October 2006 Blog with Durk and Sandy

SPECIAL REPORT ON CLIMATE CHANGE

Climate Change Keeps . . . uh . . . Changing

 
— Headline, news article in Nature, June 29, 2006

Well, not quite. This article reports on the conclusions of a National Academy of Sciences committee asked to evaluate the Michael Mann hockey-stick graph, which appears to show that the twentieth century is the warmest in the last 1000 years and which was relied upon in the last IPCC climate report. As noted in paragraph four of the article, “‘[W]e roughly agree with the substance of their [Michael Mann and coworkers] findings,’ says Gerald North, the committee’s chair and a climate scientist at Texas A&M University in College Station. In particular, he says, the committee has a ‘high level of confidence’ that the second half of the twentieth century was warmer than any other period in the past four centuries. But, he adds, claims for the earlier period covered by the study, from A.D. 900 to 1600, are less certain. This earlier period is particularly important because global-warming skeptics claim that the current warming trend is a rebound from a ‘little ice age’ around 1600.” The article states that the committee felt that the conclusions concerning the pre-1600 period had only a two-to-one chance of being correct. We seriously doubt that two-to-one guesstimate. New data demonstrate that the Michael Mann hockey-stick graph misses a lot, including the medieval warm period and the little ice age.

A report commissioned by the House Energy Committee on the Michael Mann hockey-stick-graph model of climate change was released on July 14, 2006. The report was prepared by three statisticians (not climatologists), Edward J. Wegman of George Mason University, David W. Scott of Rice University, and Yasmin H. Said of Johns Hopkins University, to evaluate the statistical methods used in the Mann papers. They concluded that the papers were plagued by basic statistical errors that call the conclusions into doubt. Moreover, Mr. Wegman, using a technique called social network analysis, concluded that the most frequently published climatologists form such a close-knit group that there was no likely effective independent review of Mr. Mann’s work. As Wegman said, “There is a tightly knit group of individuals who passionately believe in their thesis. However, our perception is that this group has a self-reinforcing feedback mechanism and, moreover, the work has been sufficiently politicized that they can hardly reassess their public positions without losing credibility.” This paragraph was taken from an editorial in The Wall Street Journal, July 14, 2006.

The Little Ice Age

A new paper¹ on “Solar modulation of Little Ice Age climate in the tropical Andes” shows that the Little Ice Age was, in fact, a global event (that is, it didn’t take place only in Europe) by demonstrating that there were four glacial advances between A.D. 1250 and 1810 in the Venezuelan Andes, coincident with solar-activity minima. As the authors say, “[t]he data presented here suggest that solar activity has exerted a strong influence on century-scale tropical climate variability during the late Holocene, modulating both precipitation and temperature.” The Mann hockey-stick graph did not show a Little Ice Age.

Medieval Warm Period

Another very recent paper² now reports strong evidence on the effects in North America of the Medieval Warm Period, 800 to 1000 years before the present (the Medieval Warm Period does not appear in the Mann hockey-stick graph either). This paper describes the MWP (Medieval Warm Period) as “a time of warmth and aridity throughout much of the western United States; this suggests that the [wind] circulation change indicated by [sand] dune morphology is part of a larger climate anomaly.”

Global climate models predict increase in snowfall in Antarctica due to warming: but snowfall hasn’t changed in 50 years

“Future scenarios from global climate models (GCMs) suggest that Antarctic snowfall should increase in a warming climate, mainly due to the greater moisture-holding capacity of warmer air, partially offsetting enhanced loss at the ice sheet peripheries.”³

A new paper reports on a 50-year time series of snowfall accumulation over Antarctica by combining model simulations and observations primarily from ice cores.³ They find that “[t]here has been no statistically significant change in snowfall since the 1950s. … If anything, our 50-year perspective suggests that Antarctic snowfall has slightly decreased during the past decade, while global mean temperatures have been warmer than at any time during the modern instrumental record.” They conclude, “Our results indicate that there is not a statistically significant global warming signal of increasing precipitation over Antarctica since the IGY [International Geophysical Year, 1957–58], inferring that GSL [global sea level] rise has not been mitigated by recently increased Antarctic snowfall as expected. It may be necessary to revisit GCM [global climate models] assessments that show increased precipitation over Antarctica by the end of this century in conjunction with projected warming.” [Emphasis added] A hypothesized increase in precipitation had been put forth heretofore to “explain” why the ice sheets in most of Antarctica are thickening, while in other areas (particularly the western ice sheet), ice is thinning.

As we have noted before, global climate is very far from understood and very far from wrapped up by a scientific “consensus.” We object, not to facts developed by scientific investigation, but to an alleged foregone conclusion (to which everybody except a few “skeptics” supposedly agrees) that a disaster of human* design is in the making andthat governments are capable of “fixing” it. There is no scientific consensus, nor is there even an attempt to find a “consensus” among economists that governments can regulate the use of the atmosphere so that benefits outweigh costs.

References

1. Polissar et al. Solar modulation of Little Ice Age climate in the tropical Andes. Proc Natl Acad Sci USA 103(24):8937-42 (2006).
2. Sridhar et al. Large wind shift on the Great Plains during the Medieval Warm Period. Science 313:345-7 (2006).
3. Monaghan et al. Insignificant change in Antarctic snowfall since the International Geophysical Year. Science 313:827-31 (2006).

 

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*Have you noticed that whenever you see the word “anthropogenic” (meaning human-caused), it is used to damn the human race? Have you ever seen “anthropogenic” used in relation to any positive benefit of the works of humans?

 

Blueberry Polyphenols Increase Lifespan and Thermotolerance in C. elegans

In this new study,¹ the authors report further beneficial effects for blueberry polyphenols, including extended lifespan. While adult wild-type C. elegans grown under the authors’ standard lab conditions had a mean lifespan of 12.7 days, with an average maximum lifespan of 19.7 days, on media containing either crude blueberry extract or their bulk polyphenols, the mean lifespan of wild-type animals was increased by 28%, and the maximum lifespan increased by 14%. The blueberry extract or polyphenols slowed aging by, for example, decreasing the accumulation of intracellular lipofuscin (reduced by 20% in treated animals) and reducing the production of 4-hydroxynonenal, a lipid peroxide breakdown product.

This study is particularly interesting because the researchers examined the effects of three different fractions of the blueberry polyphenols: one enriched in anthocyanins, one in proanthocyanidins, and the other in hydroxycinnamic esters (mainly chlorogenic acid). The only one of the three fractions that affected lifespan was the one enriched in proanthocyanidins; treatment with the proanthocyanidin-enriched fraction increased lifespan to a similar extent as the starting blueberry polyphenol mixture. Oddly, although the blueberry polyphenols increased thermotolerance in the treated C. elegans,blueberry treatment was not consistently associated with greater HSP (heat-shock protein) mRNA induction following heat shock, as compared with untreated controls.

More about proanthocyanidins

Proanthocyanidins, better known as condensed tannins, are found in many foods, such as tea, grapes, cherries, strawberry, cinnamon, red wine, and cocoa.^2,3 They are mixtures of oligomers (a few monomers polymerized together) and polymers composed of flavan-3-ol units linked together in various ways. The proanthocyanidins consisting exclusively of polymers of (epi)catechin units are designated as procyanidins. Interestingly, proanthocyanidins appear to be degraded during drying; whereas plums and grapes contain them, they are no longer detectable in prunes and raisins. Vegetables are not an important source of proanthocyanidins. However, most nuts (e.g., almonds, pistachios, pecans) contain them, and they are also found in beer (from hops⁴).

References

1. Wilson et al. Blueberry polyphenols increase lifespan and thermotolerance in Caenorhabditis elegans. Aging Cell 5:59-68 (2006).
2. Gu et al. Screening of foods containing proanthocyanidins and their structural characterization using LC-MS/MS and thiolytic degradation. J Agric Food Chem51:7513-21 (2003).
3. Santos-Buelga and Scalbert. Proanthocyanidins and tannin-like compounds—nature, occurrence, dietary intake, and effects on nutrition and health. J Sci Food Agric 80:1094-117 (2000).
4. Li and Deinzer. Structural identification and distribution of proanthocyanidins in 13 different hops. J Agric Food Chem 54:4048-56 (2006).

 

Beneficial Effects of the Laminar Shear Stress Response Mimicked by Procyanidin-Rich Grape Seed Extract and Hawthorn

As mentioned in the article above, procyanidins are proanthocyanidins consisting exclusively of (epi)catechin oligomers. Grape-seed extract and hawthorn (a medicinal herb) are high in procyanidin content. In a recent paper,¹ researchers tested the inhibitory effects of these substances on endothelin-1 (a powerful vasoconstrictor) synthesis in cultured endothelial cells. Both were equally potent as suppressors of endothelin-1 synthesis. Grape-seed extract was also shown to suppress endothelin-1 while, at the same time, inducing endothelium-dependent vasodilation; this dual effect is similar to the important beneficial response triggered by laminar shear-stress blood flow. The authors identified procyanidins as the vasoactive components in both hawthorn (used in the treatment of heart failure, including double-blind, placebo-controlled human trials) and grape-seed extract.

Heart failure (HF) is a growing problem; for one thing, large numbers of people are now surviving heart attacks and then having to deal with the resulting heart damage that, for instance, increases the risk of developing heart failure. Moreover, treatment of HF has not significantly improved survival of patients in the past thirty years. Although endothelial dysfunction is often portrayed as a simple matter of decreased nitric oxide production and release, there are other changes taking place, including, importantly, an increased vasoconstriction due to excess endothelin-1 synthesis.¹ The researchers note that endothelin-receptor antagonists initially showed promise in HF patients, but later studies proved disappointing, probably due to the inability of endothelin antagonists to correct other components of endothelial dysfunction. Although arginine supplementation can improve endothelial function by increasing nitric oxide output, we have not seen any publications on arginine reversing endothelin-1 overproduction.

Laminar shear stress (LSS) is the frictional force exerted on the endothelial cells lining blood vessels by the flow of blood passing by but moving slowly enough that it doesn’t break up into chaotic, turbulent flow. (Blood flow speeds up when blood vessels are reduced in diameter, as happens in atherosclerosis and when blood passes a blood-vessel bifurcation point.) “Reduced LSS is likely to be a key factor underlying this change [loss of endothelial function with age], precipitated by abnormalities in cardiac function and sedentary lifestyles. … In patients with HF, the beneficial effects of regular exercise may well be due to the increasing LSS occurring during exercise.”

The researchers noted that procyanidins have effects similar to the response evoked by LSS: “Thus aortic rings suspended in organ baths release NO in the absence of LSS, and synthesis of endothelin-1 by cultured endothelial cells is inhibited, two well-described responses to LSS. Moreover, treatment of endothelial cells with a procyanidin-rich red wine extract produces morphological changes with reorganization of the cytoskeleton. This results in a pattern of phosphotyrosine staining and colocalization with F-actin which is indistinguishable from that induced by LSS. Based on these observations, we hypothesize that oligomeric procyanidins act as phytochemical inducers of the LSS response, and it is this property that helps reverse the vascular dysfunction in HF.”

The researchers also note that “the endothelium-dependent vasodilation induced by procyanidins has a clear structure-activity relationship that is optimal with oligomeric procyanidins (particularly epicatechin trimers, tetramers and pentamers), but not mimicked by epicatechin monomers or dimers and, therefore, unrelated to antioxidant properties. Inhibition of endothelin-1 synthesis exhibits a similar sensitivity.”

Reference

1. Corder et al. The procyanidin-induced pseudo laminar shear stress response: a new concept for the reversal of endothelial dysfunction. Clin Sci 107:513-7 (2004). See also Corder et al. Endothelin-1 synthesis reduced by red wine. Nature 414:863-4 (2001).

 

Farmed Atlantic Salmon Highly Enriched in EPA and DHA

An examination of the fatty acid composition of visceral oil from farmed Atlantic salmon¹by researchers in the Department of Food Science of Louisiana State University Agricultural Center in Baton Rouge, Louisiana, shows that their samples of farmed Atlantic salmon contained 1.64 g EPA and 1.47 g DHA per 100 g tissue. They cite another study,^1a in which the researchers found 0.32 g/100 g tissue of EPA and 0.51 g/100 g tissue of DHA in farmed Atlantic salmon, and 0.24 g EPA/100 g tissue and 0.63 g DHA in viscera of wild Atlantic salmon. Herring, as measured by a different group,^1bcontained 0.71 g EPA/100 g tissue and 0.86 g DHA/100 g tissue.

According to the paper,¹ fish have been classified into four groups on the basis of their lipid content: lean (<2% fat, such as cod, haddock, and pollack); low (2–4% fat, such as sole, halibut, and redfish); medium (4–8%, such as most wild salmon); and high (8–20%, such as herring, mackerel, and many farmed salmon). “Farmed salmon are among the fattiest fish. The lipid concentration of viscera is significantly greater than that in fillet, whereas the moisture concentration of viscera is significantly less than that in its fillet.”

References

1. Sun et al. FA composition of the oil extracted from farmed Atlantic salmon (Salmo salar L.) viscera. JAOCS 83(7):615-9 (2006). 
   
   1a. Polvi SM. Diet and Availability of Omega-3 Fatty Acids in Salmonids. Master’s thesis, Technical University of Nova Scotia, Halifax, 1989. 
   
   1b. Exler. Composition of Foods: Finfish and Shellfish Products: Raw, Processed, Prepared. U.S. Department of Agriculture, Human Nutrition Information Service, Washington, DC, 1987.

 

C-Reactive Protein May Induce Leptin Resistance

The hormone leptin, secreted by adipocytes (fat cells), has numerous effects, including, among others, immune system regulation, regulation of the reproductive system, and acting as a nutrient signal in the hypothalamus that helps regulate food intake. In normal-weight individuals, increases in leptin signaling decrease food intake. In leptin-deficient animals and humans, treatment with leptin has a profound normalizing effect upon food intake and weight. Obese humans, however, have increased levels of leptin rather than leptin deficiency, and leptin treatment has proven ineffective in decreasing food intake and, hence, body weight. This “leptin resistance” has been extensively studied to determine how obesity decreases the effects of leptin signaling.

Authors of a very recent paper¹ propose that leptin resistance may be “partially attributed to interactions between leptin and plasma circulating factors.” They suggest that such factors might bind leptin to affect its transport or otherwise inhibit its effects. They note that “elevation of the protein suppressor of cytokine signaling-3 (SOCS-3), which is induced by leptin, might diminish the actions of leptin in the central nervous system.”

They now identify C-reactive protein (CRP), a marker of inflammation found in the bloodstream and a risk factor for cardiovascular disease, as a blood-borne substance that not only “binds to plasma leptin but also impairs leptin signaling and attenuates its: physiological effects in vivo.” Moreover, they report, “leptin directly stimulates expression of CRP in human primary hepatocytes [liver cells] in vitro.” In their experiments, the researchers found that the concentration of human CRP and rat CRP required to block one of leptin’s effects (phosphorylation of STAT3) were within the ranges observed in rat and human plasma. They also found that human CRP inhibited human leptin signaling in the leptin-triggered JAK-STAT and PI3K pathways in rat primary hypothalamic neurons. In the ob/ob (genetically obese) mouse studies, human leptin produced the expected reduction in food intake and body weight. However, when coadministered with human CRP, the result was a partially attenuated effect of leptin (at low CRP dose) or a completely blocked leptin effect (at high CRP dose). CRP alone had no effect on food intake or body weight.

Chronically elevated CRP (a state of chronic inflammation) has also been found to be positively correlated with adiposity (as well as with leptin levels).¹ The authors suggest that, because human CRP forms a doughnut-shaped pentameric structure, its binding to leptin may interfere with leptin’s passing through the blood-brain barrier to reach the medial hypothalamus, one of the features of leptin resistance.

For obese individuals, then, reduction of CRP is an important target. This is also very important for those at risk of heart attack. A recent paper² suggests that the damage due to a heart attack can be reduced by quickly suppressing CRP levels with a CRP inhibitor. As a commentary on the paper notes,³ “CRP levels increase dramatically in patients with myocardial infarction, beginning 6 hours after the onset of ischemia and peaking at approximately 50 hours. CRP values after acute myocardial infarction predict outcome, including death and heart failure.”

VITAMINS It has been reported elsewhere⁴ that, “in a post hoc analysis of a randomized, double-blind, placebo-controlled study, multivitamin use was associated with lower C-reactive protein levels.” The multivitamin used was an ordinary, commercially available, 24-ingredient vitamin and mineral formulation. “After the intervention, the prevalence of a C-reactive protein level >3.0 mg/L decreased to 14% in the multivitamin group but increased to 32% in the placebo group (P<0.05 for difference at 6 months).” Niacin also reduces C-reactive protein levels.⁹

FIBER Another study⁵ reported that, in an examination of the association between dietary fiber and serum CRP using data from the National Health and Nutrition Examination Survey 1999–2000, it was found that “fiber intake is independently associated with serum CRP concentration and support the recommendations of a diet with a high fiber content.”

ARGININE A further study⁶ reported, after analyzing the Third National Health Nutrition and Examination Survey 1988–1994, that “the likelihood of having a high level of CRP (>3.0 mg/L), from the lowest to the highest level of arginine intake, were 34.8%, 31.0%, 27.7%, and 18.4%, respectively. In the adjusted regression, subjects in the highest level (90th percentile) of arginine intake were 30% less likely to have a CRP above 3.0 mg/L than were subjects with a median arginine intake (odds ratio = 0.70, 95% confidence interval = 0.56 to 0.88).”

HORMONE REPLACEMENT It has been reported that female hormone replacement with Premarin^® conjugated horse estrogens increases levels of CRP.⁷ It is not clear, however, whether other types of hormone replacement (such as bioidentical human estrogen replacement) would have the same effect. Moreover, it appears that beginning hormone replacement shortly after menopause results in cardioprotective effects, while hormone replacement begun many years after menopause may not be protective or may actually be detrimental.

OTHER Life Extension magazine (March 2001) suggests that C-reactive protein may be suppressed by taking aspirin, vitamin E, DHEA, nettle leaf, and fish oils. Sleep loss has also been reported to increase CRP levels.⁸ Statins, weight loss, and exercise reduce CRP levels.⁹

References

1. Chen et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nature Med 12(4):425-32 (2006).
2. Pepys et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 440:1217-21 (2006).
3. Kitsis and Jialal. Limiting myocardial damage during acute myocardial infarction by inhibiting C-reactive protein. New Engl J Med 355:513-5 (2006).
4. Church et al. Reduction of C-reactive protein levels through use of a multivitamin. Am J Med 115:702-7 (2003).
5. Ajani at al. Dietary fiber and C-reactive protein: findings from National Health and Nutrition Examination Survey data. J Nutr 134:1181-5 (2004).
6. Wells et al. Association between dietary arginine and C-reactive protein. Nutrition21:125-30 (2005).
7. van Baal et al. Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women. Thromb Haemost81:925-8 (1999).
8. Meier-Ewert et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol 43(4):678-83 (2004).
9. Backes et al. Role of C-reactive protein in cardiovascular disease. Ann Pharmacother 38(1):110-8 (2004).

 

Testosterone Inhibits Early Atherogenesis in Male Mice:
Critical Role of Testosterone Conversion to Estradiol

To assess the effects of testosterone on the risk of developing atherosclerosis, male mice lacking the LDLR (LDL receptor) and fed a high-cholesterol diet, a model of human atherosclerosis, were studied.¹

The researchers found that fatty-streak-lesion formation (an early stage of atherosclerosis) in the aorta was greater in castrated animals than in animals with intact testes or in castrated animals that were supplemented with testosterone. These results were similar to earlier work by others with castrated, cholesterol-fed rabbits.

The particularly interesting part of the study was the determination of whether it was testosterone itself that produced the antiatherogenic effect or whether it was the conversion of testosterone to estradiol by the aromatase enzyme that was responsible. Aromatase has been shown to be present in endothelial cells and vascular smooth muscle cells, as well as other tissues. Thus, local conversion of testosterone to estradiol can take place in blood vessels. The results showed that in the testis-intact animals given an aromatase inhibitor, there was a greater extent of early lesion formation than in the testis-intact animals receiving only vehicle. They also found that the castrated mice supplemented with testosterone and simultaneously given an aromatase inhibitor had significantly increased lesion formation compared to the castrated mice given testosterone alone. Thus, the conversion of testosterone to estradiol was required for the atheroprotective effect of testosterone.

In a later study of testosterone and diet-induced atherosclerosis in mice² expressing or not expressing CETP [cholesteryl ester transfer protein (important for the export of cholesterol from cells)], the researchers found that castration resulted in 1.7-fold higher levels of antioxidized LDL antibodies than sham-operated (operated upon but not actually castrated). Diet-induced atherosclerosis studies showed that testosterone deficiency increased by 100%, and CETP expression reduced by 44%, the size of aortic lesion area in castrated mice. The authors stated that “[a]romatization of testosterone into 17beta-estradiol seems to be an important determinant of the beneficial effects of androgens observed in men and mice.”

It is also relevant to know that many polyphenols inhibit aromatase. One study³ reported that aromatase was inhibited in cultures of choriocarcinoma-derived JAR cells by chrysin (a flavone), naringenin (a flavanone), daidzein and genistein (isoflavones), kaempferol, myricetin, quercetin, and rutin (flavonols), catechin, epicatechin, and epigallocatechin-3-gallate (flavanols), and resveratrol (a stilbene). Chrysin, naringenin, and quercetin were the most potent polyphenols in inhibiting aromatase activity. In addition, red wine (but not white wine), green tea, and black tea also inhibited aromatase. These effects may contribute to the anticarcinogenic effects of these polyphenols and beverages in, for example, breast and prostate cancers. Another paper⁴ reported inhibition of aromatase activity by flavonoids, with apigenin (found in parsley, celery, and many other plants), chrysin, and hesperidin (found in grapefruit, especially the rind) having the greatest activity.

One advantage of the local conversion of testosterone to estradiol by aromatase in blood vessels is that it avoids the negative effects of systemic estrogen treatment in males. The moral of this story is that, unless required for treatment of a serious condition, such as cancer, men should probably not take powerful systemic aromatase inhibitors. We have seen no indication, however, of an increased cardiovascular risk in heavy tea drinkers or in moderate drinkers of red wine.

References

1. Nathan et al. Testosterone inhibits early atherogenesis by conversion to estradiol: critical role of aromatase. Proc Natl Acad Sci USA 98(6):3589-93 (2001).
2. Casquero et al. Atherosclerosis is enhanced by testosterone deficiency and attenuated by CETP expression in transgenic mice. J Lipid Res 47(7):1526-34 (2006).
3. Monteiro et al. Modulation of aromatase activity by diet polyphenolic compounds. J Agric Food Chem 54:3535-40 (2006).
4. Jeong et al. Inhibition of aromatase activity by flavonoids. Arch Pharm Res22(3):309-12 (1999).

Cognition-Enhancing Drugs May Work Exactly the Same in Rats as Environmental Enrichment

Three drugs that augment cholinergic function—tacrine (inhibits acetylcholinesterase), deprenyl (increases acetylcholine function indirectly via improved dopamine function), and nefiracetam (improves cholinergic function and increases neurite outgrowth)—as well as increasing NCAM PSA (neural cell adhesion molecule, polysialic acid expression), were tested in rats for mechanistic changes.¹ The bottom line: the researchers found that these drugs all “increase the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing.”

As the authors explain, “[w]ithin the hippocampus, a transient increase in polysialylation of neurons located at the dentate infragranular zone at 10–12 hours following learning is necessary for memory consolidation. … This neuroplastic mechanism is required for dendritic remodeling and is likely to be an important factor in the elaboration and integration of circuitry associated with the consolidation of novel behavioral repertoires. … Moreover, reduced requirement for neuroplastic activation, improved maze learning, and increased resilience against cholinergic deficits accompany the enhanced NCAM [neural cell adhesion molecule] PSA [polysialic acid] expression in the hippocampus following drug or environmental interventions.” [Citations deleted from quotes]

As a combination of treatments (drug + environmental enrichment) did not further increase basal polysialylated cell frequency, they probably work via the same mechanism(s). Thus, the authors conclude, “[t]hese findings suggest that improved memory-associated synaptic plasticity may be the fundamental mechanism underlying the disease-modifying action of drugs such as cholinesterase inhibitors.” (Galantamine, which we take, is a cholinesterase inhibitor that we would expect to function similarly to the cholinergic function-enhancing drugs tested in this study.)

The authors note that the frequency of the dentate polysialylated neurons declines markedly with age in both rodents and humans; hence the effects of a chronic, cholinergic function-enhancing drug or a complex environment “may relate to an attenuation in the decline of this cell population.”

Reference

1. Murphy et al. Chronic exposure of rats to cognition-enhancing drugs produces a neuroplastic response identical to that obtained by complex environment rearing. Neuropsychopharmacology 31:90-100 (2006).

Cognition-Enhancing Drugs May Work Exactly the Same in Rats as Environmental Enrichment

Three drugs that augment cholinergic function—tacrine (inhibits acetylcholinesterase), deprenyl (increases acetylcholine function indirectly via improved dopamine function), and nefiracetam (improves cholinergic function and increases neurite outgrowth)—as well as increasing NCAM PSA (neural cell adhesion molecule, polysialic acid expression), were tested in rats for mechanistic changes.¹ The bottom line: the researchers found that these drugs all “increase the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing.”

As the authors explain, “[w]ithin the hippocampus, a transient increase in polysialylation of neurons located at the dentate infragranular zone at 10–12 hours following learning is necessary for memory consolidation. … This neuroplastic mechanism is required for dendritic remodeling and is likely to be an important factor in the elaboration and integration of circuitry associated with the consolidation of novel behavioral repertoires. … Moreover, reduced requirement for neuroplastic activation, improved maze learning, and increased resilience against cholinergic deficits accompany the enhanced NCAM [neural cell adhesion molecule] PSA [polysialic acid] expression in the hippocampus following drug or environmental interventions.” [Citations deleted from quotes]

As a combination of treatments (drug + environmental enrichment) did not further increase basal polysialylated cell frequency, they probably work via the same mechanism(s). Thus, the authors conclude, “[t]hese findings suggest that improved memory-associated synaptic plasticity may be the fundamental mechanism underlying the disease-modifying action of drugs such as cholinesterase inhibitors.” (Galantamine, which we take, is a cholinesterase inhibitor that we would expect to function similarly to the cholinergic function-enhancing drugs tested in this study.)

The authors note that the frequency of the dentate polysialylated neurons declines markedly with age in both rodents and humans; hence the effects of a chronic, cholinergic function-enhancing drug or a complex environment “may relate to an attenuation in the decline of this cell population.”

Reference

1. Murphy et al. Chronic exposure of rats to cognition-enhancing drugs produces a neuroplastic response identical to that obtained by complex environment rearing. Neuropsychopharmacology 31:90-100 (2006).

Interleukin-1beta, a Mediator of Inflammation and Possibly Aging: Protection by Cholinesterase Inhibitors, EPA, and Pomegranate Fruit Extract

Increased expression of the proinflammatory cytokine IL-1beta (interleukin-1beta), as occurs in the aged brain, has been associated with neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease.¹ It has been reported that patients with an inherited defect in a certain gene (NALP3) are prone to secrete excess quantities of IL-1beta and IL-18 (another proinflammatory cytokine) and suffer from systemic inflammatory diseases. These patients have a high circulating concentration of proinflammatory factors, including IL-6, serum amyloid A, and C-reactive protein, each of which decreases rapidly upon blockade of the IL-1 receptor1. Elevated IL-6 levels in humans are correlated with increased mortality and reflect IL-1 activity in vivo.¹ IL-1 is released as an important part of the immune response to infection, but excessive or chronic release can cause damaging side effects. IL-lbeta also promotes angiogenesis, tumor growth, and metastasis. Moreover, “IL-1beta expression is increased, in parallel with cell damage, in experimental models of ischemia, excitotoxicity, and traumatic lesions.”³

A recent paper² reports that peripheral administration of the acetylcholinesterase inhibitors tacrine, rivastigmine, or neostigmine to mice significantly reduced the production of IL-1beta in the hippocampus and blood, along with the reduction of acetylcholinesterase activity. The authors suggest that this might be a mechanism whereby acetylcholinesterase inhibitors improve brain function; in particular, acetylcholine has been shown to inhibit the lipopolysaccharide (bacterial LPS)-induced production of proinflammatory cytokines in the brain, including IL-1, from macrophages and microglia. We have written before on how the benefit of increasing cholinergic function in the brain may also be mediated in the body by the acetylcholine anti-inflammatory pathway operating via the vagus nerve. On page 744 of this paper, the authors also refer to this mechanism: “[r]ecent studies show that in the periphery, cholinergic neurons of the efferent vagus nerve inhibit acute inflammation, providing a rapid, localized, and adaptive anti-inflammatory reflex system. Specifically, ACh [acetylcholine], which is secreted by the vagal efferents, inhibits LPS-induced secretion of tumor necrosis factor-alpha and IL-1beta by macrophages, as well as by microglia, through the alpha7 unit of the nicotinic receptor that is expressed by these cells.” It is interesting to note that the cholinesterase inhibitor galantamine also activates the alpha7 nicotinic receptors.

The cholinesterase inhibitors tested in this study included neostigmine, which does not cross the blood-brain barrier and, therefore, cannot have a direct effect on brain inflammatory activity. However, neostigmine completely blocked the production of IL-1beta in the hippocampus, “suggesting that the peripheral effect of cholinesterase inhibitors contributes to the prevention of IL-1beta overproduction within the brain.” [Emphasis added] These peripheral effects would provide protection to the whole body against damaging inflammation due to excess IL-1beta activity.

In addition to cholinesterase inhibitors, there are two other supplements that provide protection against the effects of IL-1beta that we’d like to mention here: eicosapentaenoic acid (EPA)³ (in rat brain) and pomegranate fruit extract⁴ (in human cartilage cells—chondrocytes—in vitro).

References

1. Dinarello. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am J Clin Nutr 83(Suppl):447S-455S (2006).
2. Pollak et al. Acetylcholinesterase inhibitors reduce brain and blood interleukin-1beta production. Ann Neurol 57:741-5 (2005).
3. Martin et al. Apoptotic changes in the aged brain are triggered by interleukin-1beta-induced activation of p38 and reversed by treatment with eicosapentaenoic acid. J Biol Chem 277(37):34239-46 (2002).
4. Ahmed et al. Punica granatum L. extract inhibits IL-1beta-induced expression of matrix metalloproteinases by inhibiting the activation of MAP kinases and NF-kappaB in human chondrocytes in vitro. Nutrition 135:2096-102 (2005). “Taken together, these novel results indicate that PFE [pomegranate fruit extract] or compounds derived from it may inhibit cartilage degradation in OA [osteoarthritis] and may also be a useful nutritive supplement for maintaining joint integrity and function.”

 

Changes in White Blood Cell Counts May Predict Increased Risk of Mortality in Older Women

Inflammation tends to increase with age and is associated with many pathological processes of aging. One marker of systemic inflammation is an increase in total white blood cell count. Of course, it is normal for white blood cells to increase in response to the inflammatory processes induced by infection. To evaluate the relationship of total white blood cell counts and differential counts with mortality in older adults, researchers conducted a study on 624 community-dwelling women aged 65–101 who were part of the Women’s Health and Aging Study cohort.¹ Those who had white blood cell counts above the normal range were excluded. The results showed that, after adjusting for age, race, body mass index, smoking, and education, those with baseline higher total white blood cell counts, higher neutrophil counts, or lower lymphocyte counts were independently associated with increased mortality. No significant associations of eosinophil, monocyte, or basophil counts with mortality were observed.

The authors note that data from a recent study of theirs from the Women’s Health and Aging Studies (WHAS) “have shown direct in vivo associations of total WBC [white blood cells] and specific differential counts with circulating IL-6 levels, the hallmark of the age-related inflammatory phenotype.” They also report that “[a] recent study of participants in the trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE), including young male and female patients (aged 21 years and above), has demonstrated that baseline total WBC as well as neutrophil counts are independent predictors of recurrent ischemic events and vascular death. Data of 105 healthy older men from the Baltimore Longitudinal Study of Aging (BLSA) have shown that there is a significantly lower lymphocyte count within 3 years of death when compared with 5 or 10 years before death.” [Citations omitted from quotes]

Reference

1. Leng et al. Baseline total and specific differential white blood cell counts and 5-year all-cause mortality in community-dwelling older women. Exp Gerontol40:982-7 (2005).