In order to improve your game, you must study the endgame before everything else, for whereas the endings can be studied and mastered by themselves, the middle game and the opening must be studied in relation to the endgame.
— Jose Raul Capablanca, Cuban chess player who was world chess champion from 1921 to 1927 and one of the greatest players of all time.
(The above wise quote was taken from Endgame by John Mauldin and Jonathan Tepper, Wiley & Sons, Inc., 2011, a book about the Endgame that is the end of the debt supercycle and how it changes everything. The quote could as well apply to the Endgame of life: aging and death.)
We all know we have seen the end of an era, and now we have courtside seats to watch the Endgame unfold. We are watching the end of Act I: the Debt Supercycle. Now we will get to see how Act II: The Endgame plays out.
— John Mauldin & Jonathan Tepper, The Endgame, Chapter I, page 4
I very rarely think in words at all. A thought comes, and I may try to express it in words afterwards.
— Albert Einstein
Nothing gives life more zest than running for your life.
— Robert A. Heinlein, The Cat Who Walks Through Walls, 1985)
When I was a kid I used to pray for a bicycle. Then I realized that the Lord doesn’t work that way, so I stole one and asked him to forgive me.
— Emo Philips
You do not need a parachute to skydive. You only need a parachute to skydive twice.
Knowledge is knowing a tomato is a fruit. Wisdom is not putting it in a fruit salad.
[Total] Olive Oil Consumption in U.S passed Greece in 2009, with the U.S. becoming the third largest consumer of olive oil, reaching a per capita consumption of 0.9 liters of oil a year. Meanwhile, however, Greece’s per capita consumption was 21 liters/year.
— Catherine E. Watkins, associate editor of Inform in the Sept. 2012 Inform
Thomas Jefferson first saw olive trees in the Alps in 1788 and called them “the richest gift of heaven” and “the most interesting plant in existence.”
— Tom Mueller, author of “Extra Virginity: The Sublime and Scandalous World of Olive Oil” in Watkins, book review in the Sept. 2012 Inform
New research suggests that sexual experience is not only pleasurable, but also reduces anxiety and increases adult neurogenesis in adult male rats. We report here on three recent studies.1–3
Why do rats have all the fun by getting to be the subjects in these sexual studies? First, rats are much easier to maintain under constant laboratory conditions and to sample for plasma constituents such as glucocorticoids, which could inhibit sexual activity, induce anxiety, and inhibit neurogenesis. Rats are also easier to get in groups with similar genetic background, thus avoiding some confounding effects. Anyway, the rats in these studies were very enthusiastic subjects but were still “sacrificed” in the end in order to assess brain effects. Well it was fun while it lasted.
In the first paper,1 the researchers studied whether sex, a rewarding stressor that, like other stressors, increases glucocorticoids, would have similar negative effects as non-rewarding stressors.
The adult male rats1 were exposed to a sexually-receptive female rat once (acute) or once daily for 14 consecutive days (chronic) and their levels of circulating glucocorticoids were measured. Their sexual encounters were videotaped and then analyzed for mounts, intromissions, and ejaculations. On the last day, the rats were injected with BrdU (bromodeoxyuridine, a DNA synthesis marker). The scientists explain that “the majority of new cells in the dentate gyrus express the mature neuronal marker NeuN 2 weeks post BrdU labeling.” An additional cohort of naive and sexually-experienced rats were tested for anxiety on the elevated plus maze and on the novelty-suppressed feeding paradigm (where the latency to chew a ~2 g food pellet in the center of a bright area was recorded. The longer latency indicated anxiety).
The results showed that chronic sexual experience enhanced cell proliferation and adult neurogenesis without altering glucocorticoid levels. Sexual experience produced more new neurons (those labeled with BrdU and examined after a 2 week survival). Acute sexual experience (a single encounter with a sexually-receptive female rat) resulted in enhanced cell proliferation in the dentate gyrus despite substantially elevated glucocorticoid levels.
The sexually experienced rats were less anxious than naive controls when tested on the novelty suppressed feeding paradigm.
As the researchers note, despite the increase in glucocorticoids (in the rats receiving a single (acute) sexual experience), neurogenesis still took place, even though stressors that increase glucorticoids generally reduce adult neurogenesis. The authors suggest that whether glucocorticoids increase or not, it is the rewarding (hedonic) aspect of the brain stimulation that overrides the inhibitory effect of glucocorticoids on neurogenesis. As the researchers also note, another example of a rewarding stressor is exercise that, despite increasing glucocorticoids, also reduces anxiety and enhance adult neurogenesis in mice and men.
In the second paper,2 researchers studied the effect of oral feeding of Lycium barbarum< (wolfberry, also called Goji) polysaccharides (LBP) in adult male Sprague-Dawley rats for its effects on copulation, ejaculation, and shortening of ejaculation latency. After 21 days of LBP feeding, there was significant improvement of all these sexual functions. Moreover, the sexual inhibition caused by chronic corticosterone (glucocorticoids) was prevented by LBP. While increased corticosterone suppressed neurogenesis in subventricular zone and hippocampus of adult rats, this was reversed by LBP.
“Significant correlation was found between neurogenesis and sexual performance, suggesting that the newborn neurons are associated with reproductive successfulness. Blocking neurogenesis in male rats abolished the pro-sexual effect of LBP.”2 “Our results showed that the beneficial effect was not only revealed in normal, healthy rats, but also in rats with sexual inhibition induced by corticosterone. The ‘rescuing’ effect of LBP on male sexual behavior suggests that LBP may be useful to treat male sexual dysfunction.”2 As in the study1 discussed above, adult neurogenesis in the SVZ (assessed by the number of BrdU-positive cells in the corticosterone-treated animals was significantly lower than that in animals not given corticosterone.
An in vitro study carried out by the same researchers as part of the study showed that LBP treatment at 1 μg/ml and 10 μg/ml increased cell proliferation in a neural stem cell line. Corticosterone treatment suppressed the cell proliferation of the neural stem cells, while co-administration with LBP at 10 μg/ml could reverse the suppression.2
Unsurprisingly, the third paper3 is very similar to the second paper2 as the researchers were the same; paper #3 was published the year before paper #2. Accordingly, the adult male rats were treated with either corticosterone and/or paroxetine, an SSRI type (similar to Prozac®) antidepressant. The findings included that corticosterone treatment inhibited male sexual performance, while paroxetine enhanced it. The researchers summed it up: “These results suggest that cell proliferation in the SVZ and hippocampus may be involved in the reproduction of the male rodents, and pharmacological treatments may affect sexual functioning through alteration of neurogenesis.” Paroxetine is an SSRI antidepressant drug that, as a class, have been found to generally increase neurogenesis.
As the title of the paper1 makes clear, the bottom line of the new research is that AGEs promote insulin resistance and diabetes by depleting antioxidant defenses that protect against AGE-induced inflammation, including the AGE receptor-1 (AGER-1), a key anti-AGE defense, and SIRT1, which suppresses inflammatory signals and, importantly, enhances levels of the anti-inflammatory adipokine adiponectin to improve insulin sensitivity and fat mobilization. The researchers found that AGER1 and SIRT1 were independently suppressed by chronic oxidative stress as is found in conditions such as diabetes, obesity, aging, or high AGEs containing diets.Advanced Glycation Endproducts (AGEs) have become a hot research subject because of the coming together of mechanisms where accumulation of AGEs appear to be causative factors that go beyond overnutrition in the “epidemic” of age-associated metabolic diseases including obesity and diabetes. A newly published paper1 and an accompanying commentary2 report some of the new discoveries whereby AGEs have become the centerpiece of the causes and potential prevention of these disorders.
The researchers fed a powerful alpha-dicarbonyl glycating agent, methylglyoxal (MG), found in patients with diabetes and in those consuming high AGE diets, to mice. As we have written in an earlier Durk & Sandy newsletter, one way to reduce dietary AGEs is to cook food at a relatively low temperature, as the AGEs are formed by high temperature heating of foods containing protein and sugars. This process, called the Maillard reaction, creates tasty food that is crispy and has a brown color—hard to resist except when you consider the result of eating too much of it.
The mice on a high MG diet gained weight, with increased adiposity, and metabolic changes as compared to mice on a regular diet. In addition, the MG-fed animals had increased markers of oxidative stress and inflammation, including increased plasma 8-isoprostanes and vascular cell adhesion protein-1 and lower plasma adiponectin levels. Moreover, insulin action was impaired in the MG+ mice. “… levels of AGER1 and SIRT1 were suppressed in primary adipocytes isolated from MG+ WAT [white adipose tissue from MG+ mice], and NF-kappaB acetylp65 and RAGE levels were increased, compared with adipocytes from MG-mice, suggesting the presence of a proinflammatory state in MG+ WAT adipocytes.”1
The researchers comment: “It is notable that this combination of features is virtually absent in genetically identical mice born and raised in an environment differing only with respect to the lower amount of ingested MG-AGEs.”
“Chronic MG+ intake was also associated with elevated fasting plasma insulin and leptin and suppressed adiponectin levels in MG+ mice. These findings are consistent with an insulin-resistant state, as seen previously in Reg mice, but not in MG– mice.”
According to Leonid Poretsky, the author of the commentary article,2 “[n]ew tests measuring AGEs in circulating, including those absorbed from the diet, have been developed and are poised to enter clinical practice.” This is wonderful news and we certainly hope that “poised to enter clinical practice” means pretty soon, not being delayed for years by bureaucratic process at the FDA. As the author2 also comments, “[c]irculating AGE levels can be reduced without altering the caloric content of meals simply by changing the way the food is prepared, that is, by using less heat and more water (e.g., stewing instead of frying).” He adds that “[m]edications that can reduce AGE absorption from food need to be developed, and initial steps in this direction have already been taken.”
Nutrients that block the development of AGEs or reduce the damage caused by AGEs include: benfotiamine (a lipid soluble form of thiamine), vitamin B6, alpha lipoic acid, carnosine, histidine, and rutin. We take a formulation containing all these ingredients 3 or 4 times a day. See our interview on reducing AGEs (with included references) “Reducing Glycation Reactions for Better Health and Longer Life” in the February 2008 issue of Life Enhancement.
But that isn’t the end of the story of ways available to your body for either blocking the formation of AGEs or increasing their disposal. Methylglyoxal is a major precursor of AGEs, the levels of which are elevated in, among other conditions, diabetes, dialysis, and chronic kidney disease. As a 2012 paper1 reports, “several dietary flavonoids have been shown to inhibit AGE formation through blocking the carbonyl or dicarbonyl groups and thus may prevent diabetes and its complications.”
Curcumin has now been reported1 to directly trap methylglyoxal, inhiting its conversion to AGEs and, as a result, possibly preventing methylglyoxal-induced endothelial dysfunction. The new paper1 reveals the chemical mechanism that may be responsible for the methylglyoxal trapping by curcumin. The paper also mentions other trapping agents of reactive dicarbonyl species such as methylglyoxal from dietary sources that includes the tea polyphenol EGCG, apple polyphenols phloretin and phloridzin, cinnamon proanthocyanidins, phlorotannins from brown algae, stilbene glucoside from Polygonum multiflorum Thumb. Remarkably, the researchers report that curcumin significantly and time-dependently trapped MGO (methylglyoxal) for up to 24 hours (51% reduction, p<0.05), and the effect was said to remain unchanged for up to 72 hours of incubation.1
Curcumin is readily available from turmeric root powder, an inexpensive spice which we take every day in capsules. We also take EGCG in capsules every day, too!
A very interesting new study reports that preventing the enzymatic degradation of tryptophan has significant anti-aging effects in the nematode Caenorhabditis elegans.The study specifically identifies “the tryptophan-converting enzyme tryptophan 2,3-dioxygenase (TDO-2) as a metabolic regulator of age-related protein toxicity and lifespan in C. elegans.”1
The researchers found that depletion of TDO-2 suppressed toxicity of aggregation-prone proteins, including alpha-synuclein, amyloid-beta and polyglutamine proteins, associated with diseases such as Parkinson’s, Alzheimer’s, and Huntington’s, respectively. Depletion of TDO-2, the first enzyme in the kynurenine pathway of tryptophan degradation, increased the levels of tryptophan (by decreasing its degradation), but the researchers also found that feeding the worms with extra L-tryptophan also suppressed the toxicity of aggregation-prone proteins. (Emphasis added.) Moreover, depletion of TDO-2 extended lifespan in C. elegans. Humans have evolutionarily conserved orthologs of TDO-2 (TDO and indoleamine 2,3-dioxygenase). Hence, the authors conclude, “intervening with tryptophan metabolism may offer avenues to reducing proteotoxicity in aging and age-related diseases.”1
The researchers also note that as TDO-2 naturally increases during aging, this may contribute to the age-dependent decline in protein homeostasis and, thus, inhibiting TDO (and possibly indoleamine 2,3-dioxygenase) may delay this process.
Other Natural Products Inhibit Indoleamine 2,3-Dioxygenase
Indoleamine 2,3-dioxygenase has been shown to have important effects on the immune system. “By locally degrading tryptophan, IDO inhibits the proliferation of T lymphocytes and induces T cell apoptosis, leading to suppression T cell response.”2 In a recent study, EGCG (the major catechin constituent of green tea) was shown to significantly inhibit the expression of IDO (and hence preventing immune suppression of T cells resulting from the degradation of tryptophan) in oral cancer cell lines.2
In another study,3 curcumin was reported to reverse IDO-mediated suppression of T-cell responses in bone marrow-derived dendritic cells stimulated by interferon gamma. The authors suggest that “down regulation of IDO in DCs is an important immunomodulatory property of curcumin that may be exploited therapeutically in the control of cancers.”
A study on the effects of resveratrol on IDO4 reports that in a cell culture study, resveratrol (10–100 uM) diminished tryptophan degradation by IDO.
Reduced Neurogenesis by TDO-2 Conversion of Tryptophan into Kynurenine, Catalyzed by Tryptophan-2,3-dioxygenase, is Stimulated By Cytokine-Induced Depression
Another result of degradation of tryptophan by tryptophan-2,3-dioxygenase (TDO-2) is decreased neurogenesis.5 In a 2012 paper,5 researchers report that “[t]he first step [in the conversion of tryptophan to kynurenine] is catalyzed by the enzyme tryptophan-2,3-dioxygenase and, especially in response to inflammation, also by indoleamine-2,3-dioxygenase (IDO). This pathway is clearly activated during cytokine-induced depression. For example, administration of LPS [lipopolysaccharide, a component of bacterial cell wall, which stimulates the immune system] in rodents activates IDO and induces depression-like symptoms, which in turn can be prevented by an IDO antagonist.” Importantly, the researchers go on to explain that “[f]ollowing IDO activation, both the reduced peripheral availability of tryptophan (putatively leading to reduced serotonin synthesis in the brain) and the relative balance between QUIN [quinolinic acid] and KYNA [kynurenic acid] [both products of TDO and/or IDO], have been proposed to be of significance in depression and neurodegeneration. Indeed, TDO-/- [TDO knockout] mice show increased neurogenesis.” Accordingly, the researchers chose to test the hypothesis that the kynurenine pathway is involved in the IL-1beta (a proinflammatory cytokine)-induced reduction of neurogenesis.
The researchers report finding that differentiated human hippocampal progenitor cells constitutively express both IDO and TDO, the enzymes that degrade tryptophan into KYN (kynurenine). In culture of the cells, it was found that tryptophan levels decreased by 19% and kynurenine levels increased by 20%, leading to an overall 53 ± 13% (p<0.05) increase in the ratio of kynurenine/tryptophan. In other words, the IL-1beta increased the levels of a functional IDO enzyme.
The authors conclude that “our results show for the first time that IL-1beta reduces human hippocampal neurogenesis …” “We also show that, upon activation of IDO, treatment with IL-1beta results in a decrease of tryptophan together with an increase in kynurenine levels.”5
Another new paper6 also reports, in a mouse model of neuroinflammation-induced depression, that the inhibition of indoleamine 2,3-dioxygenase by its competitive inhibitor 1-methyl-tryptophan, prevented the development of depressive-like behavior. This is consistent with current thinking that the activation of IDO by proinflammatory cytokines is a link between IDO and neurodegenerative diseases such as Alzheimer’s disease and depression.6
An early (1998) paper1 described how arachidonic acid, an omega-6 fatty acid, stimulates proliferation of prostate cancer cells through its metabolite 5-HETE, produced by the action of 5-lipoxygenase. They refer to multiple studies that have suggested a role for arachidonic acid and its precursor, linoleic acid, in prostate cancer growth and metastasis. In their paper,1 the authors show that 5-HETE is also a potent survival factor for human prostate cancer cells. They showed that, by inhibiting 5-lipoxygenase, 5-HETE production was completely prevented and that this resulted in massive apoptosis (programmed cell death) in both hormone-responsive (LNCaP) and -nonresponsive (PC3) human prostate cancer cells. The apoptosis was blocked by the thiol antioxidant N-acetylcysteine. These results, the authors state, identifies a possible mechanism by which high dietary fat can promote the progression of prostate cancer.
A more recent (2007) paper2 follows up on these earlier findings by reporting on the use of 5-LOX inhibitors to block the conversion of arachidonic acid to 5-LOX products associated with various disorders, including osteoporosis and cancers (e.g., prostate, pancreas and breast), as well as atherosclerosis, heart attack, and stroke. The author describes many natural products that act as 5-LOX inhibitors or inhibitors of 5-LOX products, including nordihydroguaiaretic acid (NDGA), caffeic acid, quercetin, luteolin, silibinin, curcumin, gingerols (derived from ginger), rosmarinic acid, and resveratrol. Also, see article (below) on benfotiamine.
Boswellic acids have also been reported as inhibitors of 5-LOX, have potent anti-inflammatory activity, and have been extensively investigated for their activity against tumor cells and in cancer chemoprevention.3
A recent study reveals a causal role for serotonin in the serotonin neurons in the midbrain dorsal raphe nucleus in the ability of rats to wait for a delayed reward. This is consistent with studies showing that reduced serotonin brain levels are associated with increased impulsivity, especially with respect to violent acts, including suicide.
In the new study,1 the authors explain that the dorsal raphe nucleus (DRN) is the major origin of serotonergic projections to the forebrain. They had previously reported that “DRN serotonergic neurons increase tonic firing while rats wait for delayed rewards and cease firing before rats give up waiting for long delayed rewards.”1 However, these results did not reveal whether the activation of serotonergic neurons is causal and necessary for waiting for delayed rewards. Hence, the researchers conducted this new study.
In the new study, the rats performed a task and could receive a prompt reward (waiting for 2 seconds) or a delayed reward (where they had to wait 7–11 seconds). The rats had to alternatively visit food and water sites to acquire rewards after either the rapid or delayed reward condition. The researchers found that “the suppression of 5-HT [serotonin] neural activity in the DRN increased premature exit from reward sites before the delivery of rewards, which indicated impaired patience for delayed rewards.”1
Interestingly, selective serotonin reuptake inhibitors (SSRIs) can have inconsistent results on the ability to wait for delayed rewards. “For example, some studies showed the administration of SSRIs increased the selection rate of a large, delayed reward over a small, immediate reward, indicating a decrease in impulsive choice. By contrast, a lack of effect has also been reported. Furthermore, opposite effects of different doses of citalopram in a probabilistic reversal learning have been reported. These inconsistent results may be due to opposing effects of SSRI on 5-HT neuron firing and postsynaptic 5-HT concentrations.”1 These inconsistencies may also relate to the occasional reports of impulsive violent acts carried out by adolescents treated with SSRIs, including schoolyard shootings and suicides. These unfortunate effects might be avoided by taking tryptophan or 5-hydroxytryptophan (5-HTP) supplements but the exact amounts needed will differ between individuals and require careful titration. Those individuals with lower levels of the enzyme required to convert tryptophan to 5-hydroxytryptophan (the first step in the conversion of tryptophan to serotonin) are likely to find taking 5-hydroxytryptophan rather than tryptophan a more effective way to increase their serotonin levels.
Another mechanism described by the researchers is hypobaric hypoxia leading to low blood oxygen saturation that triggers the production of erythropoietin (to increase the number of red blood cells). They go on to explain that increases in red blood cells induce hypoxic inflammation by producing reactive oxygen species. The researchers carried out a study to identify “a potent therapeutic agent which can reduce hypobaric hypoxia-induced oxidative stress, as well as inflammation” as a possible way to reduce high altitude cerebral edema.1 Quercetin has been found to have powerful antioxidant and antiinflammatory effects. Moreover, quercetin has been reported in several studies to reduce inflammation by attenuating the redox-sensitive transcription factor NFkappaB, as well as scavenging free radicals. The researchers compared the effects of quercetin with dexamethasone (a synthetic corticosteroid, which acts as an antiinflammatory) against high altitude cerebral edema in male Sprague Dawley rats.A new paper1 starts by telling you about the dangers of traveling to high altitudes or mountain climbing without adequate acclimatization. You could end up like one of the millions of people who every year suffer from acute high altitude mountain sickness, from which 5% can develop life threatening high altitude cerebral edema. High altitude cerebral edema has been described as, “although uncommon, high altitude cerebral edema causes significant morbidity and occasionally death in otherwise perfectly healthy individuals.” The researchers1 report that their recent study “proved that oxidative stress and inflammation play an important role in high altitude cerebral edema via the redox-sensitive transcription factor, NFkappaB activation.” NFkappaB is a major regulator of inflammation-associated genes.
In the study, rats were exposed to an altitude of 25,000 feet for 24 hours, as a result of which they showed a significant rise in various blood parameters including white blood cells, red blood cells, lymphocytes, monocytes, granulocytes, hemoglobin, platelets, MCV, and HCT (hematocrit). The authors hypothesize that increase in red blood cells, hemoglobin, and hematocrit might lead to increased blood viscosity and stasis of blood, increasing the risk of blood clots. However, administration of quercetin or dexamethasone prior to hypoxia exposure resulted in a reduction in many of these changes. Quercetin was more effective than dexamethasone as an antioxidant (decreasing reactive oxygen species and increasing superoxide dismutase) as well as an antiinflammatory by downregulating NFkappaB. Unlike dexamethasone, quercetin does not have the many side effects commonly observed in corticosteroid therapy (such as severe allergic reactions, loss of appetite, depression, diarrhea, dizziness, fever, muscle weakness, severe nausea or vomiting, swelling of feet or legs, and others).
According to the authors, the MSD (material safety data sheet) for quercetin in the rat for LD50 (dose that kills 50% of the animals) is 161 mg/kg of body weight. For a human of 70 kg, this would be equivalent to about 11,270 mg. The basic multinutrient formulation we both take daily contains in the recommended 12 capsules a day 128 mg of quercetin or nearly two orders of magnitude lower than the LD50 for rats.
Anti-inflammatory Effects of Benfotiamine Mediated By Regulation of Arachidonic Acid Pathway in Macrophages
As noted in the article (above), arachidonic acid stimulates the proliferation of prostate cancer cells through its metabolite HETE, produced by 5-lipoxygenase. Interestingly, a 2012 paper2 reports that benfotiamine, a lipid soluble form of vitamin B1 (thiamine) inhibits the formation of arachidonic acid metabolites by preventing the LPS-induced metabolizing of arachidonic acid via 5-lipoxygenase and other arachidonic acid metabolizing enzymes such as COX-2 (cyclooxygenase 2), TXB (thromboxane) synthase, and PG12 (prostacyclin) synthase. Moreover, benfotiamine has been found to be a potent blocker of AGEs (advanced glycation end products) as well as antiinflammatory against LPS (lipopolysaccharide). “Bacterial lipopolysaccharide (LPS), the structural component of the Gram-negative bacterial outer cell wall, is a potent initiator of the inflammatory response during most commonly seen bacterial infections.”2
Going back even a couple hundred years, bleeding was a popular therapy for a wide variety of disorders, but the mechanism(s) was (were) not understood so that the likelihood of doing harm (recall the case of George Washington, for example) was probably in most cases greater than the likelihood of benefit. As reported in a paper in the latest issue of The Journal of Clinical Investigation,1 “phlebotomy [bleeding] of humans with impaired glucose tolerance and ferritin values in the highest quartile of normal increased adiponectin and improved glucose tolerance. These findings demonstrate a causal role for iron as a risk factor for metabolic syndrome and a role of adipocytes in modulating metabolism through adiponectin in response to iron stores.”
Ferritin is the commonly used marker for total body iron stores. Phlebotomy improves blood glucose levels and aspects of the “metabolic syndrome” associated with obesity and diabetes (e.g., insulin resistance). The latter suggests that excess iron, which can be decreased by bleeding, may be a causal factor in these disorders.1 The authors note that recent studies have found a negative correlation between serum ferritin and the insulin-sensitizing adipokine, adiponectin. Moreover, obesity and diabetes are associated with lower levels of adiponectin, with the latter being causally related to insulin resistance. “Studies in cell culture, mouse models, and humans demonstrate that iron plays a direct and causal role in determining adiponectin levels and diabetes risk.”1
One of the findings of this paper was that mice on a high-iron diet had a significant decrease in their maximal glucose disposal rate per gram of lean tissue, indicating impaired glucose tolerance.
The researchers found that when ferroportin, an iron channel and exporter in adipocytes, was deleted (knocked out) in mice, they had increased adipocyte iron levels, decreased serum adiponectin, and increased insulin resistance. In the ferroportin knockout mice, there was an increased level of adipocyte iron accompanied with a 58% decrease in adipocyte adiponectin RNA, which was reflected in decreased serum adiponectin. The researchers also studied human subjects with impaired glucose tolerance that had serum ferritin levels in the highest quartile of the normal range. By about six months after phlebotomy, there was a fall in serum ferritin to the lowest quartile of normal, with the average blood donation being 3.7 units.
These findings suggest that frequent blood donations could help reduce the risk of diabetes and could even be therapeutic for those who already had the disease, although we do not know whether blood from diabetics taking drugs for their medical condition would be suitable for transfusion to normal subjects.
Another 2012 paper2 reports finding similar results in an epidemiological study of 27,548 people (16,644 women mainly aged 35–65 years and 10,904 men mainly aged 40–65 years) as part of the multicentre European Prospective Investigation into Cancer and Nutrition (EPIC). High ferritin levels were associated with higher risk of type 2 diabetes independently of established diabetic risk factors and a range of diabetes biomarkers. The authors conclude that “[t]hese results support the hypothesis that higher iron stores below the level of haemochromatosis [iron overload disorder] are associated with risk of type 2 diabetes.” In order to reduce the possibility of including individuals with undiagnosed haemochromatosis, the researchers excluded subjects in whom serum ferritin was elevated beyond three times the SD (standard deviation) from the mean (25 women with ferritin over 37.3 mg/l, 21 men with ferritin over 100.0 mg/l).2
A third 2012 paper3 also reported an association between iron metabolism and adipocyte insulin resistance and plasma adiponectin, suggesting (per the authors) that “factors related to iron and iron metabolism may contribute to adipocyte IR [insulin resistance] early in the pathogenesis of T2DM [type 2 diabetes mellitus].”
A 2012 paper1 reports that, in male animals, mild exercise enhances hippocampal synthesis of dihydrotestosterone and increases adult hippocampal neurogenesis as a result of androgenic action.
The paper begins its introduction by explaining that testosterone (T) and dihydrotestosterone (DHT) exert neuroprotective effect via androgen receptors in the hippocampus. Interestingly, current studies have shown that androgens can be synthesized in the hippocampus, not only be (as generally understood previously) androgen production in the testes and distribution to the brain by the bloodstream. Moreover, the beneficial effects of exercise on cognition and mood (such as results from mild exercise on wheel and treadmill running exercise) may be mediated by exercise-induced neurogenesis in adults. The authors developed a mild exercise using a treadmill that didn’t result in lactate production and produced minimal stress. They further showed that that amount of mild exercise was able to induce hippocampal neuronal activity and neurogenesis.1
The researchers then examined the effects of 2 weeks of this mild exercise on androgen levels in hippocampus and adult hippocampal neurogenesis. They found that treatment with an androgen receptor antagonist resulted in suppression of the exercise-induced neurogenesis, indicating a causal involvement of androgens in the neurogenesis resulting from the mild exercise. The researchers discussing the results, speculated “[b]ecause the injection of testosterone has been shown to reduce deposits of beta-amyloid protein in vitro through the enhanced effects of neprilysin, it might be that mild exercise, in mediating paracrine effects through androgens and/or DHT [dihydrotestosterone] may, in turn, also reduce the deposits of beta-amyloid protein and protect cognitive functions.”1
It has long been thought that the loss of insulin release by pancreatic beta cells in diabetes is the result of the death (apoptosis) of these cells. In a new paper,1researchers have discovered that the reason the beta cells (in a FOXO1 knockout mouse model of diabetes) stopped producing insulin is not because the cells died but because they dedifferentiated to an earlier stage of development in which they cannot produce insulin. “Dedifferentiated beta cells reverted to progenitor-like cells expressing Neurogenin3, Oct4, Nanog, and L-Myc.”1 These markers indicate that these beta cells are endocrine pre-beta cells.1
The scientists studied FOXO1 immunoreactivity in beta cells of mice with insulin-resistance diabetes, including mice with mild fasting hyperglycemia and severe hyperglycemia. “As hyperglycemia increased, loss of FOXO1 immunoreactivity paralleled loss of insulin content. To determine whether the loss of FOXO1 was a cause or effect of the beta cell failure and what happened to the “missing” beta cells, e.g., did they die or what, the researchers then studied mice with the FOXO1 gene knocked out in their beta cells. They were surprised to find that the beta cells without FOXO1 stopped producing insulin but nearly all of the cells remained alive. “The findings indicate that ‘empty’ beta cells in IKO [knockout] mice are not degranulated beta cells, but represent a distinctive pre-beta cell differentiation stage.”1
The authors point out, however: “While the metabolic abnormalities in mice with beta cell-specific FOXO1 specific knockout are not as marked as those seen in the other diabetic models, this might be due to compensatory increases in other FOXOs. Nevertheless, the impairment of beta cell mass and function caused by lack of FOXO1 is consistently observed in other models of diabetes.” “Importantly, we show that beta cell dedifferentiation is a regression to an endocrine progenitor-like stage rather than a degenerative stage.” “The model arising from our observations can help explain why decreases in beta cell mass occur slowly as a function of diabetes duration. It is consistent with and provides an explanation for the slow progression and temporary reversibility of beta cell dysfunction, vindicating the concept of ‘beta cell rest’ as a diabetes treatment.”
This mechanism (if reproduced) suggests that beta cell function might be restored in diabetes during a “window of opportunity” by redifferentiating the dedifferentiated beta cells, providing for a potential cure for diabetes. We offer our congratulations to the researchers who performed this work.
A new paper1 reports that amyloid-beta is removed from the brain via apoE and that the apoE4 form, which is associated with an increased risk for Alzheimer’s disease as compared to other forms of apoE, exhibited the slowest rate of amyloid beta clearance from the brain as compared to the other forms of apoE. LDLR is known to play an important role in the periphery in mediating removal of cholesterol and cholesterol esters, but the authors note that little is known about its function in the brain. In this paper, the authors explain that recent work has identified LDLR as a major apoE receptor in the CNS that “profoundly affects the accumulation of amyloid beta.” In this new paper,1 the authors found that LDLR regulates clearance from the brain of exogenously administered amyloid beta across the blood-brain barrier.
The researchers created a mouse that overexpresses LDLR in the setting of CNS expression of human amyloid beta and the PDAPP mouse model of beta-amyloidosis. “We found that LDLR overexpression in young PDAPP mice markedly decreases apoE and decreases amyloid beta deposition in aged PDAPP mice.”1 They found, moreover, that LDLR overexpression significantly increased the appearance rate of endogenously produced human amyloid beta from brain to blood, suggesting, the authors stated, that this is a mechanism whereby LDLR regulates brain amyloid beta accumulation by eliminating it from brain to blood.
The researchers say, in their final paragraph, that LDLR has very few identified ligands for modulating the expression of LDLR and that affords an opportunity for discovery to identify innovative avenues for Alzheimer’s disease prevention and treatment.
Natural Products That Upregulate LDLR in the Periphery
Some natural products are known to upregulate LDLR in the periphery, thus acting as a mechanism to remove cholesterol from the circulation. That includes a green tea catechin extract that upregulates the LDLR in the rat liver,2 Mulberry extracts that were shown to exhibit a hypolipidemic effect on liver cells,3 and the medicinal plant goldenseal that is a natural LDL-lowering agent.4 However, whether these peripheral forms of LDLR would also have an effect in the brain of removing amyloid beta was not discussed in these papers.
In setting the scene for the important health information that follows, please note: If you have recently entered a box looking like a weird telephone booth (but not a Tardis) and ended up with your head on a fly’s body (or, worse yet, your body with a fly’s head), the following health information may apply to you. On the other hand, even if you haven’t done anything remotely like this (and we certainly hope you haven’t), it still might apply to you. This silly introduction is just for fun, but the research is real.Note: If you have not seen the movie The Fly, skip the introductory paragraph below.
A new paper1 in the December 26, 2012 Proceedings of the National Academy of Sciences USA reports that intestinal barrier dysfunction links metabolic and inflammatory markers to aging in Drosophila (“the fly”). Most remarkably, however, the paper provides evidence that “[r]egardless of chronological age, intestinal barrier dysfunction predicts impending death in individual flies.” “Thus, intestinal barrier dysfunction appears to be a better predictor of this marker of aging [increased expression of antimicrobial peptides, AMP] than chronological age.” Elie Metchnikoff, a very early investigator of the causes of aging, thought that intestinal health was an important factor in aging and recommended yogurt consumption.2
The researchers reported in an earlier paper of theirs that the loss of intestinal barrier function could be detected by the presence of a nonabsorbable blue food dye (FD&C blue dye no. 1) outside of the intestinal tract. As they1 report, “[b]oth male and female flies showed a significant age-dependent increase in the number of flies exhibiting blue dye throughout the body after feeding.” The researchers named these blue flies Smurfs. Although the blue dye itself had no effect on mortality, “all flies in the population exhibited the Smurf phenotype before death.”1 The presence of the blue dye throughout the body (indicating loss of intestinal barrier function) was found to be a predictor of age-onset mortality.
The authors found intestinal barrier dysfunction in Drosophila to be linked to a variety of markers of aging, including systemic metabolic dysfunction, increased expression of immunity-related genes, and reduced spontaneous physical activity.1
The “revenge” of the fly, mentioned above, would be manifest if the blue dye experiments were replicated in humans with similar results. In the meantime, the authors report that several age-related changes take place in the intestinal epithelium of rodents, including barrier dysfunction. Defects in intestinal barrier function have been associated in humans with intestinal or extraintestinal inflammatory disorders, multiple sclerosis, chronic heart failure, cancer, and Parkinson’s disease, as well as being a common event in critically ill patients.1 In a recent paper,3 researchers noted that increased intestinal permeability allowing the abnormal passage of substances from inside the intestines to enter the general circulation may be responsible for food allergies and even metabolic syndrome.
The researchers suggest that, on the basis of prior research, a key structure in maintaining the intestinal barrier is the tight junction lining the gut. In what the authors term a “leaky gut” dietary AGEs (advanced glycation endproducts) can enter the general circulation, where they induce inflammation3 and, hence, may contribute to diseases such as diabetes and cardiovascular disease. These authors suggest supplementation with the amino acid glutamine, which is an important nutrient for preventing increased intestinal permeability (four papers are cited in support), and possibly curcumin because of its effects in reducing colonic inflammation and experimental colitis in animal models.
Interestingly, “intestines from aged flies contain higher counts of indigenous bacteria than their younger counterparts and this has been reported to influence epithelium renewal during aging.”1
A very recent decision by a three-judge panel of the Court of Appeals for the DC District (Jan. 25, 2013) found that an order of the NLRB (Nat’l Labor Relations Board) was void because the Board did not have a quorum. This may sound like a minor matter, but in fact was a very important ruling on how Presidents can avoid getting the advice and consent of the Senate when making appointments by using a Constitutional alternative called Recess Appointments. The painstakingly argued decision of the Court revolved around whether the appointment of three new NLRB Board members conformed to Constitutional requirements for Recess appointments and, hence, did not need to get Senate approval. The Court ruled that these appointments were unconstitutional for convincing reasons we describe below and, hence, the NLRB order that was the proximate reason for the lawsuit was void. The NLRB was ruled not to have a quorum and, hence, had no authority to issue an order.
As you ought to know by now if you have been paying attention, Constitutional limits on government powers have been failing to limit government actions and much of the blame is the failure of courts to enforce these limits. The Constitutional design for the “checks and balances” to prevent usurpation by one branch of the powers delegated by the Constitution to another branch is in its provisions establishing the separation of powers. The requirement that Presidents get the advice and consent of the Senate to make appointments (to high level policymakers at regulatory agencies and cabinet secretaries, for example) is one of these checks and balances. The Constitution does provide for when the Senate is out of session (“The Recess”) and, hence, cannot provide advice and consent, that an appointment can be made unilaterally by the President.
The requirements for making these Recess appointments are spelled out in the Constitution. The Judges followed the Constitutional wording in great detail to show that the recent appointment of three members of the NLRB Board were not made between sessions of the Senate but within a session that was in a short break in Senate business during that session. The Constitutional language as cited in the court decision is very clear on this matter. As the court noted, “[t]he Framers emphasized that the recess appointment served only as a stopgap for times when the Senate was unable to provide advice and consent.” The court further explained that when the Constitution was written, senators did not have the luxury of catching the next flight to Washington so as to be available for considering appointments. Hence, “the Framers established the ‘auxiliary’ method of recess appointments. But they put strict limits on this method, requiring that the relevant vacancies happen during ‘The Recess.’”
The court continued, “[i]t would have made little sense to extend this ‘auxiliary’ method to any intrasession break, for the ‘auxiliary’ ability to make recess appointments could easily swallow the ‘general’ route of advice and consent. The President could simply wait until the Senate took an intrasession break to make appointments, and thus ‘advice and consent’ would hardly restrain his appointment choices at all.” Moreover, the court noted, in the case of Freytag v. Commissioner of Internal Revenue (501 U.S. 868, 883 (1991)), the court had explained that “[t]he manipulation of official appointments had long been one of the American revolutionary generation’s greatest grievances against executive power, because the power of appointment to offices was deemed the most insidious and powerful weapon of eighteenth century despotism.”
In arguing against an attorney general’s support for the use of a vague definition for the length of time required to be necessary for a “Recess” in an earlier case, the court noted that the Supreme Court has observed, “when interpreting ‘major features’ of the Constitution’s separation of powers, we must ‘establish high walls and clear distinctions because low walls and vague distinctions will not be judicially defensible in the heat of interbranch conflict.”
A final argument (we haven’t discussed them all) for a possible interpretation of “The Recess” as advocated by the government’s Office of Legal Counsel in this case, is that the President should have discretion to determine that the Senate is in recess. To which the court replied in part, “This will not do. Allowing the President to define the scope of his own appointments power would eviscerate the Constitution’s separation of powers.” We keep wondering when Chevron deference whereby courts simply accept without investigation the findings of regulatory agencies on the basis of their supposed superior technical knowledge, will be thrown out on the basis that there is no Constitutional authorization for freedom from court review of purported facts when you are accused of crimes and may be subject to a prison sentence. Deference is just another word for lazy. Courts don’t have to bother protecting the public from the lies of regulatory agencies if they just “defer.” But, back to the decision:
And finally the court concludes as to whether the Board had a quorum: “Because the Board lacked a quorum of three members when it issued its decision in this case on February 8, 2012, its decision must be vacated.” Most importantly, the court resets the standard for Presidential appointments back to the Constitutional one.
The decision was 46 pages long and argued very convincingly, in our view, in great detail with extensive consideration of the Constitutional language. It is about time some of the limits on Federal power are enforced.
THE AFTERMATH: NLRB RESPONDS TO THE DECISION
The NLRB requested an en banc hearing before the entire DC Circuit Court of Appeals and was turned down.
The NLRB has issued a statement concerning the above decision (see The Wall Street Journal editorial section, Jan. 29, 2013) that is consistent with the criminality running amok in the current Administration. The Board has declared, the WSJ reports, that “it doesn’t like the D.C. Circuit Court of Appeals Friday ruling that three board members were illegally appointed so it plans to ignore it.” (this is how their response is described by the Journal) The Board’s Chairman Mark Pearce is quoted as saying: The Board respectfully disagrees with today’s decision and believes that the President’s position in the matter will ultimately be upheld.” Moreover, he notes, “It should be noted that this order applies to only one specific case, Noel Canning, and that similar questions have been raised in more than a dozen cases pending in other courts of appeals. “In the meantime, the Board has important work to do. The parties who come to us seek and expect careful consideration and resolution of their cases, and for that reason, we will continue to perform our statutory duties and issue decisions.” Clearly, the NLRB plans to continue doing business as usual, as if nothing had happened, as if the Constitution doesn’t apply to them.* In fact, there are some 200 rulings issued by the NLRB, according to the WSJ, that took place during this period in which there was no quorum and, hence, no authority to issue orders. How can anybody still believe that we have a rule of law in this country? Or is the Administration counting on a lot of people who don’t give a damn as long as they get their government handout? This is a scary situation, folks.
* One of the lawyers that represented the FDA in the landmark case of Pearson v. Shalala was actually heard to say that he didn’t think the First Amendment applied to the FDA!
We applaud Tina Turner, thirty-year resident of Switzerland (but forced to continue paying U.S. income taxes despite that) for her courageous action in giving up her American citizenship. The Land of the Free and the Home of the Brave is one of the very few countries that continues to tax citizens that live and work outside of their borders. In fact, many countries have extradiction treaties so that the IRS can have you forcibly returned to the U.S. and imprisoned if you don’t keep paying despite not living in the U.S.
The opinions expressed in the editorial sections of this newsletter are those of Durk Pearson and Sandy Shaw and do not necessarily represent the views of Life Enhancement Products, its owners, officers, and its employees.
The Germans sent auditors to the Federal Reserve of New York City in 2007 and again in 2011 and were refused the right to examine, let alone audit, their own gold. In 2011 they were allowed a glimpse of some gold and to weigh a few bars, but that was all. According to the latest deal with the Fed, Germany will be able to get their gold in 7 years (!).If the U.S. wanted another war with Germany (or, at least to risk retaliatory seizures of U.S. property in Germany) they are doing the “right” things to get it. The news as of this morning (Feb. 1, 2013) is that the Germans are becoming downright belligerent in demanding the return of their gold, about half of which is stored in the U.S. Federal Reserve building in New York, after earlier attempts to repatriate their gold—or even to see it—from the U.S. failed. The German Central Bank is required to count and weigh the gold it owns every year, but the German gold reserves kept in the U.S. have not been weighed or counted once in three decades.
If this sounds ominous, it also suggests that an audit should be immediately conducted of the U.S.’s store of gold supposedly under the Federal Reserve’s control.
The news has gotten around and stimulated similar demands. The Dutch, for example, have asked for an audit and full transparency. A question of concern is why it would take 7 years for Germany to get its gold. Keith Barron, a geologist and consultant responsible for one of the largest gold discoveries in 25 years, has been quoted in King World News: “I believe that most of the Western world’s gold, which is supposed to be in central bank vaults, has been leased out. Much of it is now in private hands in India, and what remains continues going East to China and other Asian vaults. So most of the Western gold has vanished from the vaults and it’s now just a book entry … Obviously the trust is breaking down in the system.”
The story concluded with a warning that we may be seeing the start of a run by other nations on central-bank (importantly including the Federal Reserve) stored gold. (The pie graph in the story showed the U.S.’s central bank as storing about one third of the world’s store of gold.)
The story suggests that the price of gold may skyrocket in response to a panic stemming from fears over where one’s gold has gone and how to get it back. The morale of this story is to hold your gold in your physical possession, not stored in the dungeons (er, vaults) of central banks.
The above is from a report of LewRockwell.com (written by Peter Krauth, Feb. 1, 2013)
The Jan. 31, 2013 Wall Street Journal reports that the Federal Reserve has announced (after their first policy meeting of 2013) that they plan to continue purchasing $85 billion a month of mortgage-backed and Treasury securities. Meanwhile, the fourth quarter of 2012 showed the economy contracting by 0.1%, despite the massive amounts of Federal Reserve funny money flooding the economy.
“Many Fed officials want the two sides [Republicans and Democrats] to come up with a plan that reduces federal budget deficits over several decades [!!], without pulling back so fast that it crushes economic growth.” As if economic growth is doing fine with the federal budget deficit as it is … One can easily see that a “plan” to reduce the deficit over several decades is a way of ensuring that it will never happen.
The ultimatum game has become a highly studied model for human behavior that has been widely interpreted to mean that humans prefer “fairness” (roughly close to a 50:50 division of money between the two players), so much so that they are willing to forego some money if the division deviates from a roughly 50:50 split.*
* The ultimatum game is an economic game played by two players. The proposer has a sum of money (supplied by the researchers) which he/she can divide as he/she chooses into two shares, one he/she proposes to keep while the other share is offered to the second player, the responder. If the responder accepts the offer, they split the money as agreed. If the responder rejects the offer as too low (or “unfair”), neither the proposer nor responder get to keep any of the money.
Now, a new paper1 has appeared that comes to a different interpretation of the rejection of “unfair” offers that occur in the ultimatum game. The new interpretation involved running some other games with slightly different rules to see whether the results are consistent with the view that the ultimatum game supports a strong reciprocity model of cooperation where individuals punish noncooperators (those who keep an “unfairly” large share of the money for themselves), even though it means giving up the share offered to them (less than 50% of the divided sum of money).
As the authors explain, “a strong reciprocator is defined as an individual who is willing to ‘sacrifice resources for rewarding fair and punishing unfair behavior EVEN IF THIS IS COSTLY [TO THEM] AND PROVIDES NEITHER PRESENT NOR FUTURE MATERIAL REWARDS FOR THE RECIPROCATOR.” “In other words, strong reciprocators reciprocate both positively AND negatively — positive reciprocity promotes cooperation, and negative reciprocity stabilizes it.”1 “The rejection of unfair offers that is frequently observed in UG [ultimatum game] experiments has been regarded as evidence of strong reciprocity that is driven by a preference for reciprocal fairness and inequity aversion on the part of the responder.”1
The researchers tested this hypothesis by comparing the results of the UG to other social preference games. For example, the impunity game is similar to the UG, but a responder who rejects an offer as “unfair” gets to keep no part of the offered split (eg., the responder gets $0 if he/she rejects the offer as unfair, same as in the UG) but the proposer gets to keep the entire amount of money he proposed as his/her share. The decision of the responder has no effect on how much money the proposer gets, unlike in the UG, where the rejection of the offer as unfair by the responder means that neither the responder nor the proposer get anything. Yet, responders in the impunity game still rejected 30–40% of the “unfair” offers (about half of the responders reject offers in which they would receive less than 30% of the total sum). This is not consistent with the usual interpretation that the rejection of “unfair” offers represents a form of negative reciprocity, since rejection of the “unfair” offer does not “punish” the proposer who makes the “unfair” offer. The responder loses by rejecting a possible share of the divided money but gets no reward by punishing the proposer.
Instead, the researchers propose that the rejection of unfair offers in the ultimatum game is the responder’s way of rejecting the imposition of an inferior status or a “wounded pride hypothesis” as it has been described in an earlier paper.
We note that the proposed interpretation may or may not be the correct one, but there can be no doubt that the widely held belief that the rejection of “unfair” offers represents a form of strong reciprocity cannot be correct.
Perhaps what is needed is a game designed to test whether the rejection of “unfair” offers represents a negative emotional response to reduced status. How about a game with the same rules as the ultimatum game and when the offer is accepted, both parties get their agreed upon split, but the proposer has to pay a “tax” of 15% to a third party, while the responder has to pay a “tax” of 5% to that third party. The offer began as a “fair” offer (since it was accepted by both proposer and responder), but does it remain “fair” with the split altered by the imposed (and unequal) taxes? Could a new rule of the game be added to allow the proposer and responder an option to “punish” the tax collector that would restore “fairness” to the arrangement?