November 2008 Blog with Durk and Sandy

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

Not only was the United States the last major country to abolish slavery, but we were the only country to do so violently. 
— Thomas H. Naylor, Secession, 2008

I try to save my money. Who knows, maybe one day it’ll become valuable again.
— Milton Berle

WISDOM FROM THE MYTH OF THE RATIONAL VOTER BY BRYAN CAPLAN

The belief that you can outrun a cheetah would prove fatal at the wrong place and the wrong time. But given the chance of cheetah encounters, it is usually a safe mistake.

False beliefs range in material cost from free to enormous.

Assuming that all people are fully rational all the time is bad economics. It makes more sense to assume that people tailor their degree of rationality to the costs of error.

When voters talk about solving social problems, their primary aim is to boost their self-worth by casting off the work-a-day shackles of objectivity.

“We encounter the price-sensitivity of irrationality whenever someone unexpectedly offers us a bet based on our professed beliefs.” Suppose you insist that imposing increased costs on the production of coal and gas—such as a carbon tax—will not have a negative impact on economic activity and your standard of living. Then someone challenges you, saying, “If you’re really ‘sure,’ you won’t mind giving me ten-to-one odds.” Why are you unlikely to accept this offer? Perhaps you never believed your own words; your statements were poetry—or lies. But it is implausible to tar all reluctance to bet with insincerity. People often believe that their assertions are true until you make them “put up or shut up.” A bet moderates their views—that is, changes their minds—whether or not they retract their words . . . an offer to bet triggers standby rationality. Two facts then come into focus. First, being wrong endangers your net worth. Second, your belief received little scrutiny before it was adopted.

Intuitively, if one vote cannot change policy outcomes, the price of irrationality is zero.

. . . in elections with millions of voters, the probability that your erroneous policy beliefs cause unwanted policies is approximately zero.

D&S comment: Hence, you (as an individual) risk nothing in an election by voting for your favorite false beliefs.

 

THE LOGIC OF BUSINESS IN A HEAVILY REGULATED ECONOMY, THEN AND NOW

A better way of understanding the behavior of business in that era is to think of the consequences of the regime’s actions in destroying essential mechanisms of the market economy: prices (controlled by price restraints), interest rates or the price of money (which were capped), and dividends (which were limited). Profits in themselves made no sense, but capturing the political process that then increasingly shaped economic outcomes rather certainly did. Instead of competing in a market for market share, businesses competed for influence in a political market that functioned on its own terms and logic.

— Harold James, The Deutsche Bank and the
Nazi Economic War Against the Jews

Cambridge University Press, 2001, pp. 213-214

With the exception of the racially motivated attack on Jewish possessions, the fundamental principle of private ownership was left untouched. The laws defining what ownership involved, people’s “property rights,” however, were utterly transformed. Germany remained a private economy, but without the guidance of those signals usually associated with the operation of a market: freely determined (not administered) prices, interest rates, or exchange quotations. It was an economy without a market mechanism, which was supposed to behave as its new masters wished. Prices are essential to the market. Their suppression and distortion leads to a command economy.

— Harold James, op. cit., pp. 32-33

 

 

AGE INHIBITORS: POTENTIAL THERAPY FOR PREVENTION AND/OR TREATMENT OF DEMENTIA

It takes “forever” for the FDA to get around to approving new therapies for dementia, one reason being that only xenobiotic drugs have a chance to be approved for that purpose. Natural substances, no matter how potentially useful in protecting against brain aging and dementia, cannot be patented, and hence the approximately $1 billion in developmental costs needed to get FDA approval will never be invested by entities whose owners (shareholders) expect something back for their investments. So we have to wait while xenobiotics are developed, generally as modified versions of natural substances and with (usually) greater risks of toxicity compared to the starting natural substance.

While we are waiting for that, though, we should pay more attention to the potential value of natural products that are readily available now in the marketplace (although the FDA prohibits any claims of prevention or treatment of disease on their labels, unless they are FDA-approved as drugs). Inhibitors of AGEs, advanced glycation endproducts formed as a result of the chemical interaction in the body between amino acids and sugars, have now been reported in a growing scientific literature to be constituents of Alzheimer’s disease plaques and neurofibrillary tangles, to exert chronic oxidative stress on neurons, and to activate glial cells in the brain (that release inflammatory cytokines such as tumor necrosis factor-alpha and free radicals, such as superoxide and nitric oxide). Meanwhile, AGE-inhibiting substances, such as aminoguanidine, carnosine, and pyridoxamine, have been reported to attenuate the development of AGE-related diabetic complications.

Cellular inclusions in aged brain cells include Lewy bodies (as in Parkinson’s disease), lipofuscin (“age pigment”), and others. It has been reported that “Nuclear polymerization of Abeta [amyloid-beta, the substance that forms toxic aggregates in Alzheimer’s disease] is significantly accelerated by AGE-mediated cross-linking.”1 Abeta-AGE (AGE-modified Abeta) is a more potent activator of microglia than Abeta alone, at least in terms of inducing nitric oxide synthase and nitric oxide production, part of an inflammatory process.1 It has also been reported that the mitochondrial respiratory chain and the intracellular ATP content of cells are also reduced upon treatment with AGEs.1 “AGEs induce both proliferation of immune-competent cells and their activation, resulting in a chronic inflammatory response.”1

Carnosine has been shown to act as an antiglycating agent (inhibiting the formation of sugar-amino acid chemical interactions that, through further modifications, become irreversible AGEs) on peptides and proteins (such as alpha-crystallin, a protein in the lenses of eyes that becomes opaque through glycation with circulating sugars, such as ribose and fructose, as well as glucose).1

Carnosine as a Vasodilator

Interesting new effects are being reported for carnosine. For example, a fairly recent paper2 found that in preconstricted thoracic aorta rings from Sprague-Dawley rats, carnosine caused significant relaxation of the aorta independently of the endothelium. The fact that the relaxation did not require the presence of the endothelium means that the mechanism did not involve nitric oxide synthase activation; the authors found that the effect was at least in part due to production of cyclic GMP, as occurs when nitric oxide synthase is activated, but also by another pathway. The two constituent amino acids of carnosine, L-histidine and beta-alanine, did not reproduce this effect. L-Histidine had no effect, and beta-alanine actually caused a significant, dose-dependent increase in vascular smooth muscle tone (i.e., an increase in vascular constriction).

Carnosinase Found Almost Exclusively in Brain and Serum

Carnosinase, an enzyme that can break carnosine down into its constituent amino acids, histidine and beta-alanine, is produced mostly in the brain; hence, this regulation must be important to brain function. In fact, it has been reported that histidine levels in the frontal and temporal lobes of Alzheimer’s patients are decreased compared to normal brains,3 which could be due to carnosinase deficiency. There have been case studies of patients with carnosinase deficiency who have conditions such as progressive mental deficiency, spastic paraplegia, seizures, neurosensory hearing loss, retinitis pigmentosa, and others. Interestingly, carnosinase levels have been reported to decrease during cardiopulmonary bypass surgery. The authors speculate that this may be an adaptive mechanism, since carnosine protects against neurotoxicity in conditions of oxidative stress. The researchers3 report in this paper their study of carnosinase levels in 37 patients attending a geriatric outpatient clinic.

In this small sample of 37 patients, the scientists reported finding a significant difference between the carnosinase levels in MD (mixed dementia, with vascular lesions) and AD (Alzheimer’s disease), with levels of the enzyme lower in MD than in AD patients and with levels decreasing with the duration of disease. Interestingly, both the AD and MD patients taking antidementia medication (donepezil, galantamine,* memantine) had higher carnosinase activity compared to those not taking a dementia medication.3Moreover, carnosinase activity was higher in patients who exercised regularly as compared to those who didn’t.3

 


*You can get galantamine in a dietary supplement. We both take it to increase brain cholinergic activity for better focus and concentration.

 


 

Although the presence of carnosinase in the brain points to an important regulatory function, we would like to learn a great deal more about how the enzyme works in the brain and how control of carnosine levels and its amino acid constituents contribute to brain function. Possibly carnosinase contributes to the brain’s control of blood flow to various brain areas through the vasodilation of carnosine and the vasoconstriction of beta- alanine, though that is just a speculation on our part.

AGEless™, which contains carnosine and other potent natural antiglycation molecules, includes (in 2 capsules taken 4 times a day) 1336 mg of carnosine.

References

  1. Dukic-Stefanovic et al. AGES in brain ageing: AGE-inhibitors in neuroprotective and anti-dementia drugs? Biogerontology 2:19-34 (2001).
  2. Ririe et al. Vasodilatory actions of the dietary peptide carnosine. Nutrition 16:168-72 (2000).
  3. Balion et al. Brain type carnosinase in dementia: a pilot study. BMC Neurol5(7):38 (2007).

 

PROTECTION BY SPICES AGAINST CELL DAMAGE CAUSED BY PEROXYNITRITE

Peroxynitrite, a potent cytotoxic chemical, is formed naturally in the body by the interaction of nitric oxide and superoxide radicals. This ubiquitous toxin causes oxidative damage to proteins via attack on sulfhydryl groups and thioethers, as well as causing hydroxylation and nitrosation of aromatic amino acids comprising essential residues in proteins, leading to protein dysfunction.1 Lipids are susceptible to peroxynitrite-induced peroxidation. Peroxynitrite also causes DNA damage (including base modification and mutation, as well as DNA strand breakage).1 Peroxynitrite has been implicated in many diseases, especially those associated with inflammation, including (for example) spinal cord injury,2 apoptosis (programmed cell death) in motor neurons,3 arthritis,4 apoptosis of heart muscle cells,5 and respiratory diseases.6

Interestingly, many commonly used spices have potent protective properties against peroxynitrite. A recent paper reports on the protective effects of cardamom, cinnamon, cloves, cumin, nutmeg, paprika, rosemary, and turmeric.1 The authors of this paper note that people typically get a surprisingly large amount of spices in their diet, with the per capita consumption of spices in America growing from 2.6 g/person per day in 1980 to approximately 4 g/person per day in 2000.

The authors examined a number of measures of protective effects. In one test, they examined the listed spices for protection against peroxynitrite oxidation of fluorescein, finding that, at 100 µg/mL, turmeric inhibited 96.3% of the fluorescein oxidation, while cloves, nutmeg, cinnamon, and rosemary inhibited it by 74.5%, 71.0%, 63.5%, and 58.0%, respectively. The other spices at that concentration inhibited the fluorescein oxidation by less than 50%.

In another test, the researchers looked at the effects of spices on peroxynitrite-mediated lipid peroxidation (using the TBARS test). Here they found the proportional inhibition to be: cinnamon 63.9%; cloves 58.5%; rosemary 54.0%; turmeric 44.3%; and nutmeg 35.5%. The other spices inhibited the reaction by less than 10%.

In the test of the protective capacities of the spices against peroxynitrite-induced DNA strand breakage, the spices (at 100 µg/mL) decreased the DNA strand breakage by the following amounts: cinnamon 81%; nutmeg 80%; turmeric 49%; cloves 44%; rosemary 40%; cardamom 29%; paprika 26%; and cumin 22%.

The TEAC assay for antioxidant capacity ranked the spices (in decreasing order): cloves > rosemary, cinnamon, turmeric > nutmeg > cumin > paprika and cardamom. The DPPH test looked at the scavenging ability of spices as IC50, the concentration of spice extract needed to quench 50% of the DPPH radical. The most active was cloves, with an IC50 value of 62 µg/mL. The next most effective was rosemary, with an IC50value of 149 µg/mL.

We also found another paper showing that zingerone, a pungent pyrolytic product of ginger oleoresin found in ginger root, is a strong scavenger of peroxynitrite as well.6

References

  1. Ho et al. Protective capacities of certain spices against peroxynitrite-mediated biomolecular damage. Food Chem Toxicol 46:920-8 (2008).
  2. Genovese et al. Beneficial effects of FeTSPP, a peroxynitrite decomposition catalyst, in a mouse model of spinal cord injury. Free Rad Biol Med 43:763-80 (2007).
  3. Ye et al. Prevention of peroxynitrite-induced apoptosis of motor neurons and PC12 cells by tyrosine-containing peptides. J Biol Chem 282(9):6324-37 (2007).
  4. Bezerra et al. Reactive nitrogen species scavenging, rather than nitric oxide inhibition, protects from articular cartilage damage in rat zymosan-induced arthritis. Brit J Pharmacol 141:172-82 (2004).
  5. Levrand et al. Peroxynitrite is a major trigger of cardiomyocyte apoptosis in vitro and in vivo. Free Rad Biol Med 41:886-95 (2006).
  6. Shin et al. Zingerone as an antioxidant against peroxynitrite. J Agric Food Chem 53:7617-22 (2005).

TINNITUS MAY BE CAUSED BY PEROXYNITRITE NO, OH NO!

A very recent paper1 proposes that tinnitus, as well as diseases such as chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity, and posttraumatic stress disorder, may be caused by a “vicious-cycle mechanism known as the NO/ONOO (‘no, oh no!’) cycle mechanism.”1 ONOO (peroxynitrite) is the “oh no!” part of the cycle and is created by the chemical reaction between superoxide radicals and nitric oxide (NO). The authors note that “Tinnitus is also comorbid [i.e., occurs at the same time] with these illnesses, and these are comorbid with one another, suggesting a possible common etiology.”

The authors analyze these medical conditions according to their effects on the NO/ONOO cycle. They note that initiating stressors stimulate the excessive synthesis of nitric oxide or superoxide. Elements of the cycle should be elevated in the chronic phase of the illness, including nitric oxide, peroxynitrite, oxidative stress, intracellular calcium, NF-kappaB [an inflammatory cytokine] activity, other inflammatory cytokines, elevated nitric oxide synthase activity, increased superoxide levels, and activity of two receptor systems, the vanilloid receptor (which responds to capsaicin, among other molecules) and the NMDA receptor, which is excitatory. The authors propose that these illnesses are explained as being consequences of elevation of one or more of these elements and that they may best be treated by using “agents that down-regulate NO/ONOO biochemistry.”

The authors also analyze a number of stressors that initiate tinnitus and relate them to nitric oxide and other cycle elements. The stressors include acoustic overstimulation, bacterial LPS (lipopolysaccharide), carbon monoxide, ischemia, salicylate (salicylic acid or aspirin can cause ringing in the ears when taken in excess), physical trauma, infections (especially in the ear), and others. They note that physical trauma can induce NMDA, salicylate increases NMDA, ischemia increases superoxide and increases glutamate neurotoxicity (via NMDA and non-NMDA activity), bacterial LPS induces iNOS (the induced form of nitric oxide often increased in inflammatory conditions), and so on.

They cite an earlier study in which Takumida et al.2 “provided experimental support for a similar group of [NO/ONOO] agents that lower excitotoxicity (e.g., NMDA activity, nitric oxide synthase activity, superoxide levels, and peroxynitrite levels) and antioxidants to lower oxidative stress.”

References

  1. Pall and Bedient. The NO/ONOO cycle as the etiological mechanism of tinnitus. Int Tinnitus J 13(2):99-104 (2007).
  2. Takumida et al. Pharmacological models for inner ear therapy with emphasis on nitric oxide. Acta Otolaryngol 121:16-20 (2001).

 

CALORIC RESTRICTION (CR) IN SKELETAL MUSCLE OF RHESUS MONKEYS:
EFFECTS OF CR MAY BE SPECIES-SPECIFIC

Although two caloric restriction studies have been ongoing in nonhuman primates, it is not clear whether the animals’ lifespan will be increased by the end of either study. Beneficial effects have included weight loss (less body fat), increased insulin sensitivity, reduced blood glucose levels, and reduced oxidative stress-induced cytokine expression in peripheral blood mononuclear cells.1 The authors of a recent paper1reported an interesting study of the effects of 30% caloric restriction on gene expression in skeletal muscle of rhesus monkeys in a long-running caloric restriction (CR) study (begun in 1989) of adult rhesus monkeys, 8–14 years old. Rhesus monkeys have a maximum lifespan of about 40 years.

The CR experiment had examined, at the time of publication of this report, the effects of 9 years of CR in the rhesus monkeys compared to two groups of standard-fed (non-CR) rhesus monkeys: young (7–11 years old) and old (25–27 years old). The researchers identified 34 genetic transcripts that were elevated or decreased in expression with aging in muscle biopsy specimens from the vastus lateralis muscle. The authors of the paper were surprised that “we did not observe any evidence for an inhibitory effect of adult-onset CR on age-related changes in gene expression.” They speculate that “These results indicate that the induction of an oxidative stress-induced transcriptional response may be a common feature of aging in skeletal muscle of rodents and primates, but the extent to which CR modifies these responses may be species-specific.” As the authors note, this finding in rhesus monkeys is in contrast to their previous publication2 that more than 80% of age-related changes in gene expression found in skeletal muscle were either partially or completely suppressed by early-onset CR in mice.

References

  1. Kayo et al. Influences of aging and caloric restriction on the transcriptional profile of skeletal muscle from rhesus monkeys. Proc Natl Acad Sci USA 98(9):5093-8 (2001).
  2. Lee et al. Gene expression profile of aging and its retardation by caloric restriction. Science 285:1390-3 (1999).

 

VARYING EFFECTS OF CALORIE RESTRICTION IN TWO STRAINS OF MICE

A very interesting new paper1 reports on a comparison of metabolic rate and oxidative stress in two different strains of mice, one of which (C57BL/6) lives longer when calorically restricted and the other of which (DBA/2) does not, in an attempt to identify factors that predispose to benefiting from caloric restriction. The authors did this because, as they note, caloric restriction has not increased lifespan in all genotypes tested, including houseflies, which had lifespans proportionally decreased by reductions in food intake, and various strains of mice.

They particularly focused on the balance between food intake and metabolic expenditure. The factor that struck the researchers as being especially notable was that the strain that lived longer under caloric restriction (C57BL/6) gained more body weight while consuming the same amount of food as the strain that did not live longer under CR (DBA/2). This was true under both ad lib and CR feeding regimens. For example, after 12 months under 40% CR feeding, the DBA/2 mice weighed 13% less than the CB57BL/6 mice, even though both strains ate the same amount of food. Since the food intake was the same, the difference in body weight suggested a greater energy expenditure by the DBA/2 mice. Measurements of metabolic rate showed this to be true. “The rate of resting oxygen consumption, measured at 5–6 months of age, was 30% higher in DBA/2 than the C57BL/6 mice. . . . Compared to C57BL/6 mice, the maximal rate of in vitro oxygen consumption in the DBA/2 was 24% and 27% higher in homogenates of the heart and skeletal muscle, respectively.” Moreover, the rectal temperature of the DBA/2 mice over a 24-hour period was 0.7ºC higher than that of the C57BL/6 mice.

In an earlier study2 cited by the authors, it was reported that “in an AL[ad lib]-fed population of rats, animals that tended to gain relatively more weight than that expected solely on the basis of their food intake, had a correspondingly shorter life span. Furthermore, retrospective analysis indicated that the positive energy balance, expressed as the time taken to double the body weight, was a significant predictor of life span.” Thus, the researchers1 reason, “. . . if a positive energy balance under AL-feeding conditions tends to have a life-shortening effect in a particular genotype, then, conversely, a CR-induced decrease in energy balance in such a genotype could have an opposing effect [i.e., induce an increase] on longevity.”

The authors speculate, “. . . though a cause and effect relationship has yet to be established, the present and previous studies tend to point to oxidative stress, generated by a positive energy balance, as a key factor linking the amount of food intake and life span.”

Much of the analysis leading to the authors’ conclusion was not included above to isolate the bottom line. There were other differences between the two strains. The DBA/2 mice had greater oxidative stress at a young age, as shown by a significantly lower GSH/GSSG ratio in heart and skeletal muscle at 3 months of age. However, there was a relatively greater age-related decline in GSH/GSSG in the C57BL/6 mice in both tissues as compared with the DBA/2. The shift to pro-oxidizing conditions (redox potential) took place with age in heart and skeletal muscle of both strains, but the age-related change in redox potential was 40% larger in the C57BL/6 mice. Therefore, as the authors state, “It thus seems that although at the young age, the tissues of the DBA/2 mice displayed a higher level of oxidative stress than the C57BL/6 mice, the extent of the age-related rise in oxidative stress is greater in the latter than in the former.”

So why does CR lengthen the lifespan of C57BL/6 mice, but not that of DBA/2? High energy intakes (not balanced by increased energy expenditure) stimulate regulatory pathways, such as PI3K/mTOR/Akt, that increase cell growth and proliferation while increasing oxidative stress. Hence, a positive energy balance would create pro-oxidative conditions that could be corrected by reducing energy balance to neutral, through CR, for example. But since the DBA/2 already has a neutral energy balance throughout most of its life, the reduction of energy intake through CR wouldn’t “correct” an energy imbalance.

It is still not clear whether healthy people (or even healthy rhesus monkeys!) can live longer through CR, but reduction in food intake certainly does extend the lifespan of people with diseases of positive energy balance, such as diabetes.

References

  1. Ferguson et al. Comparison of metabolic rate and oxidative stress between two different strains of mice with varying response to calorie restriction. Exp Gerontol43:757-63 (2008).
  2. Ross et al. Dietary practices and growth responses as predictors of longevity. Nature 262:548-53 (1976).

 

ANOTHER DOGMA BITES THE DUST! ADULT HUMANS DO HAVE BROWN FAT

It has long been believed that, although human infants do have brown adipose (fat) tissue (BAT), adult humans do not. As the authors of a recent paper1 note, “The alleged absence of brown adipose tissue . . . precludes that alterations in amount and activity of brown adipose tissue could be an explanatory contributory factor for obesity in humans, in contrast to what seems to be the case in rodents.” The authors report that since 2002, brown adipose tissue was discovered serendipitously and most curiously in humans.

The discovery was at first considered a nuisance! Scientists had developed a way to identify tissues that were taking up unusually large amounts of glucose, such as tumors, which rely on glycolytic production of energy (ATP) and, hence, require large supplies of glucose. The new methodology required both fluorodeoxyglucose positron emission tomography (FDG PET) and computer tomography (CT). But because brown adipose tissue takes up much more glucose than normal tissue under cool conditions, such as during the testing procedures, which activate the BAT, the “spots” of the BAT that showed up were seen as a “disturbing complication” in the effort to identify tumors. As the authors of the paper explain, “. . . experimental efforts in nuclear medicine have concentrated on how to eliminate the problem of brown fat uptake. Accordingly, all data concerning FDG uptake in brown adipose tissue have been published in journals addressing nuclear medicine scientists, i.e., journals not normally studied by physiologists.”1

The sites of the adult BAT are consistent with the location of BAT in human infants. The neck depots (supraclavicular and neck) constitute the two largest and most often occurring depots in man; then there is a pattern of small depots located along the spinal cord as a paravertebral depot, also in the mediastinum, particularly in the para-aortic area, and around the heart, particularly the apex. Then there is an infradiaphragmatic depot, particularly in the perirenal area. (See paper for diagram showing depot locations.)

The tissue has been examined for evidence that it is indeed BAT. “The one identifying characteristic of brown adipose tissue is the presence of UCP1 [uncoupling protein 1] in the tissue.”1 Several studies are cited that have shown the presence of functional characteristics indicating the presence of UCP1 as well as UCP1 protein or UCP1 mRNA in these depots. Moreover, the activity of the purported BAT is induced by acute exposure to cold. It has been found that if patients are kept warm during the hour from injection of FDG to PET imaging, FDG uptake into the BAT is fully suppressed.1

The bottom line is that BAT exists in adult humans, and therefore BAT thermogenesis is a potentially useful method of weight control in humans by increasing energy expenditure.

Reference

  1. Nedergaard et al. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 293:E444-52 (2007).

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