March 2006 Blog with Durk and Sandy

It does not take a majority to prevail … but rather an irate, tireless minority, keen on setting brushfires of freedom in the minds of men.— Samuel Adams, American revolutionary

No one, no government agency has jurisdiction over the truth.— Fox Mulder, The X-Files

In the end, more than they wanted freedom, they wanted security. When the Athenians finally wanted not to give to society, but for society to give to them, when the freedom they wished for was freedom from responsibility, then Athens ceased to be free.— Edward Gibbon

We borrowed the profit motive [of the West] but not the entrepreneurial spirit. We borrowed the acquisitive appetites of capitalism, but not the creative risk-taking. We are at home with Western gadgets but are bewildered by Western workshops. We wear the wristwatch but refuse to watch it for the culture of punctuality. We have learned to parade in display, but not to drill in discipline. The West’s consumption patterns have arrived, but not necessarily the West’s technique of production.— Ali A. Mazrui, State University of New York at Binghamton, 
on the economic problems of Africa

Pomegranate Juice Reduces Cholesterol Synthesis in Macrophages in Cell Culture

Statins are widely used to decrease cholesterol synthesis in humans by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which catalyzes the rate-limiting step in the synthesis of mevalonate, from which cholesterol is synthesized. However, mevalonate is also the starting material for the production of other important biological chemicals, including CoQ10 and selenoproteins, such as glutathione peroxidase. The decreased production of CoQ10 and selenoproteins^{1, 2, 2a}may be responsible for many side effects (potentially severe) of statin use. See more on this in the article that follows. In our view, the inhibition of the synthesis of mevalonate is a blunt instrument in the search for inhibitors of cholesterol synthesis and inhibits too many desirable products of mevalonate as an unwanted side effect.

That is one reason for our interest in pomegranate juice and other natural products that may decrease production of cholesterol without inhibiting HMG-CoA reductase. A recent paper³ reports that cholesterol biosynthesis by macrophages was inhibited by 50% after cell incubation with pomegranate juice. However, this inhibition did not take place at the HMG-CoA reductase level in the synthetic pathway. Thus, the synthesis of mevalonate was not itself inhibited, but the synthesis of cholesterol from mevalonate was. In an earlier study, the same authors report publishing a paper in which they demonstrated that “supplementation of pomegranate juice to atherosclerotic, apolipoprotein E-deficient mice, which already exhibit advanced atherosclerotic lesions, reduced macrophage lipid peroxides along with a reduction in macrophage cholesterol accumulation and foam cell formation.”

We hope that there will be follow-up on these findings, but it will all come to naught if the FDA (and FTC) can continue to prohibit the communication of truthful scientific information (including distributing peer-reviewed scientific papers) concerning dietary supplements and foods. (More on this in the FDA Update and Legislative Updatebelow.) In the meantime, we are drinking a reduced-sugar (8 grams per 8-ounce cup) pomegranate juice diluted with water to 25% juice (Langers), which makes for a very tasty drink.

References

1. Moosmann, Behl. Hypothesis: selenoprotein synthesis and side-effects of statins. Lancet 363:892-4 (2004).
2. Warner et al. Inhibition of selenoprotein synthesis by selenocysteine tRNA[Ser]Sec lacking isopentyladenosine. J Biol Chem 275:28110-9 (2000). 
   2a. Dale et al. Statins and cancer risk. JAMA 295:74-80 (2006).
3. Fuhrman et al. Pomegranate juice inhibits oxidized LDL uptake and cholesterol biosynthesis in macrophages. J Nutr Biochem 16:570-6 (2005).

Pomegranate Juice Inhibits Serum Angiotensin-Converting Enzyme (ACE) Activity and Reduces Systolic Blood Pressure

A major class of drugs used in the treatment of hypertension, congestive heart failure, and myocardial infarction are inhibitors of angiotensin-converting enzyme (ACE), which converts angiotensin I to the potent vasoconstrictor angiotensin II. Interestingly, the use of ACE inhibitors has been associated with increased lower-extremity muscle mass^1,1a(in older persons), with moderate attenuation of decline in physical performance² (aged male rats), and slowed or halted decline in muscle strength³ (elderly women). In a 2001 paper,⁴ researchers studied the effects of pomegranate juice consumption (50 ml, about 2 ounces), 1.5 mmol of total polyphenols per day for two weeks), by hypertensive patients (seven males and three females). Mean blood pressure was initially 155±7 / 83±7 mmHg. The soluble polyphenols content of pomegranate juice varies from 0.2 to 1.0% and includes tannins, ellagic tannins, anthocyanins, catechins, and gallic and ellagic acids.

The researchers found that, as a result of drinking pomegranate juice at the dose schedule given above, there was a 36% decrease in serum ACE activity and a 5% reduction in systolic blood pressure. (Drinking 1 cup a day of the 25% pomegranate juice Langers product that we use would provide the equivalent to the 2 ounces of pomegranate juice consumed each day by subjects in this study.) The authors note that they had recently published a paper showing “potent” antiatherogenicity of pomegranate juice in healthy humans and in atherosclerotic mice and identified tannins as the components responsible for the antioxidative properties against LDL oxidation.

In another paper,⁵ researchers report that ACE activity was inhibited by flavan-3-ols and procyanidins, components of many plant foods, in rabbit lung. Procyanidins are a group of polymeric polyphenols composed of the flavan-3-ol units, (-)-epicatechin (epicatechin) and (+)-catechin (catechin). Procyanidins are found in foods such as nuts, cranberries, apples, red wine, tea, and cocoa or chocolate. The authors suggest that “The finding that certain flavonoid-rich foods can induce reductions in blood pressure and inhibit ACE activity, both in vivo and in vitro, opens up the possibility that consumption of select flavonoid-rich foods may mimic synthetic ACE inhibitors and provide health benefits but without adverse side effects. In this regard, it was observed that after regular consumption of a diet rich in flavan-3-ols and procyanidins for 14 days, blood pressure was significantly diminished in aged people. … It was observed that flavan-3-ols and procyanidins isolated from cocoa compete for enzyme-active sites with synthetic ACE substrates.”

In a follow-up paper⁶ by the same authors of Reference 5, they used solid foods (black tea, green tea, chocolate) to prepare high-procyanidin-containing extracts. In addition, they used Argentinean cabernet sauvignon, malbec, generics, and white wines from commercial sources. For example, they used 2 grams of tea in 250 ml of boiling water to prepare the black and green tea extracts. Chocolate extracts were prepared using 25 grams of chocolate (one serving) in 250 ml of hot water. The high-procyanidin and low-procyanidin chocolates were provided by Mars, Inc. Their earlier study⁵ had found ACE-inhibiting activity by purified flavanols and procyanidins in vitro. Now they examined the effects of procyanidin extracts prepared from commonly eaten foods on ACE activity in rat kidney membranes. Of those foods tested (and compared to captopril, an ACE inhibitor drug), high-procyanidin chocolate inhibited ACE by 70%, while low-procyanidin chocolate inhibited ACE by 45%. The most effective in inhibiting pure ACE were (in order of potency) cabernet sauvignon wine, high-procyanidin chocolate, and chocolate. Of the several polyphenols tested, only epigallocatechin (green tea is an excellent source) inhibited the enzyme with IC50 (the amount required for 50% inhibition) in the micromolar range.

As the authors concluded,⁶ “The occurrence of such inhibition in vivo needs to be determined; however, the association between the consumption of flavonol-rich foods and reduction in blood pressure provides an important rationale supporting this hypothesis.”

References

1. Di Bari et al. Antihypertensive medications and differences in muscle mass in older persons: the Health, Aging, and Body Composition Study. J Am Geriatr Soc52:961-6 (2004). 
   1a. Carter et al. Angiotensin-converting enzyme inhibition intervention in elderly persons: effects on body composition and physical performance. J Gerontol60A(11):1437-46 (2005).
2. Carter et al. Angiotensin-converting enzyme inhibition, body composition, and physical performance in aged rats. J Gerontol: Biol Sci 59A(5):416-23 (2004).
3. Onder et al. Relation between use of angiotensin-converting enzyme inhibitors and muscle strength and physical function in older women: an observational study. Lancet 359:926-30 (2002).
4. Aviram, Dornfeld. Pomegranate juice consumption inhibits serum angiotensin-converting enzyme activity and reduces systolic blood pressure. Atherosclerosis158:195-8 (2001).
5. Actis-Goretta et al. Inhibition of angiotensin converting enzyme (ACE) activity by flavan-3-ols and procyanidins. FEBS Lett 555:597-600 (2003).
6. Actis-Goretta et al. Inhibition of angiotensin converting enzyme activity by flavanol-rich foods. J Agric Food Chem 54:229-34 (2006).

L-Arginine Therapy in Acute Myocardial Infarction: Why the Negative Results? Could It Have Been Prevented?

A new paper¹ reports the results of a clinical trial of 153 patients who were given L-arginine following a first ST-segment-elevation heart attack because of previous studies (cited by the authors) in which arginine improved endothelial function (that is, the dilation of blood vessels caused by nitric oxide) in healthy elderly individuals and patients with vascular disease, as well as improving noninvasive measures of vascular stiffness. This study stopped enrollment at 2.5 years due to excess mortality in the arginine group (there were six deaths among those on arginine, while none of those on placebo died). Moreover, they found no significant change in vascular stiffness or left ventricular ejection fraction. They concluded that “L-arginine should not be recommended following acute myocardial infarction.”

Subjects had a mean age of 60 (13.6 standard deviations) years, with 68% men. Patients were randomly assigned to receive L-arginine (1 gram three times daily for a week, 2 grams three times daily for the next week, and 3 grams three times a day for the third week and thereafter for a total of six months) or placebo.

Those who died were apparently not autopsied. “Two patients were found dead at home without prior symptoms, and two patients died of presumed sepsis.” We don’t really know why those patients died.* Moreover, the sixth death was of a patient taking arginine who “died suddenly 4 months following his acute myocardial infarction and 3 weeks following cessation of study drug.” Any excess arginine would have been gone after one day, let alone three weeks, and hence there is no reason to believe that arginine had anything to do with this.

*iNOS (inducible nitric oxide synthase) is dramatically upregulated in inflammation, and the overproduction of NO can play a role in cell death. See Sedlak and Snyder. Messenger molecules and cell death. JAMA 295(1):85 (2006). We would expect that the choline and vitamin B5 that we have in our arginine formulation would mitigate this, because acetylcholine is anti-inflammatory as well as stimulating desired eNOS (endothelial nitric oxide synthase) activity.

The key to this study’s findings, we believe, is the fact that 96% of the arginine-receiving subjects were taking a statin (97% of those receiving placebo were also on a statin). See our article just above on statin-induced reduction in CoQ10 and selenoproteins. We believe that taking the statin was what caused the negative results with arginine in these patients. It is well known that CoQ10 is an important part of the body’s antioxidant protective mechanisms; it regenerates the tocopheryl radical back to tocopherol, for instance. Selenoproteins (such as glutathione peroxidase) are also important parts of the body’s antioxidant protections. In the presence of arginine and under oxidative conditions, the nitric oxide synthase cofactor tetrahydrobiopterin is oxidized (rather than in its proper reduced condition), which results in the production not of nitric oxide but of superoxide radicals.^2,3,4 The problems with reduced CoQ10 and selenoproteins would also affect those on placebo, who were also taking statins, but the additional arginine in the arginine-supplemented subjects would have resulted in a much greater increase in the nitric oxide synthase-produced superoxide radicals. Moreover, nitric oxide radicals react very rapidly with superoxide radicals to form peroxynitrite, a very powerful oxidant.

This problem might have been solved by giving the patients supplements including vitamin C⁵ (which increases the availability of tetrahydrobiopterin in mice) and folic acid^2,2a (which either increases the amount of available tetrahydrobiopterin or actually mimics its effects). It would be very unfortunate if this poorly designed study (none of the effects of statins on antioxidant status were considered) were to discourage the use of L-arginine. However, we do not recommend that those who have recently had heart attacks take L-arginine (even with the addition of vitamin C, folic acid, and CoQ10) until there is more knowledge about the reasons for this study’s results.

References

1. Schulman et al. L-Arginine therapy in acute myocardial infarction: the Vascular Interaction with Age in Myocardial Infarction (VINTAGE MI) Randomized Clinical Trial. JAMA 293(1):58-64 (2006).
2. Hyndman et al. Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function. Am J Physiol Heart Circ Physiol 282:H2167-72 (2002). “Tetrahydrobiopterin is a critical cofactor for nitric oxide synthase and maintains this enzyme as a nitric oxide- versus superoxide-producing enzyme. … 5-methyltetrahydrofolate [the physiological form of folic acid] attenuates superoxide production (induced by inhibition of tetrahydrobiopterin synthesis) and improves endothelial function in aortae isolated from tetrahydrobiopterin-deficient rats. We suggest that 5-methyltetrahydrofolate directly interacts with nitric oxide synthase to promote nitric oxide (vs. superoxide) production and improve endothelial function.” 
   2a. Gori et al. Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study. Circulation 104:1119-23 (2001). “We think that the effectiveness, low cost, and safety of folic acid supplementation confer direct clinical relevance to our findings.” Subjects were 18 healthy, nonsmoking male volunteers 19 to 32 years of age. They received continuous treatment with nitroglycerin via transdermal patch while receiving either 10 mg/day of oral folic acid or placebo. One of the tests was for forearm blood flow (FBF) in response to an infusion of acetylcholine. “In the placebo group, the mean percent increase in response to the highest infused concentration of acetylcholine was 123% of the baseline FBF, whereas in the folic acid group, it was 583% (p<0.1).”
3. Vasquez-Vivar et al. The role of tetrahydrobiopterin in superoxide generation from eNOS [endothelial nitric oxide synthase]: enzymology and physiological implications. Free Rad Res 37(2):121-7 (2003). “The pteridine cofactor BH4 [tetrahydrobiopterin] has been shown to critically control eNOS activity. It has been postulated that in disease states, such as diabetes, hypertension, and atherosclerosis, endothelial levels of BH4 are reduced, which correlates with diminished nitric oxide production. Recently, we have shown that activation of eNOS under limited availability of BH4 not only results in low rates of nitric oxide formation but also increases superoxide formation.”
4. Landmesser et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 111:1201-9 (2003).
5. d’Uscio et al. Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity. Circ Res 92:88-95 (2003).

Decreasing Superoxide Radicals with Zingerone

As noted in the article above, when nitric oxide synthase becomes “uncoupled” from the production of nitric oxide, it generates superoxide radicals. One of the things superoxide radicals do is react with nitric oxide (thereby preventing it from dilating blood vessels), with the resultant creation of peroxynitrite, a powerful oxidant that accounts for many of the deleterious effects of superoxide radicals and of nitric oxide. Earlier studies^1,2 have found a correlation between serum superoxide levels and lifespan, with mammals that live longer having higher serum levels of superoxide dismutase (SOD), an antioxidant enzyme that scavenges superoxide radicals. Hence, if you intend to live a long time, increasing protective SOD and decreasing superoxide radical production is a very good idea.

Zingerone is a major flavonoid in ginger. A recent paper³ reports that zingerone treatment (it was injected i.p.) at doses of 6.5 nmol/kg body weight or 65 nmol/kg body weight protected mouse brain from the toxicity of 6-hydroxydopamine by increasing SOD activity. Although zingerone acted as an antioxidant and did scavenge superoxide directly, it was very weak (its superoxide scavenging capability was said to be about 3.1 × 10⁶ times weaker than that of Cu-Zn-SOD). Thus, it induced SOD activity rather than producing its protective effects by scavenging the superoxide itself. An inhibitor of SOD, DDC, eliminated the protective effect of zingerone, showing that its protection was mediated by increased SOD activity. The authors note another paper that reported that SOD transgenic mice (that overexpressed SOD) had resistance to 6-hydroxydopamine-induced dopaminergic neuronal damage. They also note an earlier paper of theirs in which they showed that ropinirole (Requip^®, a dopaminergic agonist) prevented 6-hydroxydopamine-induced dopamine depression in the striatum through activation of SOD.

References

1. Cutler. Antioxidants and longevity of mammalian species. Basic Life Sci 35:15-73 (1985).
2. Cutler. Antioxidants and aging. Am J Clin Nutr 53 (1 Suppl):373S-9S (1991).
3. Kabuto et al. Zingerone [4-(4-hydroxy-3-methoxyphenyl)-2-butanone] prevents 6-hydroxydopamine-induced dopamine depression in mouse striatum and increases superoxide scavenging activity in serum. Neurochem Res 30(3):325-32 (2005).

Prevention of Obesity by Anthocyanins

You may recall our article in an earlier newsletter about the obesity-preventing effects of purple corn color.¹ Anthocyanins are found in many fruits (especially berries) and some vegetables, particularly those with a blue or purple color, though they are sometimes found in red fruits, such as cherries. High-anthocyanin-containing foods include blueberry, Concord grape, and cranberry. In the paper on purple corn color, feeding this anthocyanin-rich color to mice on a high-fat diet resulted in a significant suppression of the weight gain of the group of mice on the high-fat diet but without purple corn color supplementation. It markedly reduced the hypertrophy of adipocytes (fat cells) in the epididymal white adipose tissue compared with the high-fat-fed controls. Moreover, the high-fat diet induced hyperglycemia, hyperinsulinemia, and hyperleptinemia (higher than normal levels of blood sugar, blood insulin, and blood levels of the hormone leptin); these effects were completely normalized in the rats fed the high-fat diet plus purple corn color.

Following up on these findings, a new paper² reports that similar effects were found in mice fed a high-fat diet with or without a supplement of anthocyanins or ursolic acid found in Cornelian cherries. The supplemented animals received a high-fat diet (same as the controls) but containing 1 gram of anthocyanins or 500 mg of ursolic acid per kg of high-fat diet. The anthocyanin-treated (but not the ursolic acid-treated) mice had a 24% decrease in weight gain compared to the high-fat-fed controls. The mice fed the anthocyanin- or ursolic acid-supplemented diets showed improved glucose tolerance compared to controls.

Cornelian cherries, which are used to treat diabetes in China, are said to be similar to tart (sour) cherries,² though we do not know what the comparable figures are for anthocyanin content, and the authors note that the active compounds in the Cornelian cherries used in diabetes therapy are not fully characterized. It is known, however, that “Generally, sour cherries had higher concentrations of total phenolics than sweet cherries, due to a higher concentration of anthocyanins and hydroxycinnamic acids.”^2a

The one thing that raises a red flag here is that the insulin levels were dramatically increased in the anthocyanin-treated mice on the high-fat diet. Whereas insulin levels measured by radioimmunoassay for control animals fed normal and high-fat diets were 0.47 ± 0.14 and 0.41 ± 0.1 ng/ml, respectively, the animals fed diets containing anthocyanins and ursolic acid showed 567.98 ± 32.36 and 52.25 ± 8.84 ng/ml, respectively. However, the authors found that the anthocyanins and ursolic acid protected the pancreatic islet architecture compared to the nonsupplemented high-fat-fed mice. (The authors verified the insulin increases using two different methods, RIA and ELISA.) The high-fat-fed control mice had enlarged islets with diffuse staining (for insulin) and irregular structure compared to the anthocyanin-supplemented mice, which had islets that were similar in size and structure to islets from mice fed a normal diet. Though these latter findings are reassuring, the insulin increase is substantial and possibly undesirable. The dosage used (1 gram of anthocyanins per kg of diet) may be considerably more than a human would get on a diet of high-anthocyanin-containing foods.

Another possibility, on the insulin increase, is that this works differently in humans. If a human had such a high insulin level, he or she would go into insulin shock from hypoglycemia. (It is strange that the mice didn’t go into comas.) Durk can eat a pound of cherries or blueberries at a single sitting and has never had symptoms of hypoglycemia afterward. We hope that human follow-up studies using doses of anthocyanins that can be obtained from an anthocyanin-rich diet are done.

References

1. Tsuda et al. Dietary cyanidin 3-O-ß-D-glucoside-rich purple corn color prevents obesity and ameliorates hyperglycemia in mice. J Nutr 133:2125-30 (2003).
2. Jayaprakasam et al. Amelioration of obesity and glucose intolerance in high-fat-fed C57BL/6 mice by anthocyanins and ursolic acid in Cornelian cherry (Cornus mas). J Agric Food Chem 54:243-8 (2006). 
   2a. Kim et al. Sweet and sour cherry phenolics and their protective effects on neuronal cells. J Agric Food Chem 53:9921-7 (2005).

Prevention of Obesity by Anthocyanins

You may recall our article in an earlier newsletter about the obesity-preventing effects of purple corn color.¹ Anthocyanins are found in many fruits (especially berries) and some vegetables, particularly those with a blue or purple color, though they are sometimes found in red fruits, such as cherries. High-anthocyanin-containing foods include blueberry, Concord grape, and cranberry. In the paper on purple corn color, feeding this anthocyanin-rich color to mice on a high-fat diet resulted in a significant suppression of the weight gain of the group of mice on the high-fat diet but without purple corn color supplementation. It markedly reduced the hypertrophy of adipocytes (fat cells) in the epididymal white adipose tissue compared with the high-fat-fed controls. Moreover, the high-fat diet induced hyperglycemia, hyperinsulinemia, and hyperleptinemia (higher than normal levels of blood sugar, blood insulin, and blood levels of the hormone leptin); these effects were completely normalized in the rats fed the high-fat diet plus purple corn color.

Following up on these findings, a new paper² reports that similar effects were found in mice fed a high-fat diet with or without a supplement of anthocyanins or ursolic acid found in Cornelian cherries. The supplemented animals received a high-fat diet (same as the controls) but containing 1 gram of anthocyanins or 500 mg of ursolic acid per kg of high-fat diet. The anthocyanin-treated (but not the ursolic acid-treated) mice had a 24% decrease in weight gain compared to the high-fat-fed controls. The mice fed the anthocyanin- or ursolic acid-supplemented diets showed improved glucose tolerance compared to controls.

Cornelian cherries, which are used to treat diabetes in China, are said to be similar to tart (sour) cherries,² though we do not know what the comparable figures are for anthocyanin content, and the authors note that the active compounds in the Cornelian cherries used in diabetes therapy are not fully characterized. It is known, however, that “Generally, sour cherries had higher concentrations of total phenolics than sweet cherries, due to a higher concentration of anthocyanins and hydroxycinnamic acids.”^2a

The one thing that raises a red flag here is that the insulin levels were dramatically increased in the anthocyanin-treated mice on the high-fat diet. Whereas insulin levels measured by radioimmunoassay for control animals fed normal and high-fat diets were 0.47 ± 0.14 and 0.41 ± 0.1 ng/ml, respectively, the animals fed diets containing anthocyanins and ursolic acid showed 567.98 ± 32.36 and 52.25 ± 8.84 ng/ml, respectively. However, the authors found that the anthocyanins and ursolic acid protected the pancreatic islet architecture compared to the nonsupplemented high-fat-fed mice. (The authors verified the insulin increases using two different methods, RIA and ELISA.) The high-fat-fed control mice had enlarged islets with diffuse staining (for insulin) and irregular structure compared to the anthocyanin-supplemented mice, which had islets that were similar in size and structure to islets from mice fed a normal diet. Though these latter findings are reassuring, the insulin increase is substantial and possibly undesirable. The dosage used (1 gram of anthocyanins per kg of diet) may be considerably more than a human would get on a diet of high-anthocyanin-containing foods.

Another possibility, on the insulin increase, is that this works differently in humans. If a human had such a high insulin level, he or she would go into insulin shock from hypoglycemia. (It is strange that the mice didn’t go into comas.) Durk can eat a pound of cherries or blueberries at a single sitting and has never had symptoms of hypoglycemia afterward. We hope that human follow-up studies using doses of anthocyanins that can be obtained from an anthocyanin-rich diet are done.

References

1. Tsuda et al. Dietary cyanidin 3-O-ß-D-glucoside-rich purple corn color prevents obesity and ameliorates hyperglycemia in mice. J Nutr 133:2125-30 (2003).
2. Jayaprakasam et al. Amelioration of obesity and glucose intolerance in high-fat-fed C57BL/6 mice by anthocyanins and ursolic acid in Cornelian cherry (Cornus mas). J Agric Food Chem 54:243-8 (2006). 
   2a. Kim et al. Sweet and sour cherry phenolics and their protective effects on neuronal cells. J Agric Food Chem 53:9921-7 (2005).

Betaine Suppresses Inflammation During Aging: Possible Antiaging Effect

Betaine (also called trimethylglycine) is a nutritional component of many foods, including wheat, shellfish, spinach, and sugar beets.¹ It is also available as an inexpensive dietary supplement. The function it serves in the plants that make it is to protect against osmotic stresses, such as drought, high salinity, or temperature stresses. Earlier studies hypothesized that betaine contained in red wine and whole grain may play a role in the cardiovascular protective effect of those foods.¹ It is also an important part of a major pathway for decreasing homocysteine in humans and other animals by contributing a methyl group for remethylating homocysteine to methionine.¹ Betaine can be synthesized from choline, hence taking a betaine supplement is a way to spare choline for its other uses, such as to make acetylcholine and phosphatidylcholine.¹ The authors of the paper (Ref 1) suggest that “… combined ingestion of folic acid and betaine may be the most effective method of lowering homocysteine.” They also note that some of the studies in which betaine supplementation lowered homocysteine concentrations and improved some clinical conditions (including heart disease and glucose tolerance in both diabetic and nondiabetic subjects) lasted for 13–16 years, and betaine dosage was typically 6 grams per day.

A new study² now reports that betaine suppresses certain proinflammatory signaling factors during aging, including NF-kappaB. NF-kappaB controls the transcription of a number of inflammatory molecules, including tumor necrosis factor (TNF), interleukins (ILs), chemokines, adhesion molecules, and inducible enzymes, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). All these inflammatory signaling agents are involved in conditions such as cancer, arthritis, and atherosclerosis. [They are also involved in certain conditions where inflammation is on net beneficial, especially fighting infections. Therefore, one should be cautious in using powerful drugs that block these signaling pathways—unless one has a serious medical condition that requires that degree of inhibition—that’s why you need a knowledgeable doctor familiar with both prescription drugs and nutrition. Otherwise, mild suppression of inflammation via appropriate dietary supplements would be the way to go for healthy people or those with only a nonsevere degree of inflammatory pathophysiology (such as mild arthritis).]

This study is interesting because it looked at aging rats (Sprague-Dawley), which, like humans, have increasing levels of NF-kappaB in association with age, as well as with atherosclerosis, cancer, and other processes associated with oxidative stress and inflammation.² “Recent reviews show that upregulated NF-kappaB activity seems to be a widespread biological phenomenon in aged animals and that NF-kappaB is a critical transcription factor involved in the pathogenesis of many disorders, including inflammatory diseases.”²

Betaine was added to regular rat chow at levels of 0.01%, 0.02%, or 0.04% and fed to 21-month-old rats for 10 days. On the basis that each rat ate on average 3 mg, 6 mg, or 12 mg of betaine, they ate 30, 60, or 120 mg/kg of body weight of betaine per day.

We suggest that, if you are not already taking betaine, you add it to your daily regimen. We both take it (Sandy takes 500 mg four times a day, and Durk takes 1 g four times a day).

References

1. Craig. Betaine in human nutrition. Am J Clin Nutr 80:539-49 (2004).
2. Eun Kyung Go et al. Betaine suppresses proinflammatory signaling during aging: the involvement of nuclear factor kappa B via nuclear factor-inducing kinase/IkappaB kinase and mitogen-activated protein kinases. J Gerontol: Biol Sci 60A(10):1252-64 (2005).

FDA UPDATE: 
Our Suit Against the FDA, Case No. 05-1937 Before the United States Court of Appeals for the Fourth Circuit

You may already know about our suit against the FDA that argues that the agency’s threats of prosecution against us (Pearson and Shaw) for distributing a government report on the benefits of SAMe (S-adenosylmethionine) is a violation of our First Amendment rights to communicate and the First Amendment rights of the public to receive truthful scientific information. Incredibly, the FDA doesn’t argue that there is anything untruthful or misleading about the report from the federal Agency for Healthcare Research and Quality¹ on SAMe’s usefulness in treating osteoarthritis (about as effective as the commonly used prescription drugs, though by a different mechanism) and depression (again, about as effective as commonly used prescription drugs, also by a different mechanism). They argue instead that distributing the information proves by their “intended use” doctrine that we are selling SAMe as a treatment and, hence, an unapproved drug. (Also in their arguments, in apparent contradiction to this, they argue that, well, maybe they won’t prosecute us if we communicate the information, but they haven’t decided yet. In fact, however, an affidavit from the FDA’s chief of labeling enforcement directly threatens our exercise of our First Amendment rights by declaring, under oath, that in his opinion the SAMe sold under our names by Life Extension Foundation is an unapproved drug.)

The district court’s decision went against us. The judge accepted the FDA’s incorrect claims that the case was not ripe (i.e., that we hadn’t suffered any injury). However, in First Amendment cases, the requirement generally to show injury in a lawsuit is relaxed, as it is recognized that one shouldn’t have to take an action that puts one in jeopardy of prison and fines in order to exercise one’s First Amendment rights. As noted in our closing brief, “It is the threat of prosecution that causes the harm.”

This is a very important case. If there is to be a large future for dietary supplements and foods to prevent and even treat disease, it has to be possible to communicate truthful, nonmisleading information concerning these uses, including the distribution of peer-reviewed scientific papers and government reports. Otherwise, only that small minority of the public that is exceptionally well read will know about these effects, and the industry will remain small, with few resources of its own for natural products research.

You can find our latest brief at www.emord.com. It is a brilliant brief that cuts through the lies and misinformation of the government’s brief and made our case with astonishing clarity and conviction. (If we do not get a good decision from the court, it will be due to the court’s failure, not that of our briefs.) If, after reading it, you appreciate this extensive effort that, if we win, will benefit you as much as ourselves, please send in any amount (no matter how small) to the Pearson & Shaw Litigation Fund, c/o Emord & Associates, 1800 Alexander Bell Drive, Suite 200, Reston, VA 20191.

Reference

1. S-Adenosyl-L-methionine for treatment of depression, osteoarthritis, and liver disease. Evidence Report/Technology Assessment No. 64, Agency for Healthcare Research and Quality, U.S. Dept. of Health and Human Services, www.ahrq.gov.

Health Freedom Protection Act, H.R. 4282, Introduced in Congress

Another approach to increasing access to truthful information is via legislation. This new bill (cosponsored by ten Representatives, last we heard) would, if enacted, amend the Food Drug and Cosmetic Act (FDCA) to permit truthful disease-treatment claims for foods and dietary supplements. It would prohibit the FDA and FTC from preventing anyone who sells foods or supplements from sending consumers government reports (and accurate quotes from them) and scientific papers on nutrient-disease associations. Other provisions, such as one prohibiting the FDA from waiving conflicts of interest in its food advisory panels, would help ensure more objective FDA decisions.

The proposed bill would also amend the deceptive advertising provisions of the Federal Trade Commission Act to make all publications exempt from regulation by the amendment to the FDCA to be also exempt from regulation by the FTC.

You can get a copy of the bill by phoning Emord & Associates at 202-466-6937 or by going to stopfdacensorship.org, where you can sign up as a supporter and send e-mails of support to your Congresscritters.

We have joined a long list of companies and individuals called The Coalition to End FDA and FTC Censorship, which is promoting the bill with a national grassroots campaign to educate the public and get signatures on the petition to support H.R. 4282. For your information, the following dietary supplement companies are not members of the coalition and are opposing the bill: A. M. Todd Botanical Therapeutics, Cornerstone Research & Development, Nature’s Way Products, Nelson Laboratories, One World Nutrition, Pharmanex (Division of NuSkin Enterprises), Sabinsa Corporation, Synergy Company, Tahitian Noni International, and USANA Health Services.

The bill, while a potential winner that would (if enacted) make the above lawsuit unnecessary, is far from certain to pass the House, let alone the Senate. That is why the lawsuit is continuing. A ruling in our favor in the suit may in fact help get the bill passed.