March 2008 Blog with Durk and Sandy

Last night I had a nightmare . . . I woke up in a cold sweat, thinking of what Bishop Samuel Wilberforce’s wife reputedly said when confronted with Darwin’s theory: ‘Let us hope it is not true. But if it is, let us hope it does not become widely known.’— Dan Graur 
Dept. of Biology and Biochemistry, University of Houston 
(in a letter to Nature)As a teenager, when I had the chance to meet him in 1946, I was bold enough to ask, ‘Mr. Winston Churchill, sir, to what do you attribute your success in life?’ He replied, instantly: ‘Conservation of effort: never stand up when you can sit down and never sit down when you can lie down.’— Paul Johnson, historian 
Imprimis, December 2007The improver of natural knowledge absolutely refuses to acknowledge authority, as such. For him, skepticism is the highest of duties, blind faith the one unpardonable sin.— T. H. Huxley 
“On the Advisableness of Improving Natural Knowledge” (1866)We cannot solve the problems we have created with the same thinking that created them.— Albert Einstein

Enhancing Learning and Memory and Neurogenesis with Tryptophan-Induced Serotonin Increase

Neurogenesis, the creation of new neurons, is now known to be a lifelong process that takes place in two particular areas of the brain in several species, including rodents, tree shrews, dogs, and humans. Decrease of neurogenesis is thought to be related to cognitive decline with aging. For example, in adult rats, mice, and tree shrews, rates of neurogenesis begin to slow by the age of 1 year, well before the onset of old age.¹ A new study¹ reports that newly generated cells (in the dentate gyrus of the hippocampus) of marmoset monkeys were significantly lower in older animals and decreased linearly with age. These changes occurred before the onset of old age, “suggesting the possibility that similar alterations occur in the human brain.”

The authors further explained that a factor that may be involved in the age-related decline is the decrease with age of “serotonin, a neurotransmitter that promotes hippocampal neurogenesis through actions at the 5-HT1a receptor [a certain serotonin receptor].” Both serotonin and the 5-HT1a receptor decrease with age, “raising the possibility of a negative effect on neurogenesis.”

Another study² reported that serotonin-induced increases in neurogenesis in 8-week-old Wistar rats were mediated through different and common 5-HT (serotonin) receptor subtypes in two brain areas, the dentate gyrus and the subventricular zone. The same laboratory had reported in an earlier study that “significant decreases in the number of newborn cells in the SVZ [subventricular zone] and SGL [subgranular layer of the dentate gyrus] are observed following either acute or chronic 5-HT depletion.”

A very recent study³ reports that the enhanced serotonergic neurotransmission in the hippocampus following tryptophan administration improves learning acquisition and memory consolidation in Wistar rats. The rats were given oral doses of 50 mg/kg body weight or 100 mg/kg body weight of tryptophan daily for 6 weeks. Long-term memory in the water maze test was significantly improved by 66.5% at the 50-mg/kg dose and by 72.4% at the 100-mg/kg dose. Short-term memory improved significantly by 54% at the 100-mg/kg dose but did not show any effects at the 50-mg/kg dose. Memory consolidation was tested by determining the retention latency (how long it took the rats to relocate the hidden platform) at 1 hour and 24 hours after training. There was a significant decrease in retention latency at both doses of tryptophan after 24 hours.

Durk & Sandy Tryptophan Formulations

We are both very happy that tryptophan is back on the market after a prolonged and unjustified FDA ban. We have two Serene Tranquility™ tryptophan formulations, one for daytime (with 550 mg tryptophan/tablespoon of powder) and the other for bedtime (also with 550 mg tryptophan/tablespoon of powder, plus melatonin). We also have a day and bedtime 5-hydroxytryptophan formulation. The difference between tryptophan and 5-hydroxytryptophan is that 5-hydroxytryptophan is one step closer to the final product, serotonin. Our tryptophan is purchased exclusively from Ajinomoto, a highly reputable firm with extensive experience in producing amino acids, whose tryptophan was not associated with the EMS (eosinophilic myalgia syndrome) that poisoned about 2000 people in the late 1980s.

References

1. Leuner et al. Diminished adult neurogenesis in the marmoset brain precedes old age. Proc Natl Acad Sci USA 104(43):17169-73 (2007).
2. Banasr et al. Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology 29:450-60 (2004).
3. Haider et al. Enhanced serotonergic neurotransmission in the hippocampus following tryptophan administration improves learning acquisition and memory consolidation in rats. Pharmacol Rep 59:53-7 (2007).

 

It’s Never Too Late! Improved Mental and Physical Performance in Centenarians Treated with L-Carnitine

A randomized controlled clinical trial was conducted in 66 centenarians who were suffering from the onset of fatigue with even slight physical activity. They were divided into two groups, in which individuals received either 2 grams of L-carnitine or placebo once daily for 6 months. They were tested for changes in total fat mass, total muscle mass, serum triacylglycerols, total cholesterol, HDL-cholesterol, LDL-cholesterol, Mini-Mental State Examination (MMSE), activities of daily living, and a 6-minute walking corridor test.

The results showed that those receiving the L-carnitine achieved a reduction of total fat mass, an increase in total muscle mass, and increased physical and cognitive activity by reducing fatigue and improving cognitive functions. For example, before L-carnitine treatment, the walking distance in meters was 10.2 ± 3.8, whereas after treatment the walking distance was significantly longer at 14.6 ± 3.9 meters. There was no significant difference between the before and after for those receiving placebo. Total fat-free mass in those receiving L-carnitine increased significantly from 35.1 ± 3.2 kg to 38.9 ± 3.9 kg. The MMSE improved significantly in the L-carnitine treated group but not in the placebo group.

We take L-acetylcarnitine, which is a more bioavailable form of L-carnitine, being better able to pass through cell membranes.

Reference

1. Malaguarnera et al. L-Carnitine treatment reduces severity of physical and mental fatigue and increases cognitive functions in centenarians: a randomized and controlled clinical trial. Am J Clin Nutr 86:1738-44 (2007).

 

Nutrients That Inhibit Age-Associated Reduction in Telomere Length

The ends of chromosomes are capped by structures called telomeres. With each cell division, telomeres become shorter due to the loss of the most distal part of the lagging strand, which cannot be replicated.¹ It was realized in the early 1990s that the reduction in telomere length with each cell division could act as a biological clock that could measure how many times a cell had divided and could eventually cause replicative senescence (the Hayflick limit), in which cells were alive but could no longer divide.

However, “cells in a senescent culture display a broad distribution of replicative histories: some cells become permanently arrested after very few cell divisions, whereas others might go through many more divisions than indicated by the Hayflick limit of the population as a whole.”¹ It has been discovered that there are many mild stressors that can accelerate telomere shortening and reduce replicative lifespan independently of how many times the cell has divided. Such stressors include mild chronic oxidative stress, chronic hyperoxia (high levels of oxygen), treatment with homocysteine, tert-butylhydroperoxide, or hydrogen peroxide, or acute treatment with a variety of DNA-damaging agents that cause damage short of long-lasting growth arrest.¹ The authors of this paper conclude that “rates of cellular ageing and telomere-shortening in bulk culture depend on the balance between oxidative stress and antioxidative defense.” Hence, “The rate of telomere shortening per cell division is not an innate constant. Rather, it changes from cell to cell, possibly from one division cycle to the next, as a function of (external) oxidative stress and (internal) antioxidant defense.”

Another paper² reported similar findings in a study of human and sheep fibroblast cell cultures exposed to a wide range of oxidant (peroxide) stress conditions. They found a continuous exponential correlation between cellular oxidative stress levels and telomere shortening rates, independent of donor age, species, and cell strain.

Longer Leukocyte Telomere Lengths with Higher Serum Vitamin D Concentrations in Women

We have written often of the various old and new health benefits of vitamin D, including reducing the risks of a number of different cancers. Decreased vitamin D has been associated with increased risks of developing autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and type 1 diabetes, and administration of vitamin D has been shown to attenuate the activity of these diseases.³

Now, excitingly, a paper reports that higher vitamin D serum levels in women are associated with longer leukocyte (a type of white blood cell) telomere length in women.³(Although we know of no mechanism whereby men would have a different response, nevertheless a similar study needs to be done in men to be certain, as there are sometimes surprising biological differences between the genders.)

The new paper reports that shorter leukocyte telomeres are found in individuals with chronic inflammation, because the inflammatory response results in an increased turnover (replication) of leukocytes. Vascular diseases and autoimmune diseases, as well as cigarette smoking and obesity, have also been associated with shorter leukocyte telomeres. They report that a recent randomized case-control analysis revealed that shortened leukocyte telomeres were an independent risk factor for coronary heart disease (CHD), not surprisingly, as inflammation is a risk factor for CHD and could also be the cause of the shorter telomeres.

In this study,³ the LTL (leukocyte telomere length) in the lowest tertile of 25-hydroxyvitamin D was 6.97; in the middle tertile, LTL was 7.02; and in the highest tertile of 25-hydroxyvitamin D, LTL was 7.08. The authors also report, “Vitamin D supplement information was available on a subset of the study population (n = 700). Vitamin D supplement users had longer LTLs, despite adjustment for age, season of vitamin D measurement, menopausal status, use of hormone replacement therapy, and physical activity, than did nonusers. Mean adjusted LTL in subjects who did not use vitamin D supplements was 6.95 kb, whereas that of current users of vitamin D supplements was 7.06 kb; however, this difference was not statistically significant . . .” at <0.06. (<0.05 would be significant, so this result just barely fails to reach significance.) It is also useful to consider that most vitamin D users receive their vitamin D as part of a one-per-day-type multivitamin supplement, where the typical dose would be 400 IU of vitamin D. This is way too low. On a summer day, 15 minutes’ exposure of the body to the sun would result in the skin’s manufacture of about 18,000 IU of vitamin D. We take our own vitamin D formulation, SunPower Vitamin D™, 2000 IU/capsule, one capsule four times a day.

Carnosine Reduces Telomere Shortening

Carnosine is a dipeptide (alanine-histidine) that has interesting antisenescence effects, having been shown to increase the lifespan (both in terms of population doublings and in chronological terms) of human diploid fibroblasts grown in culture containing 20-mM carnosine.⁴ Carnosine is also a powerful antiglycating agent, protecting proteins from becoming chemically bound to sugars circulating in the bloodstream. Carnosine is one of the ingredients in our new Durk & Sandy’s AGEless™, a formulation that inhibits the formation of advanced glycation endproducts (AGEs). Increased amounts of AGEs are associated with aging,⁵ cancer,⁶ and cardiovascular disease.⁷ Shorter telomere lengths has been associated with heart disease.⁸

A recent paper⁷ reports that human fetal lung fibroblasts grown in culture containing 20-mM carnosine “exhibited a slower telomere shortening rate and extended lifespan in population doublings. When kept in a long-term nonproliferating state, they accumulated much less damages in the telomeric DNA when cultured in the presence of carnosine.” We recommend taking 1 gram of carnosine a day in three or (preferably) four divided doses. This is the amount contained in the recommended dosage of Durk & Sandy’s AGEless.

Telomere Shortening Repressed by Phosphorylated Alpha-Tocopherol

Phosphorylated alpha-tocopherol (alpha-tocopheryl phosphate) is a water-soluble form of vitamin E that is more bioavailable than the fat-soluble alpha-tocopherol. A recent study⁹ reports that the cellular lifespan of neonatal human brain microvascular endotheliocytes, estimated from population doublings, was 2.4-fold longer when continuously exposed to 150-μM alpha-tocopheryl phosphate. Ascorbate 2-phosphate at the same concentration increased cellular lifespan 1.3-fold. Telomeric lengths were markedly shortened at a rate of 291 base pairs per population doubling for the control cells, while telomeric lengths were maintained at 165 base pairs per population doubling in cells cultured with alpha-tocopheryl phosphate. The telomeric lengths in cells cultured only in ascorbate 2-phosphate had a slight reduction in the telomere shortening rate, down to 227 base pairs per population doubling, as compared to the controls.

References

1. von Zglinicki. Oxidative stress shortens telomeres. Trends Biochem Sci27(7):339-44 (2002).
2. Richter and von Zglinicki. A continuous correlation between oxidative stress and telomere shortening in fibroblasts. Exp Gerontol 42:1039-42 (2007).
3. Richards et al. Higher serum vitamin D concentrations are associated with longer leukocyte length in women. Am J Clin Nutr 86:1420-5 (2007).
4. McFarland and Holliday. Retardation of the senescence of cultured human diploid fibroblasts by carnosine. Exp Cell Res 212:167-75 (1994).
5. Snow et al. Advanced glycation end-product accumulation and associated protein modification in type II skeletal muscle with aging. J Gerontol A Biol Sci Med Sci 62A(11):1204-10 (2007).
6. Tesarova et al. Carbonyl and oxidative stress in patients with breast cancer—is there a relation to the stage of the disease? Neoplasma 54:219-24 (2007). “In conclusion, breast cancer patients had an early increase of AGEs (marker of the carbonyl stress) followed by further increase of AGEs and elevation of AOPP (marker of oxidative stress) in patients with progressive disease.”
7. Zhang et al. Glycated proteins stimulate reactive oxygen species production in cardiac myocytes. Circulation 113:1235-43 (2006).
8. Starr et al. Association between telomere length and heart disease in a narrow age cohort of older people. Exp Gerontol 42:571-3 (2007). The authors note that the findings in this study “. . . adds to the growing body of evidence for an association between telomere shortening and ischemic heart disease. Telomere shortening in peripheral blood leukocytes is a promising index of ischemic disease risk in older people . . .”
9. Tanaka et al. Age-dependent telomere shortening is repressed by phosphorylated alpha-tocopherol together with cellular longevity and intracellular oxidative-stress reduction in human brain microvascular endotheliocytes. J Cell Biochem 102:689-703 (2007).

 

Hydrogen Sulfide Is Responsible for the Vasoactivity of Garlic

“The consumption of garlic is inversely correlated with the progression of cardiovascular disease . . .”¹ A very recent paper¹ reports that the gas hydrogen sulfide, produced by red blood cells from garlic-derived organic polysulfides, is responsible for the vasoactivity (arterial relaxation) effects of garlic. Hydrogen sulfide is a gas naturally produced in the body that acts as a signaling molecule. The authors of the new paper found that the vasoactivity of garlic was synchronous with hydrogen sulfide yield. Interestingly, glutathione and other thiols (including cysteine and N-acetylcysteine)reacted directly in the absence of red blood cells to liberate hydrogen sulfide from garlic.

The amino acid cysteine (found in our Root Food II™ and Party Pill II™) is a precursor to the formation of hydrogen sulfide in the body. Hydrogen sulfide has been shown to relax vascular smooth muscle, induce vasodilation of isolated blood vessels, and reduce blood pressure. Moreover, donors of hydrogen sulfide inhibit leukocyte adherence in the rat mesenteric microcirculation during vascular inflammation, suggesting that hydrogen sulfide is a powerful anti-inflammatory.²

In fact, a very recent paper³ reports that nematodes grown continuously in air containing 50 ppm of hydrogen sulfide (0.005%) had a longer mean lifespan (9.6 days greater than the untreated worms); an average of 77% of hydrogen sulfide-treated worms were still alive when all untreated animals had died. In addition, the hydrogen sulfide-treated animals had increased tolerance to high temperatures. Improved thermotolerance, if it also occurs in humans, could be very useful during heat waves.

References

1. Benavides et al. Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci USA 104(46):17977-82 (2007).
2. Lefer. A new gaseous signaling molecule emerges: cardioprotective role of hydrogen sulfide. Proc Natl Acad Sci USA 104(46):17907-8 (2007).
3. Miller and Roth. Hydrogen sulfide increases thermotolerance and lifespan in Caenorhabditis elegans. Proc Natl Acad Sci USA 104(51):20618-22 (2007).

 

Vitamin E Reduces Oxidative Stress and Inflammation in Patients with Coronary Artery Disease

More papers continue to be published on the effects of antioxidants in the development of cardiovascular disease, despite failures in a few high-profile randomized controlled clinical trials. Importantly, more details are being sought on how cardiovascular disease initiation and progression are affected by nutrients such as vitamin E so that those people who would benefit (i.e., reduce their risk of cardiovascular disease) can be separated from those who may not benefit.

Another such paper¹ was published recently. The authors evaluated the effects of RRR-alpha-tocopherol (natural alpha-tocopherol) as both an anti-inflammatory and an antioxidant in 90 patients with stable coronary artery disease on drug therapy. Patients received 1200 IU of vitamin E per day for two years. The results showed that the vitamin E-treated patients had significantly lower C-reactive protein, significantly reduced urinary F2-isoprostanes (a measure of oxidative stress), and significantly reduced release by monocytes of superoxide and tumor necrosis factor (inflammatory cytokine). However, no significant difference was found in total carotid IMT (intima-media thickness) or cardiovascular events seen between the patients and the controls.

This is interesting because the vitamin E effects seen are widely thought to be cardioprotective, but because the end results of IMT and cardiovascular events did not differ between the vitamin E-treated patients and the controls, it suggests that the overall disease process, which has been going on for many years before symptoms show up, is more resistant to short-term improvements in oxidative stress and inflammation by a single agent than was thought to be the case. This study does not, however, justify a conclusion that vitamin E was not beneficial to these patients, and longer-term follow-up might eventually detect improvements in IMT and cardiovascular events. Moreover, the decrease in CoQ10 production that results from statins that most patients with diagnosed cardiovascular disease are taking is a confounder that should be corrected for in antioxidant-cardiovascular disease studies, but never is. We do think that it is much more likely that a combination of antioxidants (though not at one-per-day multivitamin dosages) would provide better results.

Reference

1. Devaraj et al. Effect of high-dose alpha-tocopherol supplementation on biomarkers of oxidative stress and inflammation and carotid atherosclerosis in patients with coronary artery disease. Am J Clin Nutr 86:1392-8 (2007).

Predicting the Outcome of Elections from Rapid Impressions of Candidates’ Faces

A new paper reports, shockingly, that the rapid and nonanalytical exposure to a candidate’s face can result in a long-lived impression that correlates with how people vote. It is bad enough that there is so much at stake in political elections, but at least one can hope that there is some thought involved in voting. This new study suggests otherwise.

The researchers showed participants (120 Princeton University undergraduates, who were each paid $5) faces of candidates for gubernatorial elections (if any participant recognized a candidate, that datum was not included). They were asked to make rapid, nonjudgmental decisions on which of two individuals (the winner and the runner-up) was more competent on the basis of his or her face. Predictions were as accurate after a 100-ms exposure to the faces as after 250 ms and to unlimited exposure. The researchers then compared competence judgments collected before the election of 2006 and found that they predicted 68.6% of the outcome of the gubernatorial races and 72.4% of the Senate races!

The authors conclude that “rapid, unreflective judgments of competence from faces can affect voting decisions.”

Reference

1. Ballew and Todorov. Predicting political elections from rapid and unreflective face judgments. Proc Natl Acad Sci USA 104(46):17948-53 (2007).

 

Shadow Government Statistics: Tells You Much More About the Economy Than What the Government Tells You

Ever wonder whether the rate of inflation is really what the feds say it is or whether their “Consumer Price Index” is an accurate picture of prices consumers are paying? This Web site is John Williams’ Shadow Government Statistics at http://www.shadowstats.com/section/commentaries. You get information such as what inflation looks like using the old method of government estimation as compared to the modifications put in to reduce the communication of data on price volatility. For example, under the new rules, food and energy prices are not counted in the calculation of the Consumer Price Index. (You show us somebody who doesn’t buy food or energy and we’ll show you a dead body.) This Web site is a great source of corrective information to help you maintain a grip on economic reality.

According to Mr. Williams’s calculation, using the old government rules, inflation is now about 10%, much worse than the feds are admitting. The Federal Reserve is pumping immense amounts of money into the economy via Federal Reserve banks that lend money to other banks. This new money, however, does not represent any actual goods or services. More money chasing the same or fewer goods and services results in higher prices. A 10% rate of inflation means that, unless you can find something to put your money into that will give you a return of 10% after taxes, you are better off spending the money right away on tangible things that are likely to hold their value better than the dollar.

Find out who is lying and why by visiting this site.

From the Flash Update, December 28, 2007:

• Help-Wanted Advertising Plunges to Lowest Level Ever

From the December 2007 edition:

• Actual 2007 Federal Deficit Topped $4.0 Trillion
• Fed Allows Strongest Money Growth in 36 Years

D&S note: Money growth is known as M3. The M3 amount was given out publicly by the Federal Reserve Board in its usual reports until last June, when M3 was running at about 9%. M3 was increased to 14% after June, when M3 had disappeared from the Federal Reserve Board reports. The Fed claimed that it discontinued reporting M3 to save $14 million a year. Of course, the economic decisions people have been making in the absence of a clear picture of the increase in the money supply (and its effects on prices) are likely to result in costs to the public from economic miscalculations far in excess of $14 million a year.

 

Good News for Moderate Drinkers of Red Wine

Yet another beneficial effect of red wine has been reported.¹ Researchers have found, in a randomized crossover study of 10 healthy volunteers, that subjects who ate a meal of 250 g of turkey cutlets soaked in red wine after heating, along with 200 ml of red wine, had a 75% reduction (compared to controls*) in the absorption of malondialdehyde (MDA, a lipid peroxidation product) from the turkey meal. Those who ate the turkey cutlets that had been soaked in red wine before heating and who drank 200 ml of red wine with the meal had a 100% reduction in MDA absorption (i.e., it was completely prevented). “. . . in some volunteers, the plasma MDA level was even reduced below baseline.”¹

 

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*Controls ate 250 g of turkey cutlets without soaking in red wine and drank water, not red wine, with the meal.

 

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The red wine concentrate that was added either before or after heating the turkey cutlets contained 218 mg of polyphenols, while the 200 ml of red wine contained 403 mg of polyphenols.

This is very good to know. It suggests that cooking meats with red wine and drinking red wine along with the meal is a very effective way (at least in healthy subjects) to reduce the absorption of damaging lipid peroxidation products, which were (as shown in this study) accumulated in plasma rapidly, with MDA reaching a maximum level 3 hours after the meal. The large reduction in MDA (and presumably other lipid oxidation endproducts, such as 4-hydroxynonenal and oxycholesterol) could be expected to provide significant protection to the gastrointestinal tract against the development of cancer, especially colon cancer.

Reference

1. Gorelik et al. A novel function of red wine polyphenols in humans: prevention of absorption of cytotoxic lipid peroxidation products. FASEB J 22:41-6 (2008).

 

Bad News for the DEA: More Evidence for the Cancer-Inhibitory Effects of Cannabinoids

Matrix metalloproteinases are gelatinases that are importantly involved in the invasion of cancer cells. One of the important natural regulators of matrix metalloproteinases (MMPs) is TIMP, tissue inhibitors of MMPs. Researchers treated human cervical cancer (HeLa) cells with cannabinoids, an analog of the endogenous cannabinoid anandamide, as well as with Δ⁹-tetrahydrocannabinol (THC), a constituent of cannabis; the cells were also exposed to the presence or absence of antagonists to cannabinoid receptors CB1 or CB2 or other receptors.¹ At the lowest concentration tested, THC (0.01 μM) caused a decrease in invasion that was accompanied by an increase in the expression of TIMP-1. Pretreatment of cells with antagonists of CB11 or CB2 reversed the stimulation of TIMP-1 expression and the suppression of cell invasion.

The authors concluded, “Increased expression of TIMP-1 mediates an anti-invasive effect of cannabinoids. Cannabinoids may therefore offer a therapeutic option in the treatment of highly invasive cancers.”

Now, if only the cannabinoids could offer a therapeutic option for inhibiting highly invasive federal agencies like the DEA, EPA, and FDA.

Reference

1. Ramer and Hinz. Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1. J Natl Cancer Inst 100:59-69 (2008).