilization, leading to reduced adiposity and liver steatosis [fatty liver], normal glucose tolerance, reduced serum cholesterol, increased bile acid production, and improved motor function.”

Mice were also fed normal chow under either ad lib (eat any time) or time-restricted access to food during their natural nocturnal feeding time to establish the differences between eating at particular times. The mice fed normal chow ad lib showed a nocturnal increase in RER (respiratory exchange ratio) and food intake reflecting feeding followed by carbohydrate utilization, while RER and food intake declined during the day consistent with lipid oxidation during fasting.¹ The mice fed a HFD ad lib had dampened diurnal rhythms in food intake and RER. On the other hand, the animals fed either normal chow or a HFD on a time-restricted (eating at night only) regimen had improved RER diurnal rhythms compared to their ad lib counterparts, with higher RER during feeding and reduced RER during fasting, indicative of increased glycolysis (use of glucose for deriving energy from oxidative metabolism) and fat oxidation (deriving energy from fat metabolism), respectively.¹ Most amazingly, the HFD fed animals ate about the same amount of food, whether eating ad lib or only during the night, yet the animals eating only at night did not become obese while the ad lib mice did.

The researchers investigated the biochemical changes that were taking place in the mice during the eating during the night only as compared to the eating at any time. Eating a HFD ad lib normally perturbs the function of nutrient sensors and regulators, such as CREB, mTOR, and AMPK, resulting in an increase in tissue growth and metabolic dysfunctions associated with energy overload, such as insulin resistance, fat stored in inappropriate areas such as in muscle, etc. The nutrient sensors are supposed to be regulated by circadian rhythms entrained in part by normal exposure to food which, in wild mice, would be taking place at night and with a much lower fat content than a HFD experimental mouse food.

In the study,¹ for example, the diurnal rhythm of food intake (normal chow) induced CREB phosphorylation (activation) during daytime fasting and increased pS6 (m-TOR stimulated during nighttime feeding). Importantly, “in FA [high fat diet ad lib fed] mice, the perturbed circadian feeding pattern blunted pCREB [phosphorylated CREB] and pS6 oscillations and led to constitutively elevated pCREB and reduced pS6 levels.”

In contrast, “in the FT [high fat diet eaten only at night] mice, the tRF imposed a diurnal rhythm in food intake, thereby restoring the daytime peak in pCREB and nightime peak in pS6.”

On page 850 of the paper¹ is a startling photo of a representative FA (high fat diet ad libfed) mouse alongside a representative FT (high fat diet fed but only at night) mouse showing how fat the FA mouse looks compared to the normal looking FT mouse. “These coordinated changes in gene expression and metabolites show that the tRF [time restricted feeding] regimen temporally reprograms glucose metabolism away from gluconeogenesis [glucose synthesis by the liver] toward glycolysis, reduced glutathione, and anabolic pathways. Accordingly, FT mice did not display the hallmarks associated with glucose intolerance found in diet-induced obesity, instead showing glucose tolerance and insulin levels comparable to the control NA [normal chow ad lib fed] mice. The overall improvement in metabolic state also paralleled improved motor coordination in the mice under tRF paradigms.”¹

“Most of the extra body weight in the FA [high fat diet ad lib] mice was due to increased adiposity. FA mice showed 70% more fat deposits than those in the FT [high fat diet time restricted] mice … hyperleptinemia associated with diet-induced obesity in FA mice was absent in FT mice.”¹

These results are interestingly correlated with the results we reported in an earlier newsletter of another study² in which restricting food consumption to the active phase (dark) of the day prevented weight gain in mice, but that even low levels of light would disrupt the circadian timing of food intake, causing the mice exposed to dim light to eat more during the day, gain weight, and develop glucose intolerance. In that study, mice exposed to dim light ate 55.5% of their food during the light phase, as compared to 36.5% by mice in the standard light/dark cycle.

In an earlier study,³ scientists found that “an enzyme that responds to nutrient availability—AMPK (adenosine monophosphate-activated protein kinase)—directly phosphorylates the core clock protein cryptochrome 1 (CRY1), thereby marking it for degradation.” Thus, the interaction between the systems regulating circadian rhythms and feeding cycles is well established.

We have both changed our eating habits to eat most of our food during the day. The experimental results in mice are compelling, not only for the improvement in weight but for reduced oxidative stress and inflammation and even improved motor coordination—it is very likely to work similarly in people (except that in people, eating should take place mostly during the day rather than at night) and it is certainly a great deal easier (though not entirely without the need for some willpower) than a low calorie diet.

References

1. Hatori et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet,” Cell Metabolism 15:848-60 (2012).
2. Fonken et al. Light at night increases body mass by shifting the time of food intake. Proc Nat Acad Sci USA 107(43):18664-9 (2010).
3. Suter and Schibler. Feeding the clock,” Science 326:378-9 (2009).

Natural Products to Clear Amyloid Beta From the Brain

Vitamin D3 Promotes the Recovery of Abeta Phagocytosis in Defective AD Macrophages

A very recent paper¹ reports that 1alpha,25(OH)2-vitamin D3 (1,25D3) activation of the Vitamin D receptor (VDR), via genomic (gene expression) and nongenomic signaling, promotes the recovery of amyloid-beta phagocytosis by faulty Alzheimer’s disease macrophages. The authors note that, “[i]n support of this hypothesis, nutritional supplementation with vitamin D3 has been shown to protect against cognitive decline in elderly subjects.”^1b

Vitamin D3 has also been reported to have other neuro­protective effects. For example, one paper^1c found that vitamin D3 attenuated damage induced by the powerful neurotoxin 6-hydroxydopamine in rats.

A Curcuminoid Found in Turmeric Increased Vitamin D3 Enhanced Amyloid Beta Clearance

Alzheimer’s disease (AD) patients have defective clearance of amyloid beta by phagocytosis normally performed by peripheral blood mononuclear cells (PBMCs), as well as defective clearance via the autophagic-lysosomal pathways in AD fibroblasts and neurons. The finding by the authors of paper #1 that vitamin D3 stimulates the recovery of phagocytosis by AD macrophages of amyloid beta-42 was reported by them in an earlier paper.² In that earlier paper, the researchers also reported that bisdemethoxycurcumin, a form of curcumin found naturally in turmeric root, additively stimulated (with 1,25 D3) phagocytosis of amyloid beta-42 by type I AD macrophages. (AD macrophages have been reported by these authors to be subdivided into three types—type I, type II, and type 0—depending upon their expression of MGAT3, a gene which the authors say plays a “critical” role in phagocytosis.) They didn’t offer a hypothesis on why the curcuminoid was able to promote phagocytosis in only type I of the AD macrophages, while 1,25 D3 did so in both type I and type II AD macrophages. However, the type I macrophages are said to be the type found in the majority of AD patients.³ By using a specific inhibitor of the 1,25 D3-vitamin D receptor, the researchers² were able to show that phagocytosis of amyloid beta in patients with type I and type II macrophages was dependent on 1,25 D3.

Curcuminoids Have Neuroprotective Effects

Curcuminoids have been reported to have neuroprotective effects in other papers. See, for example, paper #4 in the references below. In that recent paper, curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) promoted neurite outgrowth from PC12 cells (a rat pheochromocytoma cell line) via complex signaling involving MAPK/ERKand PKC-dependent pathways. As noted in this paper, “neurotrophic factors are attractive candidates for therapeutic agents in chronic neurodegenerative diseases and acute injuries including trauma and stroke.”⁴

Curcumin was also reported to inhibit formation of amyloid beta fibrils^4a and to reduce indices of oxidative stress and inflammation that are associated with AD in the brains of APPs mice (mice genetically engineered to produce high levels of soluble amyloid precursor protein).^4b

… And Also Enhance Phagocytosis of Amyloid Beta by Macrophages from AD Patients

An earlier paper⁵ by the same group that published the work on vitamin D3 and curcuminoids described above reported on the treatment of peripheral blood monunuclear cells (PBMC) from six AD patients with curcuminoids (a proprietary curcumin complex) and compared the cells’ phagocytosis of amyloid beta with PBMCs from three normal controls. Phagocytosis was significantly increased in three of the six AD patients by curcuminoids, with the optimal concentration enhancing phagocytosis being 0.1 μM curcuminoids. The increase in amyloid beta uptake was through induction of intracellular phagocytosis by curcuminoids as revealed by confocal microscopy (as opposed to surface binding in untreated macrophages). The macrophages of control patients were also treated with curcuminoids but they already had a high amyloid beta uptake at baseline and their uptake was not further enhanced by curcuminoid treatment.

Critical Importance of Clearing Amyloid Beta From the Brain

“The most common form of Alzheimer’s disease [AD] occurs sporadically late in life and is typified by deposition of amyloid beta (Abeta) within the brain. Individuals with late-onset AD produce Abeta peptides at normal levels but have an impaired ability to clear them from the br ain.”^a In fact, late-onset AD patients were observed in one study^a2 to have a 30% decrease in amyloid beta clearance as compared to controls. The authors^a2calculated that this diminishment of amyloid beta metabolism is consistent with an ~10 year timeframe for the buildup of the amyloid beta in the disease. (The clearance rates were determined by collecting cerebral spinal fluid from individuals infused with 13C6-leucine to label newly synthesized proteins.)

One of the toxic effects that result from the accumulation of Abeta peptide oligomers, for example, is the reported inhibition by about 50% of choline acetyltransferase, the enzyme responsible for chemically converting choline to acetylcholine, in cultured cholinergic neurons exposed to low nanomolar concentrations of Abeta peptide oligomers.^b Acetylcholine is a neurotransmitter critically important in learning and memory, muscular contraction, as a signaling molecule for release of nitric oxide in endothelial vasodilation, as well as in many other functions.

Recent studies have focused on the importance of clearing amyloid beta from the brain. For example, a recent paper^a reported on an FDA approved drug (Bexarotene^†) that was able to reduce Abeta plaque area in a mouse model of AD by more than 50% within just 72 hours. In fact, the drug was reported to cause a rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function in the AD mice. The drug is an agonist of (activates) the retinoid X receptor (RXR) that facilitated the clearance of Abeta by enhancing the activation of ApoE (important in the clearance of Abeta) and promoting microglial phagocytosis via the activation of a complex interaction between PPARgamma:RXR and LXR(liver X receptor):RXR. Two of the authors of the paper on Bexarotene^a hold U.S. Provisional Patent Application No. 61/224,709 regarding use of the drug as a potential therapeutic for AD and are founding scientists of ReXceptor, Inc., which has licensing options from Case Western Reserve University on the use of Bexarotene in the treatment of AD. The drug as used for its current FDA approved indication is said to display a favorable side effect profile.^‡

† Bexarotene is approved for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy. (Physicians’ Desk Reference, --2011) 

‡ Mandrekar-Colucci & Landreth. Nuclear receptors as therapeutic targets for Alzheimer’s disease,” Expert Opin Ther. Targets15(9):1085-97 (2011).

If You’ve Read This Far, You’ve Passed the Test!

Well, OK, there really wasn’t any test, but we figure that if you have read to this point, your cognitive abilities are likely to be in good condition, but it is always prudent to take no chances on them staying that way. The two of us take daily supplements of vitamin D3 and turmeric root powder (which contains a variety of curcuminoids), among other supplements, as a sensible precaution^6-10 against age-associated cognitive decline.

References

2. Cramer et al, “ApoE-directed therapeutics rapidly clear beta amyloid and reverse deficits in AD mouse models,”Science335:1503-1506 (2012).
   a2. Mawuenyaga et al, Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330:1774 (2010).
   b. Nunes-Tavares et al. Inhibition of choline acetyltransferase as a mechanism for cholinergic dysfunction induced by amyloidbeta peptide oligomers. J Biol Chem287(23):19377-85 (2012). 
   1. Mizwicki et al. Genomic and nongenomic signaling induced by 1alpha,25(OH)2-vitamin D3 promotes the recovery of amyloid-beta phagocytosis by Alzheimer’s disease macrophages. J Alzheimers Dis 29:51-62 (2012).
   1b. Llewellyn et al. Vitamin D and risk of cognitive decline in elderly persons,” Arch Intern Med 170:1135-41 (2010). 
   1c. Wang et al. Vitamin D3 attenuates 6-hydroxydopamine-induced neurotoxicity in rats,” Brain Res 904(1):67-75 (2001). 
   2. Fiala et al. MGAT3 mRNA: a biomarker for prognosis and therapy of Alzheimer’s disease by vitamin D and curcuminoids. J Alzheimers Dis 25:135-44 (2011) 
   3. Avagyan et al. Immune blood markers of Alzheimer disease patients. J Neuroimmunol 210:67-72 (2009). 
   4. Liao et al. Curcuminoids promote neurite outgrowth in PC12 cells through MAPK/ERKand PKC-dependent pathways. J Agric Food Chem 60:433-43 (2012).
   4a. Ono et al. Curcumin has potent anti-amyloidogenic effects for Alzheimer’s beta-amyloid fibrils in vitro. J Neurosci Res 75:742-50 (2004). 
   4b. Lim et al. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 21:8370-7 (2001).
   5. Zhang et al. Curcuminoids enhance amyloid-beta uptake by macrophages of Alzheimer’s disease patients. J Alzheimers Dis 10:1-7 (2006).
   6. Hathcock et al. Risk assessment for vitamin D. Am J Clin Nutr 85:6-18 (2007). “Collectively, the absence of toxicity in trials conducted in healthy adults that used vitamin D dose ≥250 ug/d (10,000 iu vitamin D3) supports the confident selection of this value as the UL [upper limit].” 
   7. Murff. Review: Cholecalciferol (vitamin D3) reduces mortality in adults; other forms of vitamin D do not. Ann Intern Med 155(5):JC5-4 (15 Nov. 2011). 
   8. Lee et al. Vitamin D rejuvenates aging eyes by reducing inflammation, clearing amyloid beta and improving visual function. Neurobiol Aging doi:10.1016/j.neurobiolaging.2011.12.002. 
   9. Moore et al. Evidence that vitamin D3 reverses age-related inflammatory changes in the rat hippocampus,” Biochem Soc Transactions 33 part 4:573-7 (2005).
   10. Zhang et al. Curcumin decreases amyloid-beta peptide levels by attenuating the maturation of amyloid-beta precursor protein. J Biol Chem 285(37):28472-80 (2010).

 

Measuring Adiposity: Body Mass Index, Percent Body Fat, and Leptin

A new paper¹ provides very useful information on the best lab test for adiposity (fatness). The researchers explain that BMI (body mass index = weight in pounds/(height in inches)² x 703), the most commonly used measure for fatness, underestimates body fat, especially in women with high levels of the hormone leptin (>30 ng/ml). However, BMI is popular because of its convenience, safety, and minimal cost, and thus is widely used, despite not being able to distinguish lean body mass from fat mass.¹ The BMI, developed nearly 200 years ago, is not actually a measure of adiposity, but an imprecise mathematical estimate.¹

The authors explain: “BMI ignores several important factors affecting adiposity. Greater loss of muscle mass leading to sarcopenic obesity in women occurs increasingly with age. BMI does not acknowledge this factor, exacerbating misclassifications. Furthermore, men’s BMI also does not consider the inverse relationship between muscular strength and mortality. It fails to take into account that men lose less muscle with age than women.”¹

The researchers explain further that DXA (duel-energy x-ray absorptiometry) is a direct measure of body fat, but is not a disease correlate. Thus, scientists have investigated various factors that might explain disparities between BMI and direct fat measurements, factors that include leptin, insulin, ghrelin, and adiponectin.¹ “Leptin, a 16kDa peptide secreted primarily by adipocytes [fat cells], regulates the body’s energy balance by acting as a negative feedback adiposity signal, decreasing food intake and increasing energy expenditure.”¹ Unfortunately, obese individuals have high leptin levels but are leptin insensitive with the result that the normal leptin signaling is blunted. Leptin insensitivity is associated with a state of “obesity with normal weight” (people with normal weight but with metabolic defects usually associated with obesity that includes chronic inflammation, type II diabetes, hypertension, and myocardial injury).¹

A Strong Relationship Between Increased Leptin and Increased Body Fat

The bottom line is that a better measure of body fatness (adiposity) is needed to predict the risk of obesity-associated medical conditions and to help guide the result of therapies used to reduce obesity-associated disease risks.

“Since a recent study showed that the significant lowering of leptin impacts long term weight control, the idea of utilizing leptin as a component in the national* attack on obesity might be considered.” “… lowering elevated leptin has been associated with improved obesity and clinical outcomes.”¹

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* We are not fans of a “national” attack on obesity (if that means government programs) but are interested here in the use of leptin measurements as part of a physician/patient attack on obesity. Indeed, there is NO power authorized in the Constitution for a “national” attack on obesity (take a look at your copy) so that any attempt to carry out programs in pursuit of this goal would be unconstitutional.

The authors studied the relationship between BMI, percent body fat (as measured by DXA), and leptin in a population of 1,393 adult patients (63% of which were women, 37% were men). They found that “while there was agreement [between obesity based on BMI versus percent body fat] for 60% of the sample, 39% were misclassified as non-obese based on BMI, while meeting obesity criteria based on percent body fat … A total of 48% of women were misclassified as non-obese by BMI, but were found to be obese by percent body fat. In sharp contrast, 25% of men were misclassified as obese by BMI, but were in fact non-obese by percent body fat (i.e. the muscular body morphology).”¹They also found that 91% of their patients with high leptin levels were women.

Where You Can Get Your Leptin Level Measured

Before we wrote this article, we investigated where it would be possible to get commercial lab tests for leptin, as it would clearly be helpful in evaluating one’s adiposity. Here’s what we found out. Leptin tests:

• http://www.econolabs.com/product_p/lc-146712.htm

• http://www.labsmd.com/view_all_blood_tests.php

• http://www.walkinlab.com/leptin_serum_test.html?category_id=1&search_string=leptin&search_category_id=1

Note: These tests require a venous blood sample.

Reference

1. Shah and Braverman. Measuring adiposity in patients: the utility of body mass index (BMI), percent body fat, and leptin,” PLoS ONE 7(4):e33308 (Apr. 2012); www.plosone.org

 

The Beat Goes On: The Microbiota Influence Beyond the Gut

… the human gut microbiome contributes 36% of the small molecules that are found in human blood, and it also plays a major role in creating susceptibility to certain human diseases.

— Leroy Hood, cofounder and President
The Institute for Systems Biology, Seattle, WA 
(email: lhood@systemsbiology.org) 
As reported in the 8 June 2012 Science

 

Climategate 3 —How to Fool the Public Now Explained Openly in a Scientific Journal Rather Than Covertly in E-Mails

As if using emails to communicate ideas on how to manipulate public opinion on global warming were not enough, now we see scientists actually suggesting in a major scientific journal how to make their models look more convincing to the public by carefully and deliberately dodging the problem of uncertainties. See the article in the 14 June 2012 Nature.¹

The “problem,” as explained in the article is that “[t]he climate models they [the IPCC] are now working with, which make use of significant improvements in our understanding of complex climate processes, are likely to produce wider rather than smaller ranges of uncertainty in their predictions. To the public and to policymakers, this will look as though the scientific understanding of climate change is becoming less, rather than more, clear.” The authors go on to explain that models have a limited capability to predict the future because, first of all, “they [the models] are not reality.” (Wow! Who would have thought.) “By their very nature, models cannot capture all the factors involved in a natural system, and those that they do capture are often incompletely understood.” Indeed, the authors mention that “science historian Naomi Oreskes of the University of California at San Diego and her colleagues have argued convincingly that that makes climate models impossible to truly verify or validate.” If that is so, then the models cannot be truly falsified either, which takes them out of the realm of science altogether. Remarkable that the article’s authors didn’t see that.

There follows a list of difficulties in making predictions using climate models that includes picturing economic conditions in 100 years. “The economic collapse of 2008 showed dramatically, and to our cost, how difficult it is to predict changes in the economy.” This means that to make projections of how economic conditions in 100 years will affect how fossil fuels are being used is much more difficult than these scientists believed. (Indeed—and they do not mention this—the innovations in energy use that will have developed by 100 years from now is inherently unpredictable and of considerable importance if one is to somehow plan now for how humans should be using energy in 100 years.)

We will not list all of the “problems” the modelers complain of having with their models that are full of uncertainties. However, the article does include this little gem: “… Paul Valdes of Bristol University, UK, argues that climate models are too stable, built to ‘not fail’ rather than to simulate abrupt climate change. When the current IPCC models were tested against four major past climate changes, he notes, two were unable to even get the basic climate before the shift correct and the other two had to be fed parameters up to ten times greater than would be realistic to produce the abrupt shift.” Later in the article, the authors note that “[a]lthough their [one new model used by Dan Rowlands and his colleagues at Oxford, UK] average results matched well with IPCC projections, more extreme results, including warming of up to 4 degrees C by 2050, seemed just as likely. As computing power becomes more accessible, that ‘hidden’ uncertainty will become even more obvious.”

The authors hasten to add that “[n]one of this means that climate models are useless.” They claim that present models are “clearly able to reproduce natural climate variability over the past 150 years, and have provided an essential test of the theoretical link between CO2 and global temperatures.” (This supposes, for example, the very unlikely proposition that all of what causes natural climate variability is currently known and integrated into climate models.) On the basis of these models, then, these authors seriously propose to coercively regulate billions of human lives by, for example, investing a “huge” increase in spending (of other people’s money) on renewable energy sources to reduce reliance on oil, coal, and gas and instituting measures to lessen car use so as to increase walking and cycling (which would, they add, reduce the risk of obesity and heart attacks so all this coercion must be OK. Hey, what about requiring that people eat broccoli? A large body of data indicates that that would reduce the incidence of a number of types of cancer.).

But now look at the article’s suggestion of how to make these climate models look a whole lot more credible to the public: “One approach to tackling the public-perception problem is to subtly rephrase the conclusions, placing the uncertainty on the date by which things will happen, rather than onto whether they will happen at all.” That sounds good; just avoid the entire matter of uncertainties by simply asserting that the outcome itself is a certainty but the models just cannot tell you with any precision when they will take place. “A recent study, for example, showed that the politically expedient 2 degrees C limit will be reached between 2040 and 2100, depending on our emission pathway and the model used. This ‘when’ not ‘if’ approach is powerful.”

But the issue of WHEN things will take place, even if one assumes that sometime in the future a certain event will occur (such as an increase in average Earth temperature by 2 degrees C) is of critical importance when you are making an investment. How can you determine how much you should spend NOW to affect a certain future occurrence if you cannot know when that future occurrence will happen? It would be like investing a “huge” amount of money in a future delivery of Coca-Cola^® without knowing when the Coca-Cola will be delivered.

The Global Warming Bubble

The global warming phenomenon is a classic example of an economic bubble; it has only been able to take place because of huge amounts of public money used to pump up the supplies of global warming scientists, “renewable” energy (unable to survive in a market where people pay only for what they want at prices they are willing to pay), and myriad very costly rules and regulations that have been passed in pursuit of the impossible goal of keeping climate from changing. To add to the unreality, interest rates on borrowing money are now being set artificially low in the U.S. by the Federal Reserve, thereby destroying the signal interest rates determined by markets are supposed to provide on the preference people have for using money now as compared to saving it (or investing it) for the future, a reflection of the perception of future risk in recovering the value of money. Thus, higher interest rates come from a perception of increased risk of future losses. The Fed’s low interest rate is a fraud on the public that makes it appear that there is little economic risk in the future, thus creating another bubble, causing people who invest to underestimate the cost of recovering the value of their money in the future.

We may have (luckily) gotten past the time when public confusion about global warming might allow for global political bodies to institute the totalitarian world of Centrally Planned Climate. The current “consensus” on climate is that it will change, but there is little agreement on much else. It is even possible for there to be considerable periods of climate cooling during a period of supposed general climate warming if you hypothesize various types of climate feedback, as has been discussed in some scientific journal articles.

The authors conclude with a plea to forget about uncertainties in the models, that “we” know enough already to take immediate action by spending hundreds of billions or even trillions to reduce carbon emissions so that in 100 years … we will have different disasters to deal with but won’t have the hundreds of billions we need to fix ’em.

What a pile of BS!! This brave new world would only be better for those making the rules and regulations and controlling the huge amounts of other people’s money that would become available for those in power to distribute to themselves and the people they favor.

Reference

1. Maslin and Austin. Climate models at their limit? Nature 486:183-4 (2012).